Heterogeneity in precision oncology.

Impact statement

Precision oncology, one of the most promising applications of precision medicine, uses molecular and genetic information to customise cancer treatments, considering the individual characteristics of each patient’s tumour. To further advance the field, precision oncology increasingly incorporates knowledge of cancer heterogeneity, on both spatial and temporal levels. Addressing these complexities with modern precision radiotherapy and systemic therapies is the key to targeting all cancer cell subpopulations. The future vision of precision oncology involves continuous advancements in technological and analytical methods, leading to further treatment personalisation. This progress will ultimately contribute to a paradigm shift in cancer care to improve patient outcomes significantly. Access to advanced tools should be improved in terms of availability and affordability while addressing the need for routine genomic profiling across various regions of primary and metastatic tumours to understand cancer heterogeneity comprehensively.

Introduction

Precision medicine is a novel approach to treatment and prevention that tailors strategies to the unique characteristics of individual patients, including their genetics, environment and lifestyle. It differs from conventional evidence-based medicine, which generally relies on average clinical benefits in the studied populations (Tonelli and Shirts, 2017 ; Blackstone, 2019 ). Precision medicine is supported by advances in technology and medical research, such as using genomic sequencing and big data analysis to identify individualised treatment options.

The decision-making process in precision medicine is based on predictive biomarkers, which offer insights into the underlying molecular mechanisms of tumorigenesis and allow the identification of potential therapeutic targets. In clinical settings, biomarkers can predict which patients are most likely to benefit from specific therapies, optimise treatment efficacy and reduce toxicity. Further, biomarkers enable early cancer detection and treatment monitoring, thereby increasing its efficacy. In essence, biomarkers are transformative tools of personalised medicine, driving more accurate, effective and safer cancer treatments (Slikker, 2018 ).

The two most commonly used markers are prognostic and predictive biomarkers. A prognostic biomarker is a clinical or biological indicator that offers insights into the probable health outcome of an individual patient, such as disease recurrence or death, regardless of the treatment pursued. In turn, a predictive biomarker signifies the potential advantage to the patient, resulting from a specific treatment (Sechidis et al., 2018 ). Other biomarkers include predisposing biomarkers, indicating the potential for developing a disease (Califf, 2018 ) and pharmacogenomic biomarkers, informing about the drug efficacy and toxicity based on the underlying genetic composition (Lauschke et al., 2017 ). The United States Food and Drug Administration and the National Institutes of Health published the Biomarkers, EndpointS and other Tools (BEST) resource, describing the extensive list of biomarkers used in translational science (Cagney et al., 2018 ).

Precision oncology is a concept that customises oncological care based on unique patient genomics and clinical, genetic, proteomic, transcriptomic or phenotypic tumour features (de and Ashworth, 2010 ; Collins and Varmus, 2015 ). Precision oncology has achieved unprecedented advancements through rigorous scientific evidence and extensive computational analyses (Mirnezami et al., 2012 ). However, challenges such as accurate data interpretation, precise patient stratification and the development of successful targeted therapies for specific genomic aberrations require further efforts (Prasad et al., 2016 ).

To overcome these obstacles, precision oncology requires innovative clinical trial designs that account for patient and tumour heterogeneity and the dynamic nature of cancer evolution (Chen and Snyder, 2013 ). Integrating precision oncology into clinical practice is a key goal of the Precision Medicine Initiative, which was launched by the US government in 2015.

In the present article, we discuss the impact of tumour and patient heterogeneity on treatment outcomes in solid tumours oncology and explore how precision systemic therapies and radiotherapy can mitigate these obstacles. The analysis will focus on scrutinising pivotal studies, such as the Molecularly Aided Stratification for Tumour Eradication Research (MASTER) (Horak et al., 2017 ), the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial (Flaherty et al., 2020 and other pertinent research, to better understand customised cancer therapy. We also present current investigative endeavours and interdisciplinary collaborations to optimise cancer therapy in all patients, regardless of their genetic makeup (Topol, 2014 ; Jameson and Longo, 2015 ; Figure 1 ). The examples provided here should be considered illustrative, as no comprehensive literature analysis on this topic was attempted. Figure 1. Timeline showing the highlights of clinical precision medicine. ALK, anaplastic lymphoma kinase; ALL, acute lymphoblastic leukaemia; BCa, breast carcinoma; BRAF, v-Raf murine sarcoma viral oncogene homologue B’ BRCA, BReast CAncer gene; CAR-T, chimeric antigen receptor T-cell therapy; CML, chronic myeloid leukaemia; CR, complete response; ER+, oestrogen receptor-positive; HER2, human epidermal growth factor receptor-2; KRAS, Kirsten rat sarcoma virus; MET, hepatocyte growth factor receptor; MMRd, mismatch repair deficiency; MSI-H, high microsatellite instability; NGS, next generation sequencing; NSCLC, non-small cell lung cancer; PD-1, programmed death receptor-1; RET, Ret Proto-Oncogene; VEGF, vascular endothelial growth factor.

Systemic therapies

Systemic therapies, which involve drugs circulating throughout the body, are fundamental to cancer treatment (Chabner and Roberts, 2005 ). Precision oncology has revolutionised systemic therapies by better allocating standard chemotherapy and has paved the way for specific targeted therapies (Schwaederle et al., 2015 ). However, cancer heterogeneity, both spatial and temporal, highly impacts the effectiveness of these therapies (Greaves and Maley, 2012 ). As a result, one of the major challenges in oncology is customising systemic therapies for each patient and tumour characteristics (Leichsenring et al., 2019 ).

Tumour heterogeneity

Whereas cytotoxic chemotherapy is essential for many malignancies, it is generally recognised as a one-size-fits-all approach, which may not be optimal for patients with genetically diverse tumours. Precision oncology considers tumour genetic heterogeneity, thus can improve the efficacy of standard treatments, identify druggable targets for specific tumours and select patients who are more likely to benefit from customised treatments (Massard et al., 2017 ).

The relationship between specific genomic alterations, genetic inter- and intratumour heterogeneity and the effectiveness of cancer treatment has been well established (Schwaederle et al., 2015 ; McGranahan and Swanton, 2017 ). Tumours with certain genetic alterations differ in their susceptibility to classical cytotoxic chemotherapy. For example, mutations in the TP53 , KRAS , PTEN or RB1 genes are associated with resistance to chemotherapy (Custodio et al., 2009 ; Perrone et al., 2010 ), BRCA1 and BRCA2 mutations denote chemosensitivity to platinum compounds (Pennington et al., 2014 ), and MGMT methylation in glioblastoma is associated with a better response to temozolomide (Stupp et al., 2005 ).

Knowledge of genetic tumour heterogeneity has been extensively used in targeted cancer therapies ( Figure 2 ). If druggable, genetic alterations are primarily used as therapeutic targets; however, many also serve as predictive markers for treatment effectiveness. In colorectal cancer, cetuximab, which is a chimeric antibody against the epidermal growth factor receptor (EGFR), is effective only against wild-type rat sarcoma (RAS) family oncogenes (Van Cutsem et al., 2009 ; Douillard et al., 2013 ). Conversely, in lung cancer, EGFR tyrosine kinase inhibitors are less effective in patients with coexisting TP53 (Aggarwal et al., 2018 ; Sun et al., 2023 ) or KRAS mutations (Massarelli et al., 2007 ), which can activate alternative signalling pathways bypassing the EGFR pathway. In breast cancer, human epidermal growth factor receptor-2 (HER2) inhibitors are widely used to treat patients with HER2-overexpressing or HER2-amplified tumours, but they are less effective in patients with coexisting mutations in fibroblast growth factor receptor-1 (FGFR1) or receptor-2 (FGFR2) genes (Hanker et al., 2017 ). FGFR alterations correlate with resistance to several targeted and standard therapies across different malignancies (Babina and Turner, 2017 ), while the mechanistic and prognostic role of FGFR1–4 protein overexpression remains equivocal (Piasecka et al., 2019 ). Figure 2. Examples of precision medicine biomarkers used in oncologic practice, together with respective targeted therapies approved in patients harbouring such lesions. CPI, checkpoint inhibitor; CTL, cytotoxic lymphocyte; DDR, DNA damage response; MMR, mismatch repair; MSI, microsatellite instability; PD-L1, programmed death-ligand 1; TMB, tumour mutational burden.

Some genetic alterations are druggable only in specific tumours, whereas others can be targeted across biologically and clinically different malignancies. The inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are effective and routinely administered to treat advanced hormone receptor-positive, HER2-negative breast cancer, though CDK4/6 alterations are not a hallmark of these cancers and do not predict the effectiveness of this therapy (Suski et al., 2021 ; Cristofanilli et al., 2022 ). Furthermore, CDK4/6 inhibitors are inefficient in liposarcomas harbouring the amplification of CDK4/6 and murine double minute 2 ( MDM2 ) genes (Sbaraglia et al., 2021 ). Other examples are ivosidenib, an isocitrate dehydrogenase-1 (IDH1) inhibitor, and enasidenib, an IDH2 inhibitor, which effectively targets relapsed or refractory acute myeloid leukaemia with IDH1/2 mutations (Cerchione et al., 2021 ) but that are not effective in gliomas bearing these mutations. In turn, some targeted therapies, for example, entrectinib, which targets neurotrophic tyrosine receptor kinase ( NTRK ) fusions, and ROS oncogene 1 ( ROS1 ) rearrangements, are effective across different solid tumour types, including lung cancer, colorectal cancer and thyroid cancer (Doebele et al., 2020 ; Drilon et al., 2020 ). Similarly, V-raf murine sarcoma viral oncogene homologue B1 (BRAF) and mitogen-activated protein kinase (MEK) inhibitors were recently approved with a tumour-agnostic indication for unresectable or metastatic solid tumours harbouring the BRAF V600E mutation (Gouda and Subbiah, 2023 ).

Immune-oriented therapies, such as immune checkpoint inhibitors (ICIs) or chimeric antigen receptor T-cells (CAR-T), have revolutionised cancer treatment. However, correctly identifying good responders remains challenging. Genetic heterogeneity in tumours may elicit variable responses to ICIs. Malignancies with a high tumour mutational burden (TMB) and neoantigen load are more responsive to ICIs. Patients with high-TMB non-small cell lung cancer (NSCLC) or melanoma achieve significant improvements in survival with ICIs compared with those with low TMB (Ning et al., 2022 ; Ricciuti et al., 2022 ). However, intratumour or intersite (primary vs. metastatic foci) heterogeneity leading to spatial neoantigen expression variability might result in the escape of certain subclones from immune surveillance (McGranahan and Swanton, 2017 ). Different tumour types (e.g., colorectal or endometrial cancers) with microsatellite instability or mismatch repair deficiency are highly responsive to ICIs (Cercek et al., 2022 ; O’Malley et al., 2022 ), whereas tumours with some mutations may be ICI resistant. For instance, EGFR -mutant NSCLCs are less sensitive to ICIs than wild-type EGFR (Mazieres et al., 2019 ). Melanomas with overactive WNT/β-catenin signalling are less infiltrated by T-cells and, thus, less susceptible to ICIs (Spranger et al., 2015 ).

Cancers with high levels of intrinsic heterogeneity, which can be defined as the presence of different genetic clones within a single tumour, are usually less likely to benefit from chemotherapy and targeted therapies (McGranahan and Swanton, 2017 ) because of the presence of drug-resistant subclones within the tumour that can contribute to rapid relapse after the initial response to therapy (Burrell et al., 2013 ; Almendro et al., 2014 ). Computational modelling and in situ analyses have shown that genetic and phenotypic heterogeneity can greatly affect tumour evolution during chemotherapy and treatment outcomes (Almendro et al., 2014 ). Recent advances in genomics and single-cell sequencing have shed light on the molecular mechanisms underlying tumour heterogeneity, paving the way for the development of novel personalised therapeutic strategies (Dagogo-Jack and Shaw, 2018 ; Ramón et al., 2020 ; Labrie et al., 2022 ). Further development of precision medicine for systemic anticancer therapies heavily relies on better understanding and addressing intratumour heterogeneity. However, because of diagnostic limitations, intratumour heterogeneity cannot yet be routinely exploited in guiding treatment options. It is expected that circulating tumour DNA (ctDNA) and single-cell analysis techniques may enable a detailed characterisation of tumour cell populations and better inform personalised treatment strategies (Nath and Bild, 2021 ; Tivey et al., 2022 ). ctDNA dynamic profiling allows for real-time monitoring of tumour evolution and adapting treatment strategies as the tumour mutates and evolves. Recently, ctDNA-guided therapy was shown to be beneficial in patients with NSCLC and colorectal cancer (Jee et al., 2022 ; Tie et al., 2022 ).

Precision medicine approaches may considerably improve cancer treatment outcomes, provided that the complex interplay between tumour genetics and response to systemic treatment is better understood. Basic and translational studies are essential for identifying next-generation predictive biomarkers. Novel clinical trial designs, such as basket-type trials assessing the druggability of specific targets across different tumour types, and umbrella-type trials evaluating the efficacy of specific or various targeted therapies in specific cancer diagnoses ( Figure 3 and Table 1 ), may prompt the development of new tailored therapies (Subbiah, 2023 ). Figure 3. Types of precision medicine clinical trials. BRAF, v-Raf murine sarcoma viral oncogene homologue B; SOC, standard of care.

To compile the data presented in Tables 1 and 2 (please see below), we employed a multi-pronged search strategy. Firstly, a targeted search was conducted on PubMed using the following query: ("precision medicine"[Title/Abstract] OR “targeted therapy”[Title/Abstract] OR “personalised medicine”[Title/Abstract]) AND “clinical trial”[Publication Type] AND ("2013/01/01"[PDAT]: “2023/12/31”[PDAT]). This query was designed to yield articles classified as “clinical trials” focusing on “precision medicine,” “targeted therapy,” or “personalised medicine,” and published between January 1, 2013, and December 31, 2023. In addition to PubMed, we supplemented the articles with data from the clinical trials registry ClinicalTrials.gov and information gathered from sessions at the European Society for Medical Oncology (ESMO) Meetings and American Society of Clinical Oncology (ASCO) Annual Meetings held between 2018 and 2023. These conferences are recognised platforms that regularly feature key developments in precision medicine trials in oncology. Table 1. Selected clinical trials investigating personalised cancer therapies Trial ID/Name Patient population Intervention Precision technologies Study design Primary endpoint N Results MASTER (Molecularly Aided Stratification for Tumour Eradication Research) (Horak et al., 2021 ) Adults with advanced solid tumours (age < 51 years) and patients with rare tumours, including rare subtypes of more common entities, regardless of age (221 different ICD-O-3 codes), who exhausted curative treatment options Evaluation of biomarkers’ clinical actionability and assignment of molecularly informed therapies in semiweekly, multicentre MTB conferences WES, WGS, RNA-seq Multicentre, prospective observational study – master observational trial (Dickson et al., 2020 ) PFSr 1,310 Of 300 patients evaluable for PFSr, 107 ( 35.7% ) had a PFSr >1.3 NCI-MATCH (Molecular Analysis for Therapy Choice) ( NCT02465060 ) (Flaherty et al., 2020 ) Adults (age ≥ 18 years) with advanced solid tumours, lymphomas or myelomas that have progressed after standard treatments or for whom no standard treatment is available Targeted therapies matched to specific genetic tumour abnormalities. Patients are assigned to different treatment arms based on the genetic alterations found in their tumours Oncomine Cancer Panel (Lih et al., 2017 ) based on FFPE-extracted DNA and RNA, IHC (Khoury et al., 2018 ) Phase 2, non-randomised, open-label, multicentre clinical trial ORR 1,201 Arms: Z1B (palbociclib in BCa with amp CCND1/2/3: ORR 0% (Clark et al., 2023 ) B (afatinib in pts. with EGFR2- activating mutations): ORR 2.7% (Bedard et al., 2022 ) F (crizotinib in ALK -rearranged ca): ORR 50% G (crizotinib in ROS1 -rearranged ca): ORR 25% (Mansfield et al., 2022 ) I (taselisib in PIK3CA -mutated ca other than BCa and SCC): ORR 0% (Krop et al., 2022 ) Z1F (copanlisib in PIK3CA -mut ca): ORR 16% (Damodaran et al., 2022 ) Z1A (binimetinib in NRAS -mut ca excluding melanoma): ORR 2.1% (Cleary et al., 2021 ) Y (capivasertib in AKT1 E17K -mut ca): ORR 29% (Kalinsky et al., 2021 ) H (dabrafenib and trametiib in BRAFV600E -mut ca): ORR 38% (Salama et al., 2020 ) W (AZD4547 in FGFR amp/mut/tx ca): ORR 8% (Chae et al., 2020 ) R (trametinib in non-V600 BRAF mut ca): ORR 3% (Johnson et al., 2020 ) Z1D (nivolumab in MMRd ca): ORR 36% (Azad et al., 2020 ) Q (Ado-trastuzumab emtansine in HER2-amp ca excluding BCa and GEJ adenoCa): ORR 5.6% TAPUR (Targeted Agent and Profiling Utilisation Registry) ( NCT02693535 ) (Mangat et al., 2018 ) Patients (age ≥ 12 years) with histologically-proven locally advanced or metastatic solid tumours, multiple myeloma or B cell non-Hodgkin lymphoma who are no longer benefiting from standard anticancer treatment or no such treatment is available or indicated FDA-approved targeted therapies (usually used for other cancer types) matched to the specific genomic alterations in a patient’s tumour NGS Phase 2, non-randomised, open-label, multicentre clinical trial ORR 3,581 (planned) Two arms closed at stage I because of a lack of responses; 12 arms expanded to stage II ALK, ROS1, MET – crizotinib CDKN2A, CDK4, CDK6 – palbociclib or abemaciclib CSF1R, PDGFR, VEGFR – sunitinib mTOR, TSC – temsirolimus BRAF V600E/D/K/R – vemurafenib and cobimetinib RET, VEGFR1/2/3, KIT, PDGFRβ, RAF-1, BRAF - regorafenib BRCA1/2, ATM – olaparib NRG1 Afatinib BRCA1/2, PALB2 – talazoparib ROS1 fusion – entrectinib NTRK amplification – larotrectinib I-PREDICT (Profile Related Evidence Determining Individualised Cancer Therapy) ( NCT02534675 ) (Sicklick et al., 2019 ) Adults (age ≥ 18 years) with advanced or metastatic solid tumours that have progressed after standard treatments or for which no standard treatment is available Personalised targeted therapies and combination treatments based on genomic tumour profiling; the treatment plan designed by a molecular tumour board using DNA sequencing and other molecular analysis techniques to identify actionable genomic alterations Tissue genomic profiling using NGS (Foundation Medicine; 236–405 genes), PD-L1 IHC, TMB, MSI status, ctDNA Phase 2, single-arm, open-label, prospective clinical trial ORR 149 ORR 11.4% A High Matching Score was an independent predictor of higher DCR (OR 3.6; 95% CI 1.1–11.8; p = 0.033 ) MyPathway ( NCT02091141 ) Adults (age ≥ 18 years) with advanced solid tumours that have progressed after standard treatments or for which no standard treatment is available Targeted therapies that are matched to specific molecular tumour alterations. The trial investigates the off-label use of targeted therapies which are FDA-approved for other cancer indications IHC, FISH, NGS, FoundationOne CDx Tissue-agnostic, non-randomised, phase 2a multiple basket trial ORR 357 13 70 37 21 43 Arms: HER2 (trastuzumab + pertuzumab in HER2 -altered ca): ORR 23.3% EGFR (erlotinib in EGFR -mut. ca): ORR 7.7% BRAF (vemurafenib ± cobimetinib in BRAF -mut. ca): ORR 24.3% Hh (vismodegib in PTCH1/SMO -mut. ca): ORR 10.8% ALK (alectinib in ALK- driven ca.): ORR 30% TMB (atezolizumab in TMB-high ca): ORR 39.5% (Friedman et al., 2022 ) LUNG-MAP (Lung Cancer Master Protocol) ( NCT02154490 ) (Redman et al., 2020 ) Adults (age ≥ 18 years) with advanced or metastatic squamous or non-squamous NSCLC who have progressed after first-line standard therapy Targeted therapies and immunotherapies matched to specific tumour molecular alterations. The trial investigates the use of these therapies in patients with advanced NSCLC who have progressed after first-line standard therapy NGS (FoundationOne) IHC Phase 2/3, randomised, open-label, multicentre clinical trial ORR; OS in phase 3 substudies 1864 Substudies: S1400A (durvalumab vs. docetaxel) S1400B (taselisib vs. docetaxel in PI3KCA -mut. ca) S1400C (palbociclib vs. docetaxel in CDK4/6, CCND1/2/3 -positive ca) S1400D (AZD4547 vs. docetaxel in pts. positive for FGFR1/2/3) S1400E (rilotumumab + erlotinib vs. erlotinib in HGF/c-MET -pos. ca) S1400F (durvalumab + tremelimumab) S1400G (talazoparib in HHR-deficient ca) S1400I (nivolumab + ipilimumab vs. nivolumab) BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) (E. S. Kim et al., 2011 ) Adults (age ≥ 18 years) with advanced NSCLC who have progressed after first-line platinum-based chemotherapy Erlotinib (an EGFR inhibitor), vandetanib (a VEGFR inhibitor), erlotinib plus bexarotene (a retinoid X receptor agonist) and sorafenib (a multikinase inhibitor). Patients assigned to one of these treatments based on the molecular tumour profile, assessed using biomarkers, such as EGFR, KRAS, VEGF and cyclin D1 FISH, IHC, Sanger sequencing Phase 2, adaptive, randomised, open-label clinical trial 8-week DCR 255 The 8-week 46% DCR for the entire study population, with the following rates for each treatment arm: erlotinib: 43% vandetanib: 39% erlotinib plus bexarotene: 50% sorafenib: 53% SHIVA ( NCT01771458 ) (Le Tourneau et al., 2015 ) Adults (age ≥ 18 years) with advanced solid tumours that have progressed after standard treatments or for which no standard treatment is available Patients randomised into two groups: the experimental group receiving molecularly targeted agents based on tumour molecular profiling, and the control group receiving treatment according to the physician’s choice Targeted NGS, Cytoscan copy number analysis Phase 2, open-label, randomised, controlled clinical trial PFS 293 Median PFSl 2.3 months (95% CI 1.7–3.8) in the experimental group vs. 2.0 months (1.8–2.1) in the control group (hazard ratio 0·88, 95% CI 0.65–1.19, p = 0.41) WINTHER (Worldwide Innovative Networking in Personalised Cancer Medicine) ( NCT01856296 ) Adults (age ≥ 18 years) with advanced solid tumours that have progressed after standard treatments or for which no standard treatment is available Personalised targeted therapies and chemotherapies that are matched to specific genomic alterations or gene expression patterns in the patient’s tumour Fresh biopsy: DNA + RNA NGS testing Phase 2, non-randomised, open-label, multicentre clinical trial PFSr 107 The trial did not meet its primary endpoint, as the PFS ratio of ≥1.5 was observed in only 22% of patients in Arm A (DNA-seq-based drug matching) and 26% in Arm B (RNA-seq-based drug matching) GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment) ( NCT03970447 ) (Alexander et al., 2018 ) Adults (age ≥ 18 years) with newly diagnosed or recurrent glioblastoma Targeted therapies and immunotherapies, which are compared to standard treatment options. The specific agents tested in the trial may change over time as new treatments become available or others are dropped based on their performance in the study NR Phase 2/3, adaptive, randomised, open-label, multicentre clinical trial PFS/OS NR NR FOCUS4 (Brown et al., 2022 ) Adults (age ≥ 18 years) with advanced colorectal cancer who have completed 16 weeks of first-line chemotherapy Patients are first treated with standard chemotherapy and then, based on their molecular subtyping, are randomised into different treatment arms; the trial tests these targeted therapies against a control group receiving standard treatment or a placebo, and the specific agents tested in the trial may change over time as new treatments become available or others are dropped based on their performance in the study Pyrosequencing, NGS, IHC (Richman et al., 2022 ) Phase 2/3, randomised, open-label, multicentre clinical trial PFS/OS 361 FOCUS4-D (sapitinib in BRAF-PIK3CA-RAS wt ca) closed FOCUS4-B (aspirin in PIK3CA -mut. ca) closed FOCUS4-C (adavosertib in RAS + TP53 double mutant) (Seligmann et al., 2021 ) FOCUS4-N (nonstratified). Median PFS in the capecitabine arm 3.9 months (95% CI 3.7–4.4) and 1.9 months (95% CI 1.8–2.1) in the AM arm/Unadjusted and adjusted HRs 0.44 (95% CI 0.33–0.57), p < 0.0001 and 0.40 (95% CI 0.21–0.75), p < 0.0001, respectively NCI-COG Paediatric MATCH NCT03155620 Children and adolescents (aged 1–21 years old) with recurrent, refractory or progressive solid tumours, lymphomas and histiocytic disorders Molecularly targeted therapies matched to specific tumour genetic alterations DNA and RNA sequencing, IHC (Parsons et al., 2022 ) Phase 2, open-label, multicentre clinical trial ORR 2,316 (planned) 20 20 20 Subprotocols: A (larotrectinib in ca with NTRK fusions) B (erdafitinib in ca with FGFR1/2/3/4 mutation) C (patients with an EZH2, SMARCB1 or SMARCA4 mutation receive tazemetostat) ORR: 1 response (Chi et al., 2022 ) D (samotolisib in patients with TSC1 , TSC2 or PI3K/mTOR mutations) E (selumetnib in MAPK -mut. ca) ORR 0 % (Eckstein et al., 2022 ) F (ensartinib in ca with ALK or ROS1 alterations) G (vemurafenib in BRAF V600E -pos. ca) H (olaparib in pts. with ATM, BRCA1, BRCA2, RAD51C or RAD51D mut.) I (palbociclib in pts. with Rb -positive ca) J (ulixertinib in pts. with MAPK -mut. ca) (Vo et al., 2022 ): ORR 0% K (ivosidenib in ca with IDH1 mutations) M (tipifarnib in ca with HRAS alterations) N (selpercatinib in ca with RET alterations) SAFIR02-BREAST ( NCT02299999 ) (Mosele et al., 2020 ; Andre et al., 2022 ) Adult women (age ≥ 18 years) with metastatic breast cancer who have progressed after standard treatments or for whom no standard treatment is available Molecularly targeted therapies matched to specific genomic alterations in the patient’s tumour NGS, CGH array Phase 2, open-label, multicentre clinical trial PFS 436 157 50 40 20 17 17 7 3 3 131 148 Arms: Arm A1 (targeted arm): Patients in this arm received targeted maintenance therapy guided by genomic analysis. The therapy used eight targeted drugs. ORR: 26/157 Capivasertib in PI3K/AKT -altered ca Olaparib in BRCA/DDR -altered ca Alpelisib in PI3KCa-mut ca Selumetinib in MAPK -altered ca AZD4547 in FGFR -mut. ca Vistusertib in mTOR-altered ca Sapitinib in HER2/3 -altered ca Vandetanib Arm A2 (immunotherapy arm): Patients in this arm received durvalumab Arm B (standard maintenance chemotherapy): Patients in this arm received standard maintenance chemotherapy. ORR 9/81 (Bachelot et al., 2021 ) After a median follow-up of 21.4 months (90% CI: 17.9–27.6), patients with ESCAT I/II showed a significantly longer PFS in the targeted therapy arm than in the control arm, with a median PFS of 9.1 months (90% CI 7.1–9.8) and 2.8 months (90% CI 2.1–4.8), respectively (adjusted HR = 0.41, 90% CI 0.27–0.61; p < 0.001) IMPACT (Integrated Molecular Profiling in Advanced Cancers Trial) NCT01505400 ) (Stockley et al., 2016 ) COMPACT (Community Molecular Profiling in Advanced Cancers Trial) Adults (age ≥ 18 years) with histological confirmation of advanced breast, non-small cell lung, colorectal, genitourinary, pancreatobiliary gastrointestinal, upper aerodigestive tract, gynaecological, melanoma, unknown primary, and rare carcinomas who are candidates for systemic therapy, as well as patients who are phase 1 trial candidates Two parallel trials that aim to identify molecular alterations in patients’ tumours and match them to targeted therapies, with IMPACT being conducted at academic centres and COMPACT in community settings Targeted NGS panel and MALDI-TOF-based multiplex genotyping panel Retrospective cohort study NR 1893 ORR higher in patients treated on genotype-matched (19%) than in genotype-unmatched trials (9%; p = 0.026). In multivariate analysis, trial matching according to genotype ( p = 0.021) and female gender ( p = 0.034) were the only statistically significant factors associated with response. Genotype-matched trial patients were more likely to achieve the best response of any shrinkage in the sum of their target lesions (62%) compared with genotype-unmatched trial patients (32%; p < 0.001) MOSCATO 01 (Massard et al., 2017 ) Adults (age ≥ 18 years) with advanced solid tumours that have progressed after standard treatments or for whom no standard treatment is available Molecularly targeted therapies that are matched to specific genomic alterations in the patient’s tumour aCGH, WES, RNA-seq Phase 2, non-randomised, open-label, multicentre clinical trial PFSr 843 Molecular profiling and matching patients to targeted therapies led to an improvement in the ORR (11% vs. 5%) and PFS. Progression-Free Survival Ratio (PFS2/PFS1) >1.3 in 33% of patients. Following targeted therapy, of the evaluable patients, two had CR and 20 PR INFORM (individualised Therapy FOr Relapsed Malignancies in Childhood) (van Tilburg et al., 2021 ) Children and adolescents (age ≤ 21) with relapsed or refractory malignancies, including solid tumours, lymphomas and central nervous system tumours Molecularly targeted therapies and immunotherapies matched to specific genomic alterations and immunological tumour features WES, lcWGS, RNA sequencing, RNA-based gene expression array and DNA-methylation Prospective, noninterventional, multicentre, multinational and feasibility registry NR 519 No significant differences in PFS and OS in all patients who did and did not receive a matched targeted drug MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) Women (age ≥ 18 years) with histologically proven, operable, invasive, early-stage breast cancer who have node-negative or 1 to 3 positive lymph nodes Use of a 70-gene signature (MammaPrint) to determine the likelihood of distant recurrence in women with early-stage breast cancer. The trial compared the outcomes of patients assigned to adjuvant chemotherapy based on the traditional clinical-pathological assessment and the MammaPrint assay MammaPrint Phase 3, randomised, controlled, multicentre clinical trial 5-year DMFS rate 6,693 The primary endpoint was met; the inferior margin of 92.5% for DMFS at 60 months in the targeted subjects exceeded the 92% pre-specified threshold ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) Adults (age ≥ 18 years) with surgically resected stage IB, II or IIIA NSCLC Three separate subtrials, each using a specific targeted therapy based on the presence of particular tumour genomic alterations. Investigated targeted therapies: erlotinib (for patients with EGFR mutations), crizotinib (for patients with ALK rearrangements) and nivolumab (for patients with high PD-L1 expression) EGFR sequencing, ALK FISH, PD-L1 IHC Three integrated, phase 3, randomised, double-blind, placebo-controlled clinical trials OS 4,405 NR DRUP (The Drug Rediscovery Protocol) ( NCT02925234 ) (Hoes et al., 2022 ) Adults (age > 18 years) with a histologically-proven locally advanced or metastatic solid tumour, multiple myeloma, or B cell non-Hodgkin lymphoma who are no longer benefitting from standard anti-cancer treatment or for whom no such treatment is available or indicated The molecular profiling test results are used to determine appropriate drugs from those available in the protocol. The choice of the drug is supported by a list of potential profiles, a molecular tumour board, a knowledge library, and study coordinators for review and approval of the match Fresh biopsy: WGS; off-label use Phase II, prospective, non-randomised basket trial ORR 1,550 (planned) NR TARGET (Tumour Characterisation to Guide Experimental Targeted Therapy) ( NCT04723316 ) (Rothwell et al., 2019 ) Patients aged 16 years or over with confirmed diagnosis of advanced solid cancer The primary aim of TARGET National is to establish a national framework to offer molecular profiling of circulating tumour DNA and/or tumour tissue (optional) to patients with advanced solid cancers ctDNA testing Prospective observational trial Number of patients matched to a trial of an experimental therapeutic agent based on molecular findings from ctDNA or tumour 6,000 (planned) NR TAPISTRY (Tumour-Agnostic Precision Immuno-Oncology and Somatic Targeting Rational for You) ( NCT04589845 ) Patients with confirmed diagnosis of advanced and unresectable or metastatic solid malignancy Study evaluating the efficacy and safety of targeted therapy or immunotherapy, as single agents or in combination, in patients with unresectable, locally advanced or metastatic solid tumours divided into cohorts based on biomarkers NGS, FoundationOne CDx / FoundationOne Liquid CDx-based assays Phase II, global, multicenter, open-label, multi-cohort trial ORR 770 (planned) NR ALK, anaplastic lymphoma kinase; CBR, clinical benefit rate; CI, confidence interval; ctDNA, circulating tumour DNA; DCR, disease control rate; DMFS, distant metastasis-free survival; DNA, deoxyribonucleic acid; EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; FFPE, formalin-fixed, paraffin-embedded; ICD – O, International Classification of Diseases for Oncology; IHC, immunohistochemistry; KRAS, Kirsten Rat Sarcoma Viral oncogene homologue; MSI, microsatellite instability; MTB, molecular tumour board; NGS, next-generation sequencing; NR, not reported; NSCLC, non-small cell lung cancer; OR, odds ratio; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PFSr, PFS interval associated with molecularly informed therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1); RNA, ribonucleic acid; RNA-seq, RNA sequencing; TMB, tumour mutational burden; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WES, whole exome sequencing; WGS, whole genome sequencing. Table 2. Summary of selected clinical studies investigating radiosensitivity-predicting genomic signatures Study Cancer type Sample size Main findings Zhao et al., 2016 Prostate cancer 526 patients (196 and 330 in training and validation cohorts, respectively) 24-gene predictor of response to postoperative RT. High PORTOS score predicted a lower incidence of distant metastases in both training (HR 0.12; 95%CI: 0.03–0.41; p < 0.0001) and validation (HR 0.15; 95% CI 0.04–0.60; p = 0.002) cohorts Tang et al., 2017 Sarcomas 253 patients from The Cancer Genome Atlas 26-gene radiosensitivity signature. Predicted radiosensitive patients had better overall survival than predicted nonradiosensitive patients (HR 0.07, p < 0.001) Cui et al., 2018 Breast cancer 948 and 1,439 patients in the training and validation cohorts, respectively (METABRIC) 34-gene radiosensitivity signature. Patients administered RT had better disease-specific survival than those who did not in the radiation-sensitive group (HR 0.68, p = 0.059); a reverse effect was observed in the radiation-resistant group (HR 1.53, p = 0.059) 4-gene immune signature predictive of RT benefit. Patients who were administered RT had significantly better disease-specific survival in the immune-effective group (HR 0.46, p = 0.0076), with no difference in disease-specific survival in the immune-defective group (HR 1.27, p = 0.16) Sjöström et al., 2019 Breast cancer 748 patients from the SweBCG91-RT trial Adjuvant Radiotherapy Intensification Classifier (ARTIC) comprising 27 genes and patient age was prognostic for locoregional recurrence in breast cancer patients administered RT (HR 3.4; 95% CI: 2.0 to 5.9; p < 0.001) and was predictive of RT benefit ( p = 0.005). Patients with low ARTIC scores had a larger benefit from RT (HR 0.33; 95% CI: 0.21 to 0.52, p < 0.001) than those with high ARTIC scores (HR 0.73; 95% CI: 0.44 to 1.2, p = 0.23) Kim et al., 2020 HPV-negative head and neck squamous cell carcinomas 203 patients from The Cancer Genome Atlas (TCGA) cohort 41-gene radiation sensitivity signature (RSS). RSS predicted reduced 5-year recurrence-fee survival in the radioresistant group versus the radiosensitive group (57.8% vs. 80.1%; p = 0.035) Scott et al., 2021 Various types (breast, head and neck, NSCLC, pancreatic, endometrial, melanoma and glioma) 1,615 patients, of whom 1,298 (982 and 316 with and without RT, respectively) assessed for time to first recurrence and 677 (424 and 253 with and without RT, respectively) for overall survival Genomic-adjusted radiation dose (GARD) was associated with time to first recurrence (HR 0.98, 95% CI 0.97–0.99; p = 0.0017) and overall survival (HR 0.97, 0.95–0.99; p = 0.0007). The effect on overall survival was dependent on radiotherapy use ( p = 0.011) Feng et al., 2021 Prostate cancer 486 of 760 patients randomised in NRG/RTOG 9601 trial 22-gene genomic classifier Decipher (Decipher Biosciences Inc) was associated with distant metastases (HR 1.17; 95%CI: 1.05–1.32; p = 0.006), prostate cancer–specific mortality (HR 1.39; 95%CI: 1.20–1.63; p < 0.001) and overall survival (HR 1.17; 95%CI: 1.06–1.29; p = 0.002) Dal Pra et al., 2022 Prostate cancer 226 of 350 patients randomised in Swiss Group for Clinical Cancer Research (SAKK) 09/10 trial 22-gene genomic classifier Decipher (Decipher Biosciences Inc) was associated with biochemical progression (HR 2.26; 95%CI: 1.42–3.60; p < 0.001), clinical progression (HR 2.29, 95%CI: 1.32–3.98; p = 0.003) and use of hormone therapy (sHR 2.99, 95% CI 1.55–5.76; p = 0.001). Patients with high and low Decipher scores had 45% and 71% 5-year freedom from biochemical progression, respectively Wu et al., 2022 Gliomas 1,395 from Chinese Glioma Genome Atlas and Cancer Genome Atlas 12-gene radiosensitivity predictive index (PI12) had better predictive capacity than the traditional WHO classification system (concordance index: 0.842 vs. 0.787; p ≤ 2.2 × 10 −16 ) Sjöström et al., 2023 Breast cancer 729 patients from the SweBCG91-RT trial and Princess Margaret Hospital A 16-gene signature named Profile for the Omission of Local Adjuvant Radiation (POLAR). POLAR low-risk patients did not benefit from adjuvant RT (HR 1.1; 95% CI 0.39–3.40; p = 0.81; HR 1.5; 95% CI 0.14–16, p = 0.74). POLAR high-risk patients had a significantly lower risk of locoregional recurrence with RT (HR 0.43; 95% CI 0.24–0.78; p = 0.006; HR 0.25; 95%CI 0.07–0.92; p = 0.038) Spratt et al., 2023 Prostate cancer 215 patients from NRG Oncology/RTOG 0126 22-gene genomic classifier Decipher (Decipher Biosciences Inc) was independently prognostic for disease progression (sHR 1.12; 95%CI 1.00–1.26, p = 0.04), biochemical failure (sHR 1.22; 95%CI 1.10–1.37, p < 0.001), distant metastasis (sHR 1.28; 95%CI 1.06–1.55, p = 0.01) and prostate cancer-specific mortality (sHR 1.45; 95%CI 1.20–1.76, p < 0.001) 95%CI, 95% confidence interval; HR, hazard ratio; sHR, subdistribution hazard ratio.

Germline heterogeneity

Response and adverse reactions to systemic therapies can vary substantially between individuals. This variability has been attributed mainly to the inherited genomic variants that inactivate protein-coding genes (Karczewski et al., 2020 ). The therapy may be impacted on several levels, including direct drug–target interactions, drug metabolism (including drug activation and removal) and downstream effects (e.g., DNA damage). Hence, considering patient pharmacogenomics can improve treatment outcomes, decrease toxicity and reduce costs.

The drug-metabolising enzyme known as cytochrome P450 2D6 (CYP2D6) is the most thoroughly examined and variable polymorphic enzyme (Zhou and Lauschke, 2022 ). Its deficiency is inherited through an autosomal recessive trait, and individuals carrying this alteration are classified as poor metabolisers. However, the remaining subjects (extensive metabolisers) display considerable variability in their enzymatic activity (Bertilsson et al., 2002 ). The gene encoding the CYP2D6 protein is highly polymorphic, with over 100 allelic variants described to date (Gaedigk et al., 2018 ). Specific genetic variations in the CYP2D6 gene can cause altered activity of the cytochrome P450 2D6 enzyme, which is involved in the metabolism of tamoxifen (a selective oestrogen modulator used to treat breast cancer). Individuals with reduced CYP2D6 activity (e.g., *4, *5 and *6 alleles) account for up to 10% of patients (Ingelman-Sundberg, 2004 ; Crews et al., 2014 ). These individuals have a lower efficacy of tamoxifen than those with normal activity (Lim et al., 2007 ; Schroth et al., 2007 ; Goetz et al., 2013 ). Likewise, the ultrarapid metabolisers (e.g., with *1xN or *2xN alleles, about 1–2% of patients) show lower endoxifen (a tamoxifen metabolite) concentrations and worse outcomes compared with patients with normal CYP2D6 activity (Wegman et al., 2005 ; Schroth et al., 2007 ; Crews et al., 2014 ).

Similarly, variations in the DPYD gene (e.g., *2A or *13), which encodes the dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of fluoropyrimidines, such as 5-fluorouracil and capecitabine, can lead to reduced enzyme activity and an increased risk of severe toxicity (Amstutz et al., 2009 ; Offer et al., 2014 ; Henricks et al., 2018 ).

Finally, the UGT1A1 gene, which encodes for the uridine diphosphate glucuronosyltransferase 1A1 enzyme, is involved in the metabolism of irinotecan (a topoisomerase I inhibitor); variations reducing its activity (including *6, *27 and *28) may cause severe toxicity, including neutropenia, diarrhoea or infection (Iyer et al., 2002 ; Innocenti et al., 2004 ; Marcuello et al., 2004 ; Xu et al., 2016 ).

Genomic polymorphisms in drug targets may also affect interactions with drugs. Several HER2 gene variants have been shown to impact the effectiveness of trastuzumab (a monoclonal antibody targeting HER2) in HER2-positive breast cancer patients. The F117L variant, which is located in the extracellular domain of the HER2 protein, impairs trastuzumab binding by approximately threefold compared with wild-type HER2. Decreased binding affinity is attributed to the introduction of a leucine residue, which causes a steric hindrance and disrupts the protein conformation at the binding site (Gaborit et al., 2011 ). In turn, a variant within the HER2 intracellular kinase domain (T798I) leads to increased kinase activity, conferring resistance to lapatinib (Bose et al., 2013 ). Another example of EGFR polymorphism is R521K (rs2227983), which may decrease the response to cetuximab in patients with metastatic colorectal cancer (Graziano et al., 2008 ). As a result, patients who carry this allele experience a lower incidence of skin toxicity during cetuximab treatment (Klinghammer et al., 2010 ; Fernández-Mateos et al., 2016 ).

Finally, variants affecting the efficiency of DNA damage repair may affect the response and toxicity of numerous drugs, including platinum agents, alkylating agents, topoisomerase II inhibitors, antimetabolites and poly-ADP ribose polymerase inhibitors. The rs3212986 variant (C8092A) of the ERCC1 gene, which is a component of the nucleotide excision repair pathway, is associated with a poor response to platinum agents in NSCLC and ovarian cancer (Zhou et al., 2004 ; Krivak et al., 2008 ). Similarly, the rs13181 (L751G) single nucleotide variant (SNV) in the XPD gene is associated with the poor efficacy of platinum agents in NSCLC (Park et al., 2001 ).

Radiotherapy

Radiotherapy is a vital component of cancer treatment, applicable in around 60% of patients (Citrin, 2017 ). Until recently, radiotherapy was prescribed on the empirical basis of a one-fits-all approach, assuming a similar response to the same radiation dose. Recent advances in precision medicine have enabled the use of more targeted and personalised radiotherapy regimens tailored to the specific characteristics of individual patients and their tumours. Cancer heterogeneity poses a significant challenge for radiotherapy, as it can cause variable tumour responses and the emergence of radioresistant cell populations. Precision radiotherapy, by considering the comprehensive molecular and genetic tumour makeup, may overcome these challenges and allow for the development of tailored treatment plans. By integrating genomic data and other biomarkers, precision radiotherapy has the potential to maximise tumour control while minimising toxicity to surrounding healthy tissues.

Tumour response

Technological advancements in radiotherapy have increased the potential of physical radiation tailoring to personalise treatment. However, the optimisation process typically focuses on dose conformality, ignoring biological factors and assuming that all tumours react similarly to radiation (Price et al., 2023 ). Unlike medical oncology, where genomic signatures have become part of routine practice (e.g., MammaPrint tests, Oncotype DX or PAM50), their use in radiotherapy has been limited (Parker et al., 2023 ). Meanwhile, radiation impacts several molecular pathways, such as DNA damage, hypoxia or proliferation (Reisz et al., 2014 ; Wang et al., 2018 ; Huang and Zhou, 2020 ).

Several somatic mutations have already been established as conferring radioresistance. Numerous studies, including breast (Jameel et al., 2004 ), colorectal (Munro et al., 2005 ) and head and neck cancers (Hutchinson et al., 2020 ), gliomas (Werbrouck et al., 2019 ) and sarcomas (Casey et al., 2021 ) have shown that TP53 mutations might impair radiotherapy response. Other notable examples are KEAP1 and NFE2L2/NRF2 mutations in NSCLC and head and neck cancers (Binkley et al., 2020 ; Guan et al., 2023 ). In addition, the coexistence of KRAS and SMAD4 mutations is an indicator of radioresistance in cervical cancer (Oike et al., 2021 ).

To date, there has been scarce data on molecular predictive signatures in radiotherapy. These examples comprise the PORTOS classifier encompassing 24 genes to predict the efficacy of postoperative radiotherapy in prostate cancer (Zhao et al., 2016 ) and the Adjuvant Radiotherapy Intensification Classifier (ARTIC) and POLAR classifiers, which incorporate 27 and 16 genes, respectively, to predict outcomes of postoperative radiotherapy in breast cancer (Sjöström et al., 2019 , 2023 ).

Unlike PORTOS or POLAR, which relate to specific cancers and clinical situations, a radiosensitivity index (RSI) has also been proposed as a pan-cancer and specific marker of cellular radiosensitivity. This index is based on the expression of 10 genes ( AR, c-JUN, STAT1, PKC, Rel A, cABL, SUMO1, CDK1, HDAC1 and IRF1 ) related to DNA damage response, cell cycle, apoptosis and proliferation (Eschrich et al., 2009 ). Based on RSI, a quantitative metric for the biological effect of RT, the genomic-adjusted radiation dose (GARD) has been developed. GARD was initially validated in patients with breast cancer, lung cancer, pancreatic cancer and glioblastoma (Scott et al., 2017 ). This signature was further tested in a pooled, retrospective, pan-cancer cohort and reported as a continuous variable associated with time to first recurrence and overall survival (Scott et al., 2021 ). Recently, GARD has been employed in a provocative in silico analysis to explain the unexpected results of the seminal RTOG 0617 trial (unsuccessful radiotherapy dose escalation in locally advanced NSCLC) (Scott et al., 2021 ). The authors assumed that this model allows for deriving an optimal radiation dose in each patient. Another study employing prospectively collected tissues showed that low RSI values (denoting higher radiosensitivity) are associated with increased immune infiltration and activation (Grass et al., 2022 ). Recently, based on the reanalysis of the publicly available datasets – Merged Microarray-Acquired Dataset (Bin Lim et al., 2019 ) and the Cancer Genome Atlas (Weinstein et al., 2013 ) – RSI was shown to be associated with immune-related features and predicted response to PD-1 blockade (Dai et al., 2021 ). However, a recent analysis showed that RSI is not associated with survival and should not be used for radiation dose adjustments (Mistry, 2023 ). It was also suggested that the RSI of tumour clones remaining after RT, instead of the initial tumour population, should be evaluated to better predict the RT outcome (Alfonso and Berk, 2019 ).

Incorporating genomic signatures in radiotherapy decision-making has shown significant advancement through recent research, such as the GARD-based trial, to optimise radiotherapy for triple-negative breast cancer ( NCT05528133 ). The European Organisation for Research and Treatment of Cancer has appraised the evidence from RSI/GARD studies as a priority for phase 3 clinical trials in radiotherapy (Thomas et al., 2020 ). However, the clinical utility of these approaches warrants an evaluation that integrates molecular data into prospective clinical trials and routine clinical practice ( Table 2 ).

Radiotherapy tolerance

The impact of genetic heterogeneity on normal tissue toxicity following radiotherapy is a significant concern in cancer treatment. Individual genetic variations can influence the severity of radiation-induced side effects (Barnett et al., 2009 ). Normal tissue complications can range from mild to severe and may include skin reactions, inflammation, fibrosis and organ dysfunction (Bentzen, 2006 ). However, except for several radiosensitivity syndromes related to biallelic pathogenic mutations in DNA repair genes and deleterious heterozygous ATM mutations in young patients, no genomics-guided radiotherapy is currently used (Bergom et al., 2019 ).

Since the beginning of the twenty-first century, more than 100 articles analysing the impact of DNA sequence changes on the frequency and severity of radiation-induced complications have been published (Andreassen et al., 2016 ). Most of these studies have addressed SNVs, which typically affect the genes responsible for processes such as DNA break or inflammation. However, these studies were usually small (median of approximately 150 patients), hence lowering the statistical power for comparisons (Andreassen et al., 2016 ).

To reduce the bias associated with the publication of numerous low-quality studies, the Radiogenomics Consortium ( https://epi.grants.cancer.gov/radiogenomics/ ) was created in 2009 (West et al., 2010 ). This initiative allowed for assembling adequate groups of patients with diverse clinical characteristics and validating presumed associations of SNVs with radiation toxicity. However, the results of the prospective study published in 2012 were a huge disappointment because none of the reported relationships (98 SNVs in 46 genes) were confirmed (Barnett et al., 2012 ). However, this experience prompted the development of research employing large-scale techniques such as genome-wide association studies (GWAS). As a result, potentially interesting SNV associations with radiation reactions were found, such as variants at the locus of the TANC1 gene that was found to be encoding a protein responsible for muscle cell regeneration (Fachal et al., 2014 ). The strength of these associations is much higher, with odds ratios of 1.3–1.5, compared with 1.1–1.2 observed in typical GWAS studies (Zhong and Prentice, 2010 ). The Radiogenomics Consortium remains active, and a significant increase in sample size has led to the discovery of several potentially relevant relationships. An analysis of breast and prostate cancer patients from 17 cohorts indicated that the ATM rs1801516 SNP is associated with an increased risk of radiation toxicity (Andreassen et al., 2016 ). A recent study has revealed a strong association between radiation-induced mucositis and the rs1131769*C locus in the STING1 gene on chromosome 5 (Schack et al., 2022 ).

A definitive answer to the SNVs’ role in healthy tissues’ response to radiation may come from the international, multicentre REQUITE project ( www.requite.eu ) funded by the European Union through its 7th Framework Programme (West et al., 2014 ). The project, performed in collaboration with the Radiogenomics Consortium, aimed at predicting and reducing the risk of long-term side effects of radiotherapy and completed patient recruitment (Seibold et al., 2019 ). REQUITE reported that polygenic risk scores (PRS) may be clinically useful and that incorporation of SNP-SNP interactions improves patient classification and prediction of radiotherapy-related toxicity (Franco et al., 2021 ). This project significantly advanced the collaborations among stakeholders, including healthcare professionals, researchers and industry partners, highlighting the importance of personalised radiotherapy. Other collaborative genetic association studies at both the national and global levels include Gene-PARE (Ho et al., 2006 ), RadGenomics (Iwakawa et al., 2002 ) and RAPPER (Burnet et al., 2013 ). Understanding the impact of radiogenomic heterogeneity on normal tissue radiation toxicity is essential for developing more effective and safe personalised strategies.

In summary, for a long time, radiotherapy optimisation was focused on dosage conformity rather than biological factors. It is critical to factor in tumour heterogeneity when considering radiotherapy outcomes; hence, developing and verifying molecular signatures such as PORTOS, ARTIC and POLAR, together with pan-cancer RSI, constitute the base for resolving this predicament.

Other factors

Circadian heterogeneity

The efficacy of anticancer treatment may also be affected by circadian rhythm, a biological phenomenon displaying endogenous, untrainable 24-h oscillation (Lee, 2021 ). The circadian clock regulates several key processes in the human body, including metabolism and cell division, with 40% of the transcriptome under circadian control in at least some tissues (Ruben et al., 2018 ). Recently, a comprehensive analysis of clock genes across different human cancers was performed using primary solid tumour data from The Cancer Genome Atlas (Ye et al., 2018 ). Based on the available evidence, the International Agency for Research on Cancer classified shift work that involves circadian disruption as potentially carcinogenic to humans (IARC Monographs Vol 124 group, 2019 ).

Chronotherapy involves administering treatment at specific times of day to optimise its effectiveness and minimise side effects (Zhou et al., 2021 ). This approach has been tested in several clinical trials with conflicting results: some showed improved efficacy and reduced toxicity (Lévi et al., 1997 ; Giacchetti et al., 2006 ), whereas others did not demonstrate significant differences (Garufi et al., 2006 ; Qvortrup et al., 2010 ). Some data indicate that chronomodulation might be relevant in the context of immunotherapy. For instance, a recent provocative study reported inferior overall survival in patients who received more than 20% of immunotherapy infusions after 4:30 PM (Qian et al., 2021 ). However, these observations warrant verification in prospective randomised clinical trials. Data pertinent to radiotherapy comes from the REQUITE project, which disclosed novel serendipitous associations, for example, the interaction between time, circadian rhythm-related genes ( CLOCK , PER3 and RASD1 ) and late radiation toxicity in breast cancer patients (Webb et al., 2022 ).

Microbiome heterogeneity

The human microbiome, comprising trillions of diverse microbial organisms, plays a significant role in modulating health and disease states, including cancer (Hou et al., 2022 ). Recent research indicates that microbiome heterogeneity can greatly influence response to anticancer treatment via drug-microbiota interactions.

Bacteria-derived enzymes target chemical compounds, including drugs used in systemic treatment. For example, approximately 40% of patients treated with irinotecan experience severe mucositis, sometimes leading to treatment cessation. Irinotecan is converted into its active form, SN38, which is later reverted back to an inactive form, SN38G, in the liver. Bacterial β-glucuronidases can then convert SN38G in the gastrointestinal tract back to its toxic form (Wallace et al., 2010 ). Additionally, Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium abundancy in stool was found to be associated with increased response to anti–PD-1 treatment in patients with melanoma (Matson et al., 2018 ).

Additionally, the gut microbiome generates numerous metabolites, with short-chain fatty acids (SCFAs) being among the most prevalent and crucial. Significantly, SCFAs act as secondary messengers that facilitate signal transmission and influence the onset and progression of various diseases. Radiotherapy can modify the populations of bacteria that produce SCFAs, leading to changes in SCFA levels, which are linked to several conditions, including radiation-induced intestinal injury (Li et al., 2021 ).

The microbiome studies shape oncologic outcomes and are now being leveraged for the development of novel personalised therapeutic approaches in anticancer treatment. However, this topic exceeds the scope of this paper and has been addressed elsewhere (Chrysostomou et al., 2023 ; Yi et al., 2023 ).

Conclusions

Precision medicine has made remarkable progress in oncology by promising to administer therapy to “the right patient at the right time” (Abrahams, 2008). This review has discussed the impact of cancer heterogeneity as a major challenge facing precision oncology development. Apart from affecting treatment outcomes, heterogeneity can also be employed in the context of prevention and early detection. The results of the first large-scale observational cohort study evaluating methylation-based multicancer early detection diagnostic test (SIMPLIFY) have demonstrated the feasibility of this approach (Rebbeck et al., 2018 ; Nicholson et al., 2023 ; Tie, 2023 ).

Genomic makeup has been shown to impact the effectiveness and toxicity of systemic treatments and radiotherapy. Thus, genomic testing can identify pathogenic gene variants and polymorphisms affecting drug metabolism or mechanism of action, thus increasing the risk of treatment failure or toxicity. Spatial and temporal tumoural heterogeneity is a complex phenomenon linked to resistance to therapy, disease progression and adverse prognosis. There are substantial genetic and molecular differences across various tumour regions and between primary and metastatic foci. A better understanding of this phenomenon allowed for the development of novel strategies, for example, targeting with systemic therapies or radiation-specific tumour regions or populations of cancer cells.

Implementing advanced technologies, such as NGS, liquid biopsies and imaging modalities, has fostered precision oncology, accounting for both genomic and tumoural heterogeneity. NGS is routinely used to examine mutations in, for example, EGFR , BRAF and ALK , which are molecular targets for modern therapies. Liquid biopsies, which involve analysing circulating tumour cells or circulating tumour DNA, offer a noninvasive way to identify genetic alterations and monitor tumour progression. Several clinical trials, including the ongoing NCI-MATCH and MASTER trials and the previously completed MyPathway and MPACT trials, have been designed to identify genetic mutations associated with specific targeted therapies and develop novel treatment strategies for overcoming therapy resistance. These trials are expected to prompt further development of precision oncology.

As precision oncology continues to evolve, the future holds great promise for overcoming current challenges. Advanced tools should be more accessible and affordable. There is a need for routine, more comprehensive genomic profiling of different regions of primary and metastatic tumours to fully understand cancer heterogeneity. In addition, integrating machine learning algorithms and artificial intelligence would allow better identification of new therapeutic targets and the development of even more personalised treatment strategies. An exciting area of future research in precision oncology is the use of combination therapies that simultaneously target multiple pathways and molecular targets; this approach has the potential to overcome heterogeneity-led resistance to single-agent targeted therapies. Another area for improvement is integrating precision oncology into clinical practice and expanding access to new technologies for community oncologists and patients. This will require the development of user-friendly platforms and tools that are easily integrable into clinical workflows.

Overall, precision oncology holds great promise for improving cancer treatment efficacy by enabling personalised treatment strategies based on unique cancer and patient characteristics. Although challenges remain to be addressed, ongoing research and emerging developments create real hope for breath-taking therapeutic approaches and improved patient outcomes.

Open peer review

To view the open peer review materials for this article, please visit http://doi.org/10.1017/pcm.2023.23 .

Author contribution

J.J. and B.T. developed the paper concept and outline. B.T., F.G., M.Br. and M.Bi. collected and assembled the data. J.J. provided administrative support and oversight and revised the text. F.G. prepared the figures. B.T., F.G., M.Br., M.Bi. and J.J. wrote and approved the manuscript. B.T. and F.G. contributed equally to this work.

Financial support

F.G. is supported by Polish National Science Centre Grants PRELUDIUM 2018/31/N/NZ5/03214, ETIUDA 2020/36/T/NZ5/00610, and Polish Stem Cells Bank grant ExCELLent.

Competing interest

J.J. declares advisory roles for BMS, Roche and MSD, lectures for Roche (not compensated), Pfizer, Novartis and MSD and travel support from Takeda. Other authors have no conflicts of interest to declare.

References

Aggarwal C , Davis CW , Mick R , Thompson JC , Ahmed S , Jeffries S , Bagley S , Gabriel P , Evans TL , Bauml JM , Ciunci C , Alley E , Morrissette JJD , Cohen RB , Carpenter EL and Langer CJ ( 2018 ) Influence of TP53 mutation on survival in patients with advanced EGFR-mutant non-small-cell lung cancer . JCO Precision Oncology 2018 , PO.18.00107 . 30766968 10.1200/PO.18.00107 PMC6372114

Alexander BM , Ba S , Berger MS , Berry DA , Cavenee WK , Chang SM , Cloughesy TF , Jiang T , Khasraw M , Li W , Mittman R , Poste GH , Wen PY , Yung WKA , Barker AD and GBM AGILE Network ( 2018 ) Adaptive global innovative learning environment for glioblastoma: GBM AGILE . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 24 , 737 – 743 . 28814435 10.1158/1078-0432.CCR-17-0764

Alfonso JCL and Berk L ( 2019 ) Modeling the effect of intratumoral heterogeneity of radiosensitivity on tumor response over the course of fractionated radiation therapy . Radiation Oncology (London, England) 14 , 88 . 31146751 10.1186/s13014-019-1288-y PMC6543639

Almendro V , Cheng Y-K , Randles A , Itzkovitz S , Marusyk A , Ametller E , Gonzalez-Farre X , Muñoz M , Russnes HG , Helland A , Rye IH , Borresen-Dale A-L , Maruyama R , van Oudenaarden A , Dowsett M , Jones RL , Reis-Filho J , Gascon P , Gönen M , Michor F and Polyak K ( 2014 ) Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity . Cell Reports 6 , 514 – 527 . 24462293 10.1016/j.celrep.2013.12.041 PMC3928845

Amstutz U , Farese S , Aebi S and Largiadèr CR ( 2009 ) Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: A haplotype assessment . Pharmacogenomics 10 , 931 – 944 . 19530960 10.2217/pgs.09.28

Andre F , Filleron T , Kamal M , Mosele F , Arnedos M , Dalenc F , Sablin M-P , Campone M , Bonnefoi H , Lefeuvre-Plesse C , Jacot W , Coussy F , Ferrero J-M , Emile G , Mouret-Reynier M-A , Thery J-C , Isambert N , Mege A , Barthelemy P , You B , Hajjaji N , Lacroix L , Rouleau E , Tran-Dien A , Boyault S , Attignon V , Gestraud P , Servant N , Le Tourneau C , Cherif LL , Soubeyran I , Montemurro F , Morel A , Lusque A , Jimenez M , Jacquet A , Gonçalves A , Bachelot T and Bieche I ( 2022 ) Genomics to select treatment for patients with metastatic breast cancer . Nature 610 , 343 – 348 . 36071165 10.1038/s41586-022-05068-3

Andreassen CN , Rosenstein BS , Kerns SL , Ostrer H , De Ruysscher D , Cesaretti JA , Barnett GC , Dunning AM , Dorling L , West CML , Burnet NG , Elliott R , Coles C , Hall E , Fachal L , Vega A , Gómez-Caamaño A , Talbot CJ , Symonds RP , De Ruyck K , Thierens H , Ost P , Chang-Claude J , Seibold P , Popanda O , Overgaard M , Dearnaley D , Sydes MR , Azria D , Koch CA , Parliament M , Blackshaw M , Sia M , Fuentes-Raspall MJ , Cajal TR , Barnadas A , Vesprini D , Gutiérrez-Enríquez S , Mollà M , Díez O , Yarnold JR , Overgaard J , Bentzen SM and Alsner J ( 2016 ) Individual patient data meta-analysis shows a significant association between the ATM Rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients . Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 121 , 431 – 439 . 27443449 10.1016/j.radonc.2016.06.017 PMC5559879

Andreassen CN , Schack LMH , Laursen LV and Alsner J ( 2016 ) Radiogenomics – Current status, challenges and future directions . Cancer Letters 382 , 127 – 136 . 26828014 10.1016/j.canlet.2016.01.035

Azad NS , Gray RJ , Overman MJ , Schoenfeld JD , Mitchell EP , Zwiebel JA , Sharon E , Streicher H , Li S , McShane LM , Rubinstein L , Patton DR , Williams PM , Coffey B , Hamilton SR , Bahary N , Suga JM , Hatoum H , Abrams JS , Conley BA , Arteaga CL , Harris L , O’Dwyer PJ , Chen AP and Flaherty KT ( 2020 ) Nivolumab is effective in mismatch repair–deficient noncolorectal cancers: Results from arm Z1D—A subprotocol of the NCI-MATCH (EAY131) study . Journal of Clinical Oncology 38 , 214 – 222 . 31765263 10.1200/JCO.19.00818 PMC6968795

Babina IS and Turner NC ( 2017 ) Advances and challenges in targeting FGFR Signalling in cancer . Nature Reviews. Cancer 17 , 318 – 332 . 28303906 10.1038/nrc.2017.8

Bachelot T , Filleron T , Bieche I , Arnedos M , Campone M , Dalenc F , Coussy F , Sablin M-P , Debled M , Lefeuvre-Plesse C , Goncalves A , Reynier M-AM , Jacot W , You B , Barthelemy P , Verret B , Isambert N , Tchiknavorian X , Levy C , Thery J-C , L’Haridon T , Ferrero J-M , Mege A , Del Piano F , Rouleau E , Tran-Dien A , Adam J , Lusque A , Jimenez M , Jacquet A , Garberis I and Andre F ( 2021 ) Durvalumab compared to maintenance chemotherapy in metastatic BREAST cancer: The randomized phase II SAFIR02-BREAST IMMUNO trial . Nature Medicine 27 , 250 – 255 . 10.1038/s41591-020-01189-2 33462450

Barnett GC , Coles CE , Elliott RM , Baynes C , Luccarini C , Conroy D , Wilkinson JS , Tyrer J , Misra V , Platte R , Gulliford SL , Sydes MR , Hall E , Bentzen SM , Dearnaley DP , Burnet NG , Pharoah PDP , Dunning AM and West CML ( 2012 ) Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: A prospective analysis study . The Lancet. Oncology 13 , 65 – 77 . 22169268 10.1016/S1470-2045(11)70302-3

Barnett GC , West CML , Dunning AM , Elliott RM , Coles CE , Pharoah PDP and Burnet NG ( 2009 ) Normal tissue reactions to radiotherapy: Towards tailoring treatment dose by genotype . Nature Reviews. Cancer 9 , 134 – 142 . 19148183 10.1038/nrc2587 PMC2670578

Bedard PL , Li S , Wisinski KB , Yang ES , Limaye SA , Mitchell EP , Zwiebel JA , Moscow JA , Gray RJ , Wang V , McShane LM , Rubinstein LV , Patton DR , Williams PM , Hamilton SR , Conley BA , Arteaga CL , Harris LN , O’Dwyer PJ , Chen AP and Flaherty KT ( 2022 ) Phase II study of Afatinib in patients with tumors with human epidermal growth factor receptor 2–activating mutations: Results from the National Cancer Institute–molecular analysis for therapy choice ECOG-ACRIN trial (EAY131) subprotocol EAY131-B . JCO Precision Oncology 6 , e2200165 . 35939768 10.1200/PO.22.00165 PMC9384949

Bentzen SM ( 2006 ) Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology . Nature Reviews. Cancer 6 , 702 – 713 . 16929324 10.1038/nrc1950

Bergom C , West CM , Higginson DS , Abazeed ME , Arun B , Bentzen SM , Bernstein JL , Evans JD , Gerber NK , Kerns SL , Keen J , Litton JK , Reiner AS , Riaz N , Rosenstein BS , Sawakuchi GO , Shaitelman SF , Powell SN and Woodward WA ( 2019 ) The implications of genetic testing on radiation therapy decisions: A guide for radiation oncologists . International Journal of Radiation Oncology, Biology, Physics 105 , 698 – 712 . 31381960 10.1016/j.ijrobp.2019.07.026 PMC11913060

Bertilsson L , Dahl M-L , Dalén P and Al-Shurbaji A ( 2002 ) Molecular genetics of CYP2D6: Clinical relevance with focus on psychotropic drugs . British Journal of Clinical Pharmacology 53 , 111 – 122 . 11851634 10.1046/j.0306-5251.2001.01548.x PMC1874287

Bin Lim S , Chua MLK , Yeong JPS , Tan SJ , Lim W-T and Lim CT ( 2019 ) Pan-Cancer analysis connects tumor Matrisome to immune response . npj Precision Oncology 3 , 15 . 31123708 10.1038/s41698-019-0087-0 PMC6531473

Binkley MS , Jeon Y-J , Nesselbush M , Moding EJ , Nabet BY , Almanza D , Kunder C , Stehr H , Yoo CH , Rhee S , Xiang M , Chabon JJ , Hamilton E , Kurtz DM , Gojenola L , Owen SG , Ko RB , Shin JH , Maxim PG , Lui NS , Backhus LM , Berry MF , Shrager JB , Ramchandran KJ , Padda SK , Das M , Neal JW , Wakelee HA , Alizadeh AA , Loo BW and Diehn M ( 2020 ) KEAP1/NFE2L2 mutations predict lung Cancer radiation resistance that can be targeted by glutaminase inhibition . Cancer Discovery 10 , 1826 – 1841 . 33071215 10.1158/2159-8290.CD-20-0282 PMC7710558

Blackstone EH ( 2019 ) Precision medicine versus evidence-based medicine: Individual treatment effect versus average treatment effect . Circulation 140 , 1236 – 1238 . 31589490 10.1161/CIRCULATIONAHA.119.043014

Bose R , Kavuri SM , Searleman AC , Shen W , Shen D , Koboldt DC , Monsey J , Goel N , Aronson AB , Li S , Ma CX , Ding L , Mardis ER and Ellis MJ ( 2013 ) Activating HER2 mutations in HER2 gene amplification negative breast Cancer . Cancer Discovery 3 , 224 – 237 . 23220880 10.1158/2159-8290.CD-12-0349 PMC3570596

Brown LC , Graham J , Fisher D , Adams R , Seligmann J , Seymour M , Kaplan R , Yates E , Parmar M , Richman SD , Quirke P , Butler R , Shiu K , Middleton G , Samuel L , Wilson RH and Maughan TS ( 2022 ) Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal Cancer Clinical Trials (London, England) 19 , 146 – 157 . 35083924 10.1177/17407745211069879 PMC9036145

Burnet NG , Barnett GC , Elliott RM , Dearnaley DP , Pharoah PDP , Dunning AM , West CML and RAPPER Investigators ( 2013 ) RAPPER: The radiogenomics of radiation toxicity . Clinical Oncology (Royal College of Radiologists (Great Britain)) 25 , 431 – 434 . 23642504 10.1016/j.clon.2013.04.001

Burrell RA , McGranahan N , Bartek J and Swanton C ( 2013 ) The causes and consequences of genetic heterogeneity in cancer evolution . Nature 501 , 338 – 345 . 24048066 10.1038/nature12625

Cagney DN , Sul J , Huang RY , Ligon KL , Wen PY and Alexander BM ( 2018 ) The FDA NIH biomarkers, EndpointS, and other tools (BEST) resource in neuro-oncology . Neuro-Oncology 20 , 1162 – 1172 . 29294069 10.1093/neuonc/nox242 PMC6071649

Califf RM ( 2018 ) Biomarker definitions and their applications . Experimental Biology and Medicine (Maywood, N.J.) 243 , 213 – 221 . 10.1177/1535370217750088 PMC5813875 29405771

Casey DL , Pitter KL , Wexler LH , Slotkin EK , Gupta GP and Wolden SL ( 2021 ) TP53 mutations increase radioresistance in rhabdomyosarcoma and Ewing sarcoma . British Journal of Cancer 125 , 576 – 581 . 34017087 10.1038/s41416-021-01438-2 PMC8368014

Cercek A , Lumish M , Sinopoli J , Weiss J , Shia J , Lamendola-Essel M , El Dika IH , Segal N , Shcherba M , Sugarman R , Stadler Z , Yaeger R , Smith JJ , Rousseau B , Argiles G , Patel M , Desai A , Saltz LB , Widmar M , Iyer K , Zhang J , Gianino N , Crane C , Romesser PB , Pappou EP , Paty P , Garcia-Aguilar J , Gonen M , Gollub M , Weiser MR , Schalper KA and Diaz LA ( 2022 ) PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer . The New England Journal of Medicine 386 , 2363 – 2376 . 35660797 10.1056/NEJMoa2201445 PMC9492301

Cerchione C , Romano A , Daver N , DiNardo C , Jabbour EJ , Konopleva M , Ravandi-Kashani F , Kadia T , Martelli MP , Isidori A , Martinelli G and Kantarjian H ( 2021 ) IDH1/IDH2 inhibition in acute myeloid leukemia . Frontiers in Oncology 11 , 639387 . 33898313 10.3389/fonc.2021.639387 PMC8063727

Chabner BA and Roberts TG ( 2005 ) Timeline: Chemotherapy and the war on cancer . Nature Reviews. Cancer 5 , 65 – 72 . 15630416 10.1038/nrc1529

Chae YK , Hong F , Vaklavas C , Cheng HH , Hammerman P , Mitchell EP , Zwiebel JA , Ivy SP , Gray RJ , Li S , McShane LM , Rubinstein LV , Patton D , Williams PM , Hamilton SR , Mansfield A , Conley BA , Arteaga CL , Harris LN , O’Dwyer PJ , Chen AP and Flaherty KT ( 2020 ) Phase II study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: Results from the NCI-MATCH trial (EAY131) subprotocol W . Journal of Clinical Oncology 38 , 2407 – 2417 . 32463741 10.1200/JCO.19.02630 PMC7367548

Chen R and Snyder M ( 2013 ) Promise of personalized omics to precision medicine . Wiley Interdisciplinary Reviews. Systems Biology and Medicine 5 , 73 – 82 . 23184638 10.1002/wsbm.1198 PMC4154620

Chi SN , Yi JS , Williams PM , Roy-Chowdhuri S , Patton DR , Coffey B , Reid JM , Piao J , Saguilig L , Alonzo TA , Berg SL , Mhlanga J , Fox E , Hawkins DS , Mooney MM , Takebe N , Tricoli JV , Janeway KA , Seibel N and Parsons DW ( 2022 ) Tazemetostat in patients with tumors with alterations in EZH2 or the SWI/SNF complex: Results from NCI-COG pediatric MATCH trial arm C (APEC1621C) . Journal of Clinical Oncology 40 , 10009 – 10009 .

Chrysostomou D , Roberts LA , Marchesi JR and Kinross JM ( 2023 ) Gut microbiota modulation of efficacy and toxicity of cancer chemotherapy and immunotherapy . Gastroenterology 164 , 198 – 213 . 36309208 10.1053/j.gastro.2022.10.018

Citrin DE ( 2017 ) Recent developments in radiotherapy . The New England Journal of Medicine 377 , 1065 – 1075 . 28902591 10.1056/NEJMra1608986

Clark AS , Hong F , Finn RS , DeMichele AM , Mitchell EP , Zwiebel J , Arnaldez FI , Gray RJ , Wang V , McShane LM , Rubinstein LV , Patton D , Williams PM , Hamilton SR , Copur MS , Kasbari SS , Thind R , Conley BA , Arteaga CL , O’Dwyer PJ , Harris LN , Chen AP and Flaherty KT ( 2023 ) Phase II study of palbociclib (PD-0332991) in CCND1, 2, or 3 amplification: Results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocol Z1B . Clinical Cancer Research 29 , OF1 – OF7 . 10.1158/1078-0432.CCR-22-2150 PMC10102836 36853016

Cleary JM , Wang V , Heist RS , Kopetz ES , Mitchell EP , Zwiebel JA , Kapner KS , Chen HX , Li S , Gray RJ , McShane LM , Rubinstein LV , Patton DR , Meric-Bernstam F , Dillmon MS , Williams PM , Hamilton SR , Conley BA , Aguirre AJ , O’Dwyer PJ , Harris LN , Arteaga CL , Chen AP and Flaherty KT ( 2021 ) Differential outcomes in codon 12/13 and codon 61 NRAS-mutated cancers in the phase II NCI-MATCH trial of binimetinib in patients with NRAS-mutated tumors . Clinical Cancer Research 27 , 2996 – 3004 . 33637626 10.1158/1078-0432.CCR-21-0066 PMC8542423

Collins FS and Varmus H ( 2015 ) A new initiative on precision medicine . The New England Journal of Medicine 372 , 793 – 795 . 25635347 10.1056/NEJMp1500523 PMC5101938

Crews KR , Gaedigk A , Dunnenberger HM , Leeder JS , Klein TE , Caudle KE , Haidar CE , Shen DD , Callaghan JT , Sadhasivam S , Prows CA , Kharasch ED , Skaar TC and Clinical Pharmacogenetics Implementation Consortium ( 2014 ) Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update . Clinical Pharmacology and Therapeutics 95 , 376 – 382 . 24458010 10.1038/clpt.2013.254 PMC3975212

Cristofanilli M , Rugo HS , Im S-A , Slamon DJ , Harbeck N , Bondarenko I , Masuda N , Colleoni M , DeMichele A , Loi S , Iwata H , O’Leary B , André F , Loibl S , Bananis E , Liu Y , Huang X , Kim S , Lechuga Frean MJ and Turner NC ( 2022 ) Overall survival with palbociclib and fulvestrant in women with HR+/HER2− ABC: Updated exploratory analyses of PALOMA-3, a double-blind, phase III randomized study . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 28 , 3433 – 3442 . 35552673 10.1158/1078-0432.CCR-22-0305 PMC9662922

Cui Y , Li B , Pollom EL , Horst KC and Li R ( 2018 ) Integrating radiosensitivity and immune gene signatures for predicting benefit of radiotherapy in breast Cancer . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 24 , 4754 – 4762 . 29921729 10.1158/1078-0432.CCR-18-0825 PMC6168425

Custodio AB , González-Larriba JL , Bobokova J , Calles A , Alvarez R , Cuadrado E , Manzano A and Díaz-Rubio E ( 2009 ) Prognostic and predictive markers of benefit from adjuvant chemotherapy in early-stage non-small cell lung Cancer . Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 4 , 891 – 910 . 19433989 10.1097/JTO.0b013e3181a4b8fb

Dagogo-Jack I and Shaw AT ( 2018 ) Tumour heterogeneity and resistance to cancer therapies . Nature Reviews. Clinical Oncology 15 , 81 – 94 . 10.1038/nrclinonc.2017.166 29115304

Dai Y-H , Wang Y-F , Shen P-C , Lo C-H , Yang J-F , Lin C-S , Chao H-L and Huang W-Y ( 2021 ) Radiosensitivity index emerges as a potential biomarker for combined radiotherapy and immunotherapy . NPJ Genomic Medicine 6 , 40 . 34078917 10.1038/s41525-021-00200-0 PMC8172905

Dal Pra A , Ghadjar P , Hayoz S , Liu VYT , Spratt DE , Thompson DJS , Davicioni E , Huang H-C , Zhao X , Liu Y , Schär C , Gut P , Plasswilm L , Hölscher T , Polat B , Hildebrandt G , Müller A-C , Pollack A , Thalmann GN , Zwahlen D and Aebersold DM ( 2022 ) Validation of the decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial . Annals of Oncology: Official Journal of the European Society for Medical Oncology 33 , 950 – 958 . 35636621 10.1016/j.annonc.2022.05.007

Damodaran S , Zhao F , Deming DA , Mitchell EP , Wright JJ , Gray RJ , Wang V , McShane LM , Rubinstein LV , Patton DR , Williams PM , Hamilton SR , Suga JM , Conley BA , Arteaga CL , Harris LN , O’Dwyer PJ , Chen AP and Flaherty KT ( 2022 ) Phase II study of Copanlisib in patients with tumors with PIK3CA mutations: Results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocol Z1F . Journal of Clinical Oncology 40 , 1552 – 1561 . 35133871 10.1200/JCO.21.01648 PMC9084438

de Bono JS and Ashworth A ( 2010 ) Translating cancer research into targeted therapeutics . Nature 467 , 543 – 549 . 20882008 10.1038/nature09339

Dickson D , Johnson J , Bergan R , Owens R , Subbiah V and Kurzrock R ( 2020 ) The master observational trial: A new class of master protocol to advance precision medicine . Cell 180 , 9 – 14 . 31951522 10.1016/j.cell.2019.12.009

Doebele RC , Drilon A , Paz-Ares L , Siena S , Shaw AT , Farago AF , Blakely CM , Seto T , Cho BC , Tosi D , Besse B , Chawla SP , Bazhenova L , Krauss JC , Chae YK , Barve M , Garrido-Laguna I , Liu SV , Conkling P , John T , Fakih M , Sigal D , Loong HH , Buchschacher GL , Garrido P , Nieva J , Steuer C , Overbeck TR , Bowles DW , Fox E , Riehl T , Chow-Maneval E , Simmons B , Cui N , Johnson A , Eng S , Wilson TR , Demetri GD and Trial investigators ( 2020 ) Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials . The Lancet. Oncology 21 , 271 – 282 . 31838007 10.1016/S1470-2045(19)30691-6 PMC7461630

Douillard J-Y , Oliner KS , Siena S , Tabernero J , Burkes R , Barugel M , Humblet Y , Bodoky G , Cunningham D , Jassem J , Rivera F , Kocákova I , Ruff P , Błasińska-Morawiec M , Šmakal M , Canon JL , Rother M , Williams R , Rong A , Wiezorek J , Sidhu R and Patterson SD ( 2013 ) Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal Cancer . New England Journal of Medicine 369 , 1023 – 1034 . 24024839 10.1056/NEJMoa1305275

Drilon A , Siena S , Dziadziuszko R , Barlesi F , Krebs MG , Shaw AT , de Braud F , Rolfo C , Ahn M-J , Wolf J , Seto T , Cho BC , Patel MR , Chiu C-H , John T , Goto K , Karapetis CS , Arkenau H-T , Kim S-W , Ohe Y , Li Y-C , Chae YK , Chung CH , Otterson GA , Murakami H , Lin C-C , Tan DSW , Prenen H , Riehl T , Chow-Maneval E , Simmons B , Cui N , Johnson A , Eng S , Wilson TR , Doebele RC and trial investigators ( 2020 ) Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: Integrated analysis of three phase 1-2 trials . The Lancet. Oncology 21 , 261 – 270 . 31838015 10.1016/S1470-2045(19)30690-4 PMC7811790

Eckstein OS , Allen CE , Williams PM , Roy-Chowdhuri S , Patton DR , Coffey B , Reid JM , Piao J , Saguilig L , Alonzo TA , Berg SL , Ramirez NC , Jaju A , Mhlanga J , Fox E , Hawkins DS , Mooney MM , Takebe N , Tricoli JV , Janeway KA , Seibel NL and Parsons DW ( 2022 ) Phase II study of selumetinib in children and young adults with tumors harboring activating mitogen-activated protein kinase pathway genetic alterations: Arm E of the NCI-COG pediatric MATCH trial . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 40 , 2235 – 2245 . 35363510 10.1200/JCO.21.02840 PMC9273373

Eschrich SA , Pramana J , Zhang H , Zhao H , Boulware D , Lee J-H , Bloom G , Rocha-Lima C , Kelley S , Calvin DP , Yeatman TJ , Begg AC and Torres-Roca JF ( 2009 ) A gene expression model of intrinsic tumor radiosensitivity: Prediction of response and prognosis after chemoradiation . International Journal of Radiation Oncology, Biology, Physics 75 , 489 – 496 . 19735873 10.1016/j.ijrobp.2009.06.014 PMC3038688

Fachal L , Gómez-Caamaño A , Barnett GC , Peleteiro P , Carballo AM , Calvo-Crespo P , Kerns SL , Sánchez-García M , Lobato-Busto R , Dorling L , Elliott RM , Dearnaley DP , Sydes MR , Hall E , Burnet NG , Carracedo Á , Rosenstein BS , West CML , Dunning AM and Vega A ( 2014 ) A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1 . Nature Genetics 46 , 891 – 894 . 24974847 10.1038/ng.3020

Feng FY , Huang H-C , Spratt DE , Zhao SG , Sandler HM , Simko JP , Davicioni E , Nguyen PL , Pollack A , Efstathiou JA , Dicker AP , Todorovic T , Margrave J , Liu YS , Dabbas B , Thompson DJS , Das R , Dignam JJ , Sweeney C , Attard G , Bahary J-P , Lukka HR , Hall WA , Pisansky TM , Shah AB , Pugh SL , Shipley WU and Tran PT ( 2021 ) Validation of a 22-gene genomic classifier in patients with recurrent prostate cancer: An ancillary study of the NRG/RTOG 9601 randomized clinical trial . JAMA Oncology 7 , 544 – 552 . 33570548 10.1001/jamaoncol.2020.7671 PMC7879385

Fernández-Mateos J , Seijas-Tamayo R , Mesía R , Taberna M , Pastor Borgoñón M , Pérez-Ruiz E , Adansa Klain JC , Vázquez Fernández S , Del Barco Morillo E , Lozano A , González Sarmiento R , Cruz-Hernández JJ and Spanish Head and Neck Cancer Cooperative Group (TTCC) ( 2016 ) Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population . Oral Oncology 63 , 38 – 43 . 27938998 10.1016/j.oraloncology.2016.10.006

Flaherty Keith T , Gray RJ , Chen AP , Li S , McShane LM , Patton D , Hamilton SR , Williams PM , Iafrate AJ , Sklar J , Mitchell EP , Harris LN , Takebe N , Sims DJ , Coffey B , Fu T , Routbort M , Zwiebel JA , Rubinstein LV , Little RF , Arteaga CL , Comis R , Abrams JS , O’Dwyer PJ , Conley BA and NCI-MATCH Team ( 2020 ) Molecular landscape and actionable alterations in a Genomically guided Cancer clinical trial: National Cancer Institute molecular analysis for therapy choice (NCI-MATCH) . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 38 , 3883 – 3894 . 33048619 10.1200/JCO.19.03010 PMC7676882

Flaherty Keith T , Gray R , Chen A , Li S , Patton D , Hamilton SR , Williams PM , Mitchell EP , Iafrate AJ , Sklar J , Harris LN , McShane LM , Rubinstein LV , Sims DJ , Routbort M , Coffey B , Fu T , Zwiebel JA , Little RF , Marinucci D , Catalano R , Magnan R , Kibbe W , Weil C , Tricoli JV , Alexander B , Kumar S , Schwartz GK , Meric-Bernstam F , Lih C-J , McCaskill-Stevens W , Caimi P , Takebe N , Datta V , Arteaga CL , Abrams JS , Comis R , O’Dwyer PJ , Conley BA and for the NCI-MATCH Team ( 2020 ) The molecular analysis for therapy choice (NCI-MATCH) trial: Lessons for genomic trial design . JNCI: Journal of the National Cancer Institute 112 , 1021 – 1029 . 31922567 10.1093/jnci/djz245 PMC7566320

Franco NR , Massi MC , Ieva F , Manzoni A , Paganoni AM , Zunino P , Veldeman L , Ost P , Fonteyne V , Talbot CJ , Rattay T , Webb A , Johnson K , Lambrecht M , Haustermans K , De Meerleer G , de Ruysscher D , Vanneste B , Van Limbergen E , Choudhury A , Elliott RM , Sperk E , Veldwijk MR , Herskind C , Avuzzi B , Noris Chiorda B , Valdagni R , Azria D , Farcy-Jacquet MP , Brengues M , Rosenstein BS , Stock RG , Vega A , Aguado-Barrera ME , Sosa-Fajardo P , Dunning AM , Fachal L , Kerns SL , Payne D , Chang-Claude J , Seibold P , West CML , Rancati T and REQUITE Consortium Collaborators ( 2021 ) Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity . Radiotherapy and Oncology 159 , 241 – 248 . 33838170 10.1016/j.radonc.2021.03.024 PMC8754257

Friedman CF , Hainsworth JD , Kurzrock R , Spigel DR , Burris HA , Sweeney CJ , Meric-Bernstam F , Wang Y , Levy J , Grindheim J , Shames DS , Schulze K , Patel A and Swanton C ( 2022 ) Atezolizumab treatment of tumors with high tumor mutational burden from MyPathway, a multicenter, open-label, phase IIa multiple basket study . Cancer Discovery 12 , 654 – 669 . 34876409 10.1158/2159-8290.CD-21-0450 PMC9394388

Gaborit N , Larbouret C , Vallaghe J , Peyrusson F , Bascoul-Mollevi C , Crapez E , Azria D , Chardès T , Poul M-A , Mathis G , Bazin H and Pèlegrin A ( 2011 ) Time-resolved fluorescence resonance energy transfer (TR-FRET) to analyze the disruption of EGFR/HER2 dimers: A new method to evaluate the efficiency of targeted therapy using monoclonal antibodies . The Journal of Biological Chemistry 286 , 11337 – 11345 . 21282108 10.1074/jbc.M111.223503 PMC3064190

Gaedigk A , Ingelman-Sundberg M , Miller NA , Leeder JS , Whirl-Carrillo M and Klein TE ( 2018 ) The Pharmacogene variation (PharmVar) consortium: Incorporation of the human cytochrome P450 (CYP) allele nomenclature database . Clinical Pharmacology and Therapeutics 103 , 399 – 401 . 29134625 10.1002/cpt.910 PMC5836850

Garufi C , Vanni B , Aschelter AM , Zappalà AR , Bria E , Nisticò C , Sperduti I , Cognetti F and Terzoli E ( 2006 ) Randomised phase II study of standard versus Chronomodulated CPT-11 plus Chronomodulated 5-fluorouracil and Folinic acid in advanced colorectal Cancer patients . European Journal of Cancer (Oxford, England: 1990) 42 , 608 – 616 . 16246545 10.1016/j.ejca.2005.03.012

Giacchetti S , Bjarnason G , Garufi C , Genet D , Iacobelli S , Tampellini M , Smaaland R , Focan C , Coudert B , Humblet Y , Canon JL , Adenis A , Lo Re G , Carvalho C , Schueller J , Anciaux N , Lentz M-A , Baron B , Gorlia T , Lévi F and European Organisation for Research and Treatment of Cancer Chronotherapy Group ( 2006 ) Phase III trial comparing 4-Day chronomodulated therapy versus 2-Day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal Cancer: The European Organisation for Research and Treatment of Cancer chronotherapy group . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 24 , 3562 – 3569 . 16877722 10.1200/JCO.2006.06.1440

Goetz MP , Suman VJ , Hoskin TL , Gnant M , Filipits M , Safgren SL , Kuffel M , Jakesz R , Rudas M , Greil R , Dietze O , Lang A , Offner F , Reynolds CA , Weinshilboum RM , Ames MM and Ingle JN ( 2013 ) CYP2D6 metabolism and patient outcome in the Austrian breast and colorectal Cancer study group trial (ABCSG) 8 . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 19 , 500 – 507 . 23213055 10.1158/1078-0432.CCR-12-2153 PMC3548984

Gouda MA and Subbiah V ( 2023 ) Expanding the benefit: Dabrafenib/Trametinib as tissue-agnostic therapy for BRAF V600E–positive adult and pediatric solid tumors . American Society of Clinical Oncology Educational Book 43 , e404770 . 37159870 10.1200/EDBK_404770

Grass GD , Alfonso JCL , Welsh E , Ahmed KA , Teer JK , Pilon-Thomas S , Harrison LB , Cleveland JL , Mulé JJ , Eschrich SA , Enderling H and Torres-Roca JF ( 2022 ) The Radiosensitivity index gene signature identifies distinct tumor immune microenvironment characteristics associated with susceptibility to radiation therapy . International Journal of Radiation Oncology, Biology, Physics 113 , 635 – 647 . 35289298 10.1016/j.ijrobp.2022.03.006 PMC9250625

Graziano F , Ruzzo A , Loupakis F , Canestrari E , Santini D , Catalano V , Bisonni R , Torresi U , Floriani I , Schiavon G , Andreoni F , Maltese P , Rulli E , Humar B , Falcone A , Giustini L , Tonini G , Fontana A , Masi G and Magnani M ( 2008 ) Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 26 , 1427 – 1434 . 18349392 10.1200/JCO.2007.12.4602

Greaves M and Maley CC ( 2012 ) Clonal evolution in cancer . Nature 481 , 306 – 313 . 22258609 10.1038/nature10762 PMC3367003

Guan L , Nambiar DK , Cao H , Viswanathan V , Kwok S , Hui AB , Hou Y , Hildebrand R , von Eyben R , Holmes BJ , Zhao J , Kong CS , Wamsley N , Zhang W , Major MB , Seol SW , Sunwoo JB , Hayes DN , Diehn M and Le Q-T ( 2023 ) NFE2L2 mutations enhance radioresistance in head and neck cancer by modulating intratumoral myeloid cells . Cancer Research 83 , 861 – 874 . 36652552 10.1158/0008-5472.CAN-22-1903 PMC10023320

Hanker AB , Garrett JT , Estrada MV , Moore PD , Ericsson PG , Koch JP , Langley E , Singh S , Kim PS , Frampton GM , Sanford E , Owens P , Becker J , Groseclose MR , Castellino S , Joensuu H , Huober J , Brase JC , Majjaj S , Brohée S , Venet D , Brown D , Baselga J , Piccart M , Sotiriou C and Arteaga CL ( 2017 ) HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of resistance to dual therapeutic blockade of HER2 . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 23 , 4323 – 4334 . 28381415 10.1158/1078-0432.CCR-16-2287 PMC5540793

Henricks LM , Lunenburg CATC , de Man FM , Meulendijks D , Frederix GWJ , Kienhuis E , Creemers G-J , Baars A , Dezentjé VO , Imholz ALT , Jeurissen FJF , Portielje JEA , Jansen RLH , Hamberg P , Ten Tije AJ , Droogendijk HJ , Koopman M , Nieboer P , van de Poel MHW , Mandigers CMPW , Rosing H , Beijnen JH , Werkhoven E van , van Kuilenburg ABP , van Schaik RHN , Mathijssen RHJ , Swen JJ , Gelderblom H , Cats A , Guchelaar H-J and Schellens JHM ( 2018 ) DPYD genotype-guided dose individualisation of Fluoropyrimidine therapy in patients with Cancer: A prospective safety analysis . The Lancet. Oncology 19 , 1459 – 1467 . 30348537 10.1016/S1470-2045(18)30686-7

Ho AY , Atencio DP , Peters S , Stock RG , Formenti SC , Cesaretti JA , Green S , Haffty B , Drumea K , Leitzin L , Kuten A , Azria D , Ozsahin M , Overgaard J , Andreassen CN , Trop CS , Park J and Rosenstein BS ( 2006 ) Genetic predictors of adverse radiotherapy effects: The gene-PARE project . International Journal of Radiation Oncology, Biology, Physics 65 , 646 – 655 . 16751059 10.1016/j.ijrobp.2006.03.006

Hoes LR , van Berge Henegouwen JM , van der Wijngaart H , Zeverijn LJ , van der Velden DL , van de Haar J , Roepman P , de Leng WJ , Jansen AML , van Werkhoven E , van der Noort V , Huitema ADR , Gort EH , de Groot JWB , Kerver ED , de Groot DJ , Erdkamp F , Beerepoot LV , Hendriks MP , Smit EF , van der Graaf WTA , van Herpen CML , Labots M , Hoeben A , Morreau H , Lolkema MP , Cuppen E , Gelderblom H , Verheul HMW and Voest EE ( 2022 ) Patients with rare cancers in the drug rediscovery protocol (DRUP) benefit from genomics-guided treatment . Clinical Cancer Research 28 , 1402 – 1411 . 35046062 10.1158/1078-0432.CCR-21-3752 PMC9365364

Horak P , Heining C , Kreutzfeldt S , Hutter B , Mock A , Hüllein J , Fröhlich M , Uhrig S , Jahn A , Rump A , Gieldon L , Möhrmann L , Hanf D , Teleanu V , Heilig CE , Lipka DB , Allgäuer M , Ruhnke L , Laßmann A , Endris V , Neumann O , Penzel R , Beck K , Richter D , Winter U , Wolf S , Pfütze K , Geörg C , Meißburger B , Buchhalter I , Augustin M , Aulitzky WE , Hohenberger P , Kroiss M , Schirmacher P , Schlenk RF , Keilholz U , Klauschen F , Folprecht G , Bauer S , Siveke JT , Brandts CH , Kindler T , Boerries M , Illert AL , von Bubnoff N , Jost PJ , Spiekermann K , Bitzer M , Schulze-Osthoff K , von Kalle C , Klink B , Brors B , Stenzinger A , Schröck E , Hübschmann D , Weichert W , Glimm H and Fröhling S ( 2021 ) Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions in patients with rare cancers . Cancer Discovery 11 , 2780 – 2795 . 34112699 10.1158/2159-8290.CD-21-0126

Horak P , Klink B , Heining C , Gröschel S , Hutter B , Fröhlich M , Uhrig S , Hübschmann D , Schlesner M , Eils R , Richter D , Pfütze K , Geörg C , Meißburger B , Wolf S , Schulz A , Penzel R , Herpel E , Kirchner M , Lier A , Endris V , Singer S , Schirmacher P , Weichert W , Stenzinger A , Schlenk RF , Schröck E , Brors B , von Kalle C , Glimm H and Fröhling S ( 2017 ) Precision oncology based on omics data: The NCT Heidelberg experience . International Journal of Cancer 141 , 877 – 886 . 28597939 10.1002/ijc.30828

Hou K , Wu ZX , Chen XY , Wang JQ , Zhang D , Xiao C , Zhu D , Koya JB , Wei L , Li J and Chen ZS ( 2022 ) Microbiota in health and diseases . Signal Transduction and Targeted Therapy 7 , 1 – 28 . 35461318 10.1038/s41392-022-00974-4 PMC9034083

Huang R-X and Zhou P-K ( 2020 ) DNA damage response signaling pathways and targets for radiotherapy sensitization in Cancer . Signal Transduction and Targeted Therapy 5 , 60 . 32355263 10.1038/s41392-020-0150-x PMC7192953

Hutchinson M-KND , Mierzwa M and D’Silva NJ ( 2020 ) Radiation resistance in head and neck squamous cell carcinoma: Dire need for an appropriate sensitizer . Oncogene 39 , 3638 – 3649 . 32157215 10.1038/s41388-020-1250-3 PMC7190570

IARC Monographs Vol 124 group ( 2019 ) Carcinogenicity of night shift work . The Lancet. Oncology 20 , 1058 – 1059 . 31281097 10.1016/S1470-2045(19)30455-3

Ingelman-Sundberg M ( 2004 ) Pharmacogenetics of cytochrome P450 and its applications in drug therapy: The past, present and future . Trends in Pharmacological Sciences 25 , 193 – 200 . 15063083 10.1016/j.tips.2004.02.007

Innocenti F , Undevia SD , Iyer L , Chen PX , Das S , Kocherginsky M , Karrison T , Janisch L , Ramírez J , Rudin CM , Vokes EE and Ratain MJ ( 2004 ) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 22 , 1382 – 1388 . 15007088 10.1200/JCO.2004.07.173

Iwakawa M , Imai T , Harada Y , Ban S , Michikawa Y , Saegusa K , Sagara M , Tsuji A , Noda S and Ishikawa A ( 2002 ) ( RadGenomics project ). Nihon Igaku Hoshasen Gakkai Zasshi. Nippon Acta Radiologica 62 , 484 – 489 . 12235865

Iyer L , Das S , Janisch L , Wen M , Ramírez J , Karrison T , Fleming GF , Vokes EE , Schilsky RL and Ratain MJ ( 2002 ) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity . The Pharmacogenomics Journal 2 , 43 – 47 . 11990381 10.1038/sj.tpj.6500072

Jameel JKA , Rao VSR , Cawkwell L and Drew PJ ( 2004 ) Radioresistance in carcinoma of the breast . Breast (Edinburgh, Scotland) 13 , 452 – 460 . 15563851 10.1016/j.breast.2004.08.004

Jameson JL and Longo DL ( 2015 ) Precision medicine — Personalized, problematic, and promising . New England Journal of Medicine 372 , 2229 – 2234 . 26014593 10.1056/NEJMsb1503104

Jee J , Lebow ES , Yeh R , Das JP , Namakydoust A , Paik PK , Chaft JE , Jayakumaran G , Rose Brannon A , Benayed R , Zehir A , Donoghue M , Schultz N , Chakravarty D , Kundra R , Madupuri R , Murciano-Goroff YR , Tu HY , Xu CR , Martinez A , Wilhelm C , Galle J , Daly B , Yu HA , Offin M , Hellmann MD , Lito P , Arbour KC , Zauderer MG , Kris MG , Ng KK , Eng J , Preeshagul I , Victoria Lai W , Fiore JJ , Iqbal A , Molena D , Rocco G , Park BJ , Lim LP , Li M , Tong-Li C , De Silva M , Chan DL , Diakos CI , Itchins M , Clarke S , Pavlakis N , Lee A , Rekhtman N , Chang J , Travis WD , Riely GJ , Solit DB , Gonen M , Rusch VW , Rimner A , Gomez D , Drilon A , Scher HI , Shah SP , Berger MF , Arcila ME , Ladanyi M , Levine RL , Shen R , Razavi P , Reis-Filho JS , Jones DR , Rudin CM , Isbell JM , Li BT ( 2022 ) Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer . Nature Medicine 28 , 2353 – 2363 . 10.1038/s41591-022-02047-z PMC10338177 36357680

Johnson DB , Zhao F , Noel M , Riely GJ , Mitchell EP , Wright JJ , Chen HX , Gray RJ , Li S , McShane LM , Rubinstein LV , Patton D , Williams PM , Hamilton SR , Conley BA , Arteaga CL , Harris LN , O’Dwyer PJ , Chen AP and Flaherty KT ( 2020 ) Trametinib activity in patients with solid tumors and lymphomas harboring BRAF non-V600 mutations or fusions: Results from NCI-MATCH (EAY131) . Clinical Cancer Research 26 , 1812 – 1819 . 31924734 10.1158/1078-0432.CCR-19-3443 PMC7165046

Kalinsky K , Hong F , McCourt CK , Sachdev JC , Mitchell EP , Zwiebel JA , Doyle LA , McShane LM , Li S , Gray RJ , Rubinstein LV , Patton D , Williams PM , Hamilton SR , Conley BA , O’Dwyer PJ , Harris LN , Arteaga CL , Chen AP and Flaherty KT ( 2021 ) Effect of Capivasertib in patients with an AKT1 E17K-mutated tumor: NCI-MATCH subprotocol EAY131-Y nonrandomized trial . JAMA Oncology 7 , 271 – 278 . 33377972 10.1001/jamaoncol.2020.6741 PMC7774047

Karczewski KJ , Francioli LC , Tiao G , Cummings BB , Alföldi J , Wang Q , Collins RL , Laricchia KM , Ganna A , Birnbaum DP , Gauthier LD , Brand H , Solomonson M , Watts NA , Rhodes D , Singer-Berk M , England EM , Seaby EG , Kosmicki JA , Walters RK , Tashman K , Farjoun Y , Banks E , Poterba T , Wang A , Seed C , Whiffin N , Chong JX , Samocha KE , Pierce-Hoffman E , Zappala Z , O’Donnell-Luria AH , Minikel EV , Weisburd B , Lek M , Ware JS , Vittal C , Armean IM , Bergelson L , Cibulskis K , Connolly KM , Covarrubias M , Donnelly S , Ferriera S , Gabriel S , Gentry J , Gupta N , Jeandet T , Kaplan D , Llanwarne C , Munshi R , Novod S , Petrillo N , Roazen D , Ruano-Rubio V , Saltzman A , Schleicher M , Soto J , Tibbetts K , Tolonen C , Wade G , Talkowski ME , Neale BM , Daly MJ and MacArthur DG ( 2020 ) The mutational constraint Spectrum quantified from variation in 141,456 humans . Nature 581 , 434 – 443 . 32461654 10.1038/s41586-020-2308-7 PMC7334197

Khoury JD , Wang W-L , Prieto VG , Medeiros LJ , Kalhor N , Hameed M , Broaddus R and Hamilton SR ( 2018 ) Validation of immunohistochemical assays for integral biomarkers in the NCI-MATCH EAY131 clinical trial . Clinical Cancer Research 24 , 521 – 531 . 28839110 10.1158/1078-0432.CCR-17-1597 PMC5796858

Kim ES , Herbst RS , Wistuba II , Lee JJ , Blumenschein GR , Tsao A , Stewart DJ , Hicks ME , Erasmus J , Gupta S , Alden CM , Liu S , Tang X , Khuri FR , Tran HT , Johnson BE , Heymach JV , Mao L , Fossella F , Kies MS , Papadimitrakopoulou V , Davis SE , Lippman SM and Hong WK ( 2011 ) The BATTLE trial: Personalizing therapy for lung Cancer . Cancer Discovery 1 , 44 – 53 . 22586319 10.1158/2159-8274.CD-10-0010 PMC4211116

Kim SI , Kang JW , Noh JK , Jung HR , Lee YC , Lee JW , Kong M and Eun Y-G ( 2020 ) Gene signature for prediction of radiosensitivity in human papillomavirus-negative head and neck squamous cell carcinoma . Radiation Oncology Journal 38 , 99 – 108 . 33012153 10.3857/roj.2020.00136 PMC7533413

Klinghammer K , Knödler M , Schmittel A , Budach V , Keilholz U and Tinhofer I ( 2010 ) Association of epidermal growth factor receptor polymorphism, skin toxicity, and outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 16 , 304 – 310 . 20028750 10.1158/1078-0432.CCR-09-1928

Krivak TC , Darcy KM , Tian C , Armstrong D , Baysal BE , Gallion H , Ambrosone CB , DeLoia JA and Gynecologic Oncology Group Phase III Trial ( 2008 ) Relationship between ERCC1 polymorphisms, disease progression, and survival in the gynecologic oncology group phase III trial of intraperitoneal versus intravenous cisplatin and paclitaxel for stage III epithelial ovarian Cancer . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 26 , 3598 – 3606 . 18640939 10.1200/JCO.2008.16.1323 PMC4464668

Krop IE , Jegede OA , Grilley-Olson JE , Lauring JD , Mitchell EP , Zwiebel JA , Gray RJ , Wang V , McShane LM , Rubinstein LV , Patton D , Williams PM , Hamilton SR , Kono SA , Ford JM , Garcia AA , Sui XD , Siegel RD , Slomovitz BM , Conley BA , Arteaga CL , Harris LN , O’Dwyer PJ , Chen AP and Flaherty KT ( 2022 ) Phase II study of Taselisib in PIK3CA-mutated solid tumors other than breast and squamous lung Cancer: Results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocol I . JCO Precision Oncology 6 , e2100424 . 35138919 10.1200/PO.21.00424 PMC8865530

Labrie M , Brugge JS , Mills GB and Zervantonakis IK ( 2022 ) Therapy resistance: Opportunities created by adaptive responses to targeted therapies in cancer . Nature Reviews. Cancer 22 , 323 – 339 . 35264777 10.1038/s41568-022-00454-5 PMC9149051

Lauschke VM , Milani L and Ingelman-Sundberg M ( 2017 ) Pharmacogenomic biomarkers for improved drug therapy—Recent Progress and future developments . The AAPS Journal 20 , 4 . 29181807 10.1208/s12248-017-0161-x

Le Tourneau C , Delord JP , Delord J-P , Gonçalves A , Gavoille C , Dubot C , Isambert N , Campone M , Tredan O , Trédan O vier , Massiani MA , Mauborgne C , Armanet S , Servant N , Bièche I , Bernard V , Gentien D , Jézéquel P , Pascal Jézéquel , Valéry Attignon , Attignon V , Boyault S , Boyault S , Vincent-Salomon A , Servois V , Sablin M-P , Sablin MP , Kamal M and Paoletti X ( 2015 ) Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced Cancer (SHIVA): A multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial . Lancet Oncology 16 , 1324 – 1334 . 26342236 10.1016/S1470-2045(15)00188-6

Lee Y ( 2021 ) Roles of circadian clocks in Cancer pathogenesis and treatment . Experimental & Molecular Medicine 53 , 1529 – 1538 . 34615982 10.1038/s12276-021-00681-0 PMC8568965

Leichsenring J , Horak P , Kreutzfeldt S , Heining C , Christopoulos P , Volckmar A-L , Neumann O , Kirchner M , Ploeger C , Budczies J , Heilig CE , Hutter B , Fröhlich M , Uhrig S , Kazdal D , Allgäuer M , Harms A , Rempel E , Lehmann U , Thomas M , Pfarr N , Azoitei N , Bonzheim I , Marienfeld R , Möller P , Werner M , Fend F , Boerries M , von Bubnoff N , Lassmann S , Longerich T , Bitzer M , Seufferlein T , Malek N , Weichert W , Schirmacher P , Penzel R , Endris V , Brors B , Klauschen F , Glimm H , Fröhling S and Stenzinger A ( 2019 ) Variant classification in precision oncology . International Journal of Cancer 145 , 2996 – 3010 . 31008532 10.1002/ijc.32358

Lévi F , Zidani R and Misset JL ( 1997 ) Randomised multicentre trial of chronotherapy with Oxaliplatin, fluorouracil, and Folinic acid in metastatic colorectal Cancer. International Organization for Cancer Chronotherapy . Lancet (London, England) 350 , 681 – 686 . 9291901 10.1016/s0140-6736(97)03358-8

Li Y , Zhang Y , Wei K , He J , Ding N , Hua J , Zhou T , Niu F , Zhou G , Shi T , Zhang L and Liu Y ( 2021 ) Review: Effect of Gut microbiota and its metabolite SCFAs on radiation-induced intestinal injury . Frontiers in Cellular and Infection Microbiology 11 : 577236 . 34307184 10.3389/fcimb.2021.577236 PMC8300561

Lih C-J , Harrington RD , Sims DJ , Harper KN , Bouk CH , Datta V , Yau J , Singh RR , Routbort MJ , Luthra R , Patel KP , Mantha GS , Krishnamurthy S , Ronski K , Walther Z , Finberg KE , Canosa S , Robinson H , Raymond A , Le LP , McShane LM , Polley EC , Conley BA , Doroshow JH , Iafrate AJ , Sklar JL , Hamilton SR and Williams PM ( 2017 ) Analytical validation of the next-generation sequencing assay for a Nationwide signal-finding clinical trial: Molecular analysis for therapy choice clinical trial . The Journal of Molecular Diagnostics 19 , 313 – 327 . 28188106 10.1016/j.jmoldx.2016.10.007 PMC5397672

Lim H-S , Ju Lee H , Seok Lee K , Sook Lee E , Jang I-J and Ro J ( 2007 ) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast Cancer . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 25 , 3837 – 3845 . 17761971 10.1200/JCO.2007.11.4850

Mangat PK , Halabi S , Bruinooge SS , Garrett-Mayer E , Alva A , Janeway KA , Stella PJ , Voest E , Yost KJ , Perlmutter J , Pinto N , Kim ES and Schilsky RL ( 2018 ) Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) study . JCO Precision Oncology 2018 , 1 – 14 . 10.1200/PO.18.00122 . PMC6312096 30603737

Mansfield AS , Wei Z , Mehra R , Shaw AT , Lieu CH , Forde PM , Drilon AE , Mitchell EP , Wright JJ , Takebe N , Sharon E , Hovelson D , Tomlins S , Zeng J , Poorman K , Malik N , Gray RJ , Li S , McShane LM , Rubinstein LV , Patton D , Williams PM , Hamilton SR , Conley BA , Arteaga CL , Harris LN , O’Dwyer PJ , Chen AP and Flaherty KT ( 2022 ) Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial NPJ Precision Oncology 6 , 1 – 6 . 35233056 10.1038/s41698-022-00256-w PMC8888601

Marcuello E , Altés A , Menoyo A , Del Rio E , Gómez-Pardo M and Baiget M ( 2004 ) UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal Cancer . British Journal of Cancer 91 , 678 – 682 . 15280927 10.1038/sj.bjc.6602042 PMC2364770

Massard C , Michiels S , Ferté C , Le Deley M-C , Lacroix L , Hollebecque A , Verlingue L , Ileana E , Rosellini S , Ammari S , Ngo-Camus M , Bahleda R , Gazzah A , Varga A , Postel-Vinay S , Loriot Y , Even C , Breuskin I , Auger N , Job B , De Baere T , Deschamps F , Vielh P , Scoazec J-Y , Lazar V , Richon C , Ribrag V , Deutsch E , Angevin E , Vassal G , Eggermont A , André F and Soria J-C ( 2017 ) High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: Results of the MOSCATO 01 trial . Cancer Discovery 7 , 586 – 595 . 28365644 10.1158/2159-8290.CD-16-1396

Massarelli E , Varella-Garcia M , Tang X , Xavier AC , Ozburn NC , Liu DD , Bekele BN , Herbst RS and Wistuba II ( 2007 ) KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung Cancer . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 13 , 2890 – 2896 . 17504988 10.1158/1078-0432.CCR-06-3043

Matson V , Fessler J , Bao R , Chongsuwat T , Zha Y , Alegre ML , Luke JJ and Gajewski TF ( 2018 ) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients . Science (New York, N.Y.) 359 , 104 – 108 . 29302014 10.1126/science.aao3290 PMC6707353

Mazieres J , Drilon A , Lusque A , Mhanna L , Cortot AB , Mezquita L , Thai AA , Mascaux C , Couraud S , Veillon R , Van den Heuvel M , Neal J , Peled N , Früh M , Ng TL , Gounant V , Popat S , Diebold J , Sabari J , Zhu VW , Rothschild SI , Bironzo P , Martinez-Marti A , Curioni-Fontecedro A , Rosell R , Lattuca-Truc M , Wiesweg M , Besse B , Solomon B , Barlesi F , Schouten RD , Wakelee H , Camidge DR , Zalcman G , Novello S , Ou SI , Milia J and Gautschi O ( 2019 ) Immune checkpoint inhibitors for patients with advanced lung Cancer and oncogenic driver alterations: Results from the IMMUNOTARGET registry . Annals of Oncology 30 , 1321 – 1328 . 31125062 10.1093/annonc/mdz167 PMC7389252

McGranahan N and Swanton C ( 2017 ) Clonal heterogeneity and tumor evolution: Past, present, and the future . Cell 168 , 613 – 628 . 28187284 10.1016/j.cell.2017.01.018

Mirnezami R , Nicholson J and Darzi A ( 2012 ) Preparing for precision medicine . New England Journal of Medicine 366 , 489 – 491 . 22256780 10.1056/NEJMp1114866

Mistry HB ( 2023 ) Radiosensitivity index is not fit to be used for dose adjustments: A pan-cancer analysis . Clinical Oncology (Royal College of Radiologists (Great Britain)) 35 , 565 – 570 . 36922240 10.1016/j.clon.2023.02.018

Mosele F , Stefanovska B , Lusque A , Tran Dien A , Garberis I , Droin N , Le Tourneau C , Sablin M-P , Lacroix L , Enrico D , Miran I , Jovelet C , Bièche I , Soria J-C , Bertucci F , Bonnefoi H , Campone M , Dalenc F , Bachelot T , Jacquet A , Jimenez M and André F ( 2020 ) Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer . Annals of Oncology: Official Journal of the European Society for Medical Oncology 31 , 377 – 386 . 32067679 10.1016/j.annonc.2019.11.006

Munro AJ , Lain S and Lane DP ( 2005 ) P53 abnormalities and outcomes in colorectal cancer: A systematic review . British Journal of Cancer 92 , 434 – 444 . 15668707 10.1038/sj.bjc.6602358 PMC2362083

Nath A and Bild AH ( 2021 ) Leveraging single-cell approaches in cancer precision medicine . Trends in Cancer 7 , 359 – 372 . 33563578 10.1016/j.trecan.2021.01.007 PMC7969443

Nicholson BD , Oke J , Virdee PS , Harris DA , O’Doherty C , Park JE , Hamady Z , Sehgal V , Millar A , Medley L , Tonner S , Vargova M , Engonidou L , Riahi K , Luan Y , Hiom S , Kumar H , Nandani H , Kurtzman KN , Yu LM , Freestone C , Pearson S , Hobbs FR , Perera R and Middleton MR ( 2023 ) Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): A large-scale, observational cohort study . The Lancet Oncology 24 , 733 – 743 . 37352875 10.1016/S1470-2045(23)00277-2

Ning B , Liu Y , Wang M , Li Y , Xu T and Wei Y ( 2022 ) The predictive value of tumor mutation burden on clinical efficacy of immune checkpoint inhibitors in melanoma: A systematic review and meta-analysis . Frontiers in Pharmacology 13 , 748674 . 35355708 10.3389/fphar.2022.748674 PMC8959431

O’Malley DM , Bariani GM , Cassier PA , Marabelle A , Hansen AR , De Jesus Acosta A , Miller WH , Safra T , Italiano A , Mileshkin L , Xu L , Jin F , Norwood K and Maio M ( 2022 ) Pembrolizumab in patients with microsatellite instability–high advanced endometrial cancer: Results from the KEYNOTE-158 study . Journal of Clinical Oncology 40 , 752 – 761 . 34990208 10.1200/JCO.21.01874 PMC8887941

Offer SM , Fossum CC , Wegner NJ , Stuflesser AJ , Butterfield GL and Diasio RB ( 2014 ) Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity . Cancer Research 74 , 2545 – 2554 . 24648345 10.1158/0008-5472.CAN-13-2482 PMC4012613

Oike Tae , Sekiguchi Y , Yoshimoto Y , Oike Takahiro , Ando K , Gu W , Sasaki Y , Tokino T , Iwase A and Ohno T ( 2021 ) Mutation analysis of radioresistant early-stage cervical cancer . International Journal of Molecular Sciences 23 , 51 . 35008475 10.3390/ijms23010051 PMC8744703

Park DJ , Stoehlmacher J , Zhang W , Tsao-Wei DD , Groshen S and Lenz HJ ( 2001 ) A Xeroderma Pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal Cancer . Cancer Research 61 , 8654 – 8658 . 11751380

Parker G , Hunter S , Ghazi S , Hayeems RZ , Rousseau F and Miller FA ( 2023 ) Decision impact studies, evidence of clinical utility for genomic assays in Cancer: A scoping review . PLoS One 18 , e0280582 . 36897859 10.1371/journal.pone.0280582 PMC10004522

Parsons DW , Janeway KA , Patton DR , Winter CL , Coffey B , Williams PM , Roy-Chowdhuri S , Tsongalis GJ , Routbort M , Ramirez NC , Saguilig L , Piao J , Alonzo TA , Berg SL , Fox E , Hawkins DS , Abrams JS , Mooney M , Takebe N , Tricoli JV , Seibel NL and Team the N-CPM ( 2022 ) Actionable tumor alterations and treatment protocol enrollment of pediatric and young adult patients with refractory cancers in the National Cancer Institute–Children’s oncology group pediatric MATCH trial . Journal of Clinical Oncology . 10.1200/JCO.21.02838 PMC9273376 35353553

Pennington KP , Walsh T , Harrell MI , Lee MK , Pennil CC , Rendi MH , Thornton A , Norquist BM , Casadei S , Nord AS , Agnew KJ , Pritchard CC , Scroggins S , Garcia RL , King M-C and Swisher EM ( 2014 ) Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 20 , 764 – 775 . 24240112 10.1158/1078-0432.CCR-13-2287 PMC3944197

Perrone F , Bossi P , Cortelazzi B , Locati L , Quattrone P , Pierotti MA , Pilotti S and Licitra L ( 2010 ) TP53 mutations and pathologic complete response to neoadjuvant cisplatin and fluorouracil chemotherapy in resected Oral cavity squamous cell carcinoma . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 28 , 761 – 766 . 20048189 10.1200/JCO.2009.22.4170

Piasecka D , Braun M , Kitowska K , Mieczkowski K , Kordek R , Sadej R and Romanska H ( 2019 ) FGFs/FGFRs-dependent signalling in regulation of steroid hormone receptors – Implications for therapy of luminal breast cancer . Journal of Experimental & Clinical Cancer Research: CR 38 , 230 . 31142340 10.1186/s13046-019-1236-6 PMC6542018

Prasad V , Fojo T and Brada M ( 2016 ) Precision oncology: Origins, optimism, and potential . The Lancet. Oncology 17 , e81 – e86 . 26868357 10.1016/S1470-2045(15)00620-8

Price JM , Prabhakaran A and West CML ( 2023 ) Predicting tumour radiosensitivity to deliver precision radiotherapy . Nature Reviews. Clinical Oncology 20 , 83 – 98 . 10.1038/s41571-022-00709-y 36477705

Qian DC , Kleber T , Brammer B , Xu KM , Switchenko JM , Janopaul-Naylor JR , Zhong J , Yushak ML , Harvey RD , Paulos CM , Lawson DH , Khan MK , Kudchadkar RR and Buchwald ZS ( 2021 ) Effect of immunotherapy time-of-Day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): A propensity score-matched analysis of a single-Centre, longitudinal study . The Lancet. Oncology 22 , 1777 – 1786 . 34780711 10.1016/S1470-2045(21)00546-5

Qvortrup C , Jensen BV , Fokstuen T , Nielsen SE , Keldsen N , Glimelius B , Bjerregaard B , Mejer J , Larsen FO and Pfeiffer P ( 2010 ) A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer . Annals of Oncology: Official Journal of the European Society for Medical Oncology 21 , 87 – 91 . 19622596 10.1093/annonc/mdp272

Ramón Y , Cajal S , Sesé M , Capdevila C , Aasen T , De Mattos-Arruda L , Diaz-Cano SJ , Hernández-Losa J and Castellví J ( 2020 ) Clinical implications of Intratumor heterogeneity: Challenges and opportunities . Journal of Molecular Medicine (Berlin, Germany) 98 , 161 – 177 . 31970428 10.1007/s00109-020-01874-2 PMC7007907

Rebbeck TR , Burns-White K , Chan AT , Emmons K , Freedman M , Hunter DJ , Kraft P , Laden F , Mucci L , Parmigiani G , Schrag D , Syngal S , Tamimi RM , Viswanath K , Yurgelun MB and Garber JE ( 2018 ) Precision prevention and early detection of cancer: Fundamental principles . Cancer Discovery 8 , 803 – 811 . 29907587 10.1158/2159-8290.CD-17-1415

Redman MW , Papadimitrakopoulou VA , Minichiello K , Hirsch FR , Mack PC , Schwartz LH , Vokes E , Ramalingam S , Leighl N , Bradley J , Miao J , Moon J , Highleyman L , Miwa C , LeBlanc ML , Malik S , Miller VA , Sigal EV , Adam S , Wholley D , Sigman C , Smolich B , Blanke CD , Kelly K , Gandara DR and Herbst RS ( 2020 ) Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (lung-MAP SWOG S1400): A biomarker-driven master protocol . The Lancet. Oncology 21 , 1589 – 1601 . 33125909 10.1016/S1470-2045(20)30475-7 PMC8109255

Reisz JA , Bansal N , Qian J , Zhao W and Furdui CM ( 2014 ) Effects of ionizing radiation on biological molecules—Mechanisms of damage and emerging methods of detection . Antioxidants & Redox Signaling 21 , 260 – 292 . 24382094 10.1089/ars.2013.5489 PMC4060780

Ricciuti B , Wang X , Alessi JV , Rizvi H , Mahadevan NR , Li YY , Polio A , Lindsay J , Umeton R , Sinha R , Vokes NI , Recondo G , Lamberti G , Lawrence M , Vaz VR , Leonardi GC , Plodkowski AJ , Gupta H , Cherniack AD , Tolstorukov MY , Sharma B , Felt KD , Gainor JF , Ravi A , Getz G , Schalper KA , Henick B , Forde P , Anagnostou V , Jänne PA , Van Allen EM , Nishino M , Sholl LM , Christiani DC , Lin X , Rodig SJ , Hellmann MD and Awad MM ( 2022 ) Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels . JAMA Oncology 8 , 1160 – 1168 . 35708671 10.1001/jamaoncol.2022.1981 PMC9204620

Richman SD , Hemmings G , Roberts H , Gallop N , Dodds R , Wilkinson L , Davis J , White R , Yates E , Jasani B , Brown L , Maughan TS , Butler R , Quirke P and Adams R ( 2022 ) FOCUS4 biomarker laboratories: From the benefits to the practical and logistical issues faced during 6 years of centralised testing . Journal of Clinical Pathology 76 , 548 . 35256486 10.1136/jclinpath-2022-208233 PMC7614788

Rothwell DG , Ayub M , Cook N , Thistlethwaite F , Carter L , Dean E , Smith N , Villa S , Dransfield J , Clipson A , White D , Nessa K , Ferdous S , Howell M , Gupta A , Kilerci B , Mohan S , Frese K , Gulati S , Miller C , Jordan A , Eaton H , Hickson N , O’Brien C , Graham D , Kelly C , Aruketty S , Metcalf R , Chiramel J , Tinsley N , Vickers AJ , Kurup R , Frost H , Stevenson J , Southam S , Landers D , Wallace A , Marais R , Hughes AM , Brady G , Dive C and Krebs MG ( 2019 ) Utility of CtDNA to support patient selection for early phase clinical trials: The TARGET study . Nature Medicine 25 , 738 – 743 . 10.1038/s41591-019-0380-z 31011204

Ruben MD , Wu G , Smith DF , Schmidt RE , Francey LJ , Lee YY , Anafi RC and Hogenesch JB ( 2018 ) A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine . Science Translational Medicine 10 , eaat8806 . 30209245 10.1126/scitranslmed.aat8806 PMC8961342

Salama AKS , Li S , Macrae ER , Park J-I , Mitchell EP , Zwiebel JA , Chen HX , Gray RJ , McShane LM , Rubinstein LV , Patton D , Williams PM , Hamilton SR , Armstrong DK , Conley BA , Arteaga CL , Harris LN , O’Dwyer PJ , Chen AP and Flaherty KT ( 2020 ) Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: Results of the NCI-MATCH trial subprotocol H . Journal of Clinical Oncology 38 , 3895 – 3904 . 32758030 10.1200/JCO.20.00762 PMC7676884

Sbaraglia M , Bellan E and Dei Tos AP ( 2021 ) The 2020 WHO classification of soft tissue tumours: News and perspectives . Pathologica 113 , 70 – 84 . 33179614 10.32074/1591-951X-213 PMC8167394

Schack LMH , Naderi E , Fachal L , Dorling L , Luccarini C , Dunning AM , Head and Neck Group of the Radiogenomics Consortium, Danish Head and Neck Cancer Group (DAHANCA) , Ong EHW , Chua MLK , Langendijk JA , Alizadeh BZ , Overgaard J , Eriksen JG , Andreassen CN and Alsner J ( 2022 ) A genome-wide association study of radiotherapy induced toxicity in head and neck Cancer patients identifies a susceptibility locus associated with mucositis . British Journal of Cancer 126 , 1082 – 1090 . 35039627 10.1038/s41416-021-01670-w PMC8980077

Schroth W , Antoniadou L , Fritz P , Schwab M , Muerdter T , Zanger UM , Simon W , Eichelbaum M and Brauch H ( 2007 ) Breast Cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 25 , 5187 – 5193 . 18024866 10.1200/JCO.2007.12.2705

Schwaederle M , Zhao M , Lee JJ , Eggermont AM , Schilsky RL , Mendelsohn J , Lazar V and Kurzrock R ( 2015 ) Impact of precision medicine in diverse cancers: A meta-analysis of phase II clinical trials . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 33 , 3817 – 3825 . 26304871 10.1200/JCO.2015.61.5997 PMC4737863

Scott JG , Berglund A , Schell MJ , Mihaylov I , Fulp WJ , Yue B , Welsh E , Caudell JJ , Ahmed K , Strom TS , Mellon E , Venkat P , Johnstone P , Foekens J , Lee J , Moros E , Dalton WS , Eschrich SA , McLeod H , Harrison LB and Torres-Roca JF ( 2017 ) A genome-based model for adjusting radiotherapy dose (GARD): A retrospective, cohort-based study . The Lancet. Oncology 18 , 202 – 211 . 27993569 10.1016/S1470-2045(16)30648-9 PMC7771305

Scott JG , Sedor Geoff , Scarborough JA , Kattan MW , Peacock J , Grass GD , Mellon EA , Thapa R , Schell M , Waller A , Poppen S , Andl G , Teer JK , Eschrich SA , Dilling TJ , Dalton WS , Harrison LB , Fox T and Torres-Roca JF ( 2021 ) Personalizing radiotherapy prescription dose using genomic markers of Radiosensitivity and Normal tissue toxicity in NSCLC . Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 16 , 428 – 438 . 33301984 10.1016/j.jtho.2020.11.008 PMC8549863

Scott JG , Sedor Geoffrey , Ellsworth P , Scarborough JA , Ahmed KA , Oliver DE , Eschrich SA , Kattan MW and Torres-Roca JF ( 2021 ) Pan-Cancer prediction of radiotherapy benefit using genomic-adjusted radiation dose (GARD): A cohort-based pooled analysis . The Lancet. Oncology 22 , 1221 – 1229 . 34363761 10.1016/S1470-2045(21)00347-8 PMC12818176

Sechidis K , Papangelou K , Metcalfe PD , Svensson D , Weatherall J and Brown G ( 2018 ) Distinguishing prognostic and predictive biomarkers: An information theoretic approach . Bioinformatics 34 , 3365 – 3376 . 29726967 10.1093/bioinformatics/bty357 PMC6157098

Seibold P , Webb A , Aguado-Barrera ME , Azria D , Bourgier C , Brengues M , Briers E , Bultijnck R , Calvo-Crespo P , Carballo A , Choudhury A , Cicchetti A , Claßen J , Delmastro E , Dunning AM , Elliott RM , Fachal L , Farcy-Jacquet M-P , Gabriele P , Garibaldi E , Gómez-Caamaño A , Gutiérrez-Enríquez S , Higginson DS , Johnson K , Lobato-Busto R , Mollà M , Müller A , Payne D , Peleteiro P , Post G , Rancati T , Rattay T , Reyes V , Rosenstein BS , De Ruysscher D , De Santis MC , Schäfer J , Schnabel T , Sperk E , Symonds RP , Stobart H , Taboada-Valladares B , Talbot CJ , Valdagni R , Vega A , Veldeman L , Ward T , Weißenberger C , West CML , Chang-Claude J and REQUITE consortium ( 2019 ) REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate Cancer . Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 138 , 59 – 67 . 31146072 10.1016/j.radonc.2019.04.034

Seligmann JF , Fisher DJ , Brown LC , Adams RA , Graham J , Quirke P , Richman SD , Butler R , Domingo E , Blake A , Yates E , Braun M , Collinson F , Jones R , Brown E , de Winton E , Humphrey TC , Parmar M , Kaplan R , Wilson RH , Seymour M and Maughan TS ( 2021 ) Inhibition of WEE1 is effective in TP53- and RAS-mutant metastatic colorectal Cancer: A randomized trial (FOCUS4-C) comparing Adavosertib (AZD1775) with active monitoring . Journal of Clinical Oncology 39 , 3705 – 3715 . 34538072 10.1200/JCO.21.01435 PMC8601321

Sicklick JK , Kato S , Okamura R , Schwaederle M , Hahn ME , Williams CB , De P , Krie A , Piccioni DE , Miller VA , Ross JS , Benson A , Webster J , Stephens PJ , Lee JJ , Fanta PT , Lippman SM , Leyland-Jones B and Kurzrock R ( 2019 ) Molecular profiling of cancer patients enables personalized combination therapy: The I-PREDICT study . Nature Medicine 25 , 744 – 750 . 10.1038/s41591-019-0407-5 PMC6553618 31011206

Sjöström M , Chang SL , Fishbane N , Davicioni E , Zhao SG , Hartman L , Holmberg E , Feng FY , Speers CW , Pierce LJ , Malmström P , Fernö M and Karlsson P ( 2019 ) Clinicogenomic radiotherapy classifier predicting the need for intensified locoregional treatment after breast-conserving surgery for early-stage breast cancer . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 37 , 3340 – 3349 . 31618132 10.1200/JCO.19.00761 PMC6901281

Sjöström M , Fyles A , Liu F-F , McCready D , Shi W , Rey-McIntyre K , Chang SL , Feng FY , Speers CW , Pierce LJ , Holmberg E , Fernö M , Malmström P and Karlsson P ( 2023 ) Development and validation of a genomic profile for the omission of local adjuvant radiation in breast cancer . Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 41 , 1533 – 1540 . 36599119 10.1200/JCO.22.00655 PMC10022846

Slikker W ( 2018 ) Biomarkers and their impact on precision medicine . Experimental Biology and Medicine (Maywood, N.J.) 243 , 211 – 212 . 10.1177/1535370217733426 PMC5813864 28927290

Spranger S , Bao R and Gajewski TF ( 2015 ) Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity . Nature 523 , 231 – 235 . 25970248 10.1038/nature14404

Spratt DE , Liu VYT , Michalski J , Davicioni E , Berlin A , Simko JM , Efstathiou JA , Tran PT , Sandler HM , Hall WA , Thompson DJ , Parliament MB , Dayes IS , Correa RJM , Robertson JM , Gore EM , Doncals DE , Vigneault E , Souhami L , Karrison TG and Feng FY ( 2023 ) Genomic classifier performance in intermediate-risk prostate cancer: Results from NRG Oncology/RTOG 0126 randomized phase III trial . International Journal of Radiation Oncology, Biology, Physics 117 , 370 . 37137444 10.1016/j.ijrobp.2023.04.010 PMC10949135

Stockley TL , Oza AM , Berman HK , Leighl NB , Knox JJ , Shepherd FA , Chen EX , Krzyzanowska MK , Dhani N , Joshua AM , Tsao M-S , Serra S , Clarke B , Roehrl MH , Zhang T , Sukhai MA , Califaretti N , Trinkaus M , Shaw P , van der Kwast T , Wang L , Virtanen C , Kim RH , Razak ARA , Hansen AR , Yu C , Pugh TJ , Kamel-Reid S , Siu LL and Bedard PL ( 2016 ) Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: The Princess Margaret IMPACT/COMPACT trial . Genome Medicine 8 , 109 . 27782854 10.1186/s13073-016-0364-2 PMC5078968

Stupp R , Mason WP , van den Bent MJ , Weller M , Fisher B , Taphoorn MJB , Belanger K , Brandes AA , Marosi C , Bogdahn U , Curschmann J , Janzer RC , Ludwin SK , Gorlia T , Allgeier A , Lacombe D , Cairncross JG , Eisenhauer E , Mirimanoff RO , European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and National Cancer Institute of Canada Clinical Trials Group ( 2005 ) Radiotherapy plus concomitant and adjuvant Temozolomide for glioblastoma . The New England Journal of Medicine 352 , 987 – 996 . 15758009 10.1056/NEJMoa043330

Subbiah V ( 2023 ) The next generation of evidence-based medicine . Nature Medicine 29 , 49 – 58 . 10.1038/s41591-022-02160-z 36646803

Sun H , Ren P , Chen Y , Lan L , Yan Z , Yang Y , Wang B , Wang C , Li Yanwei , Li L , Zhang Y , Li Yanyang , Wang Z , Pan Z and Jiang Z ( 2023 ) Optimal therapy for concomitant EGFR and TP53 mutated non-small cell lung Cancer: A real-world study . BMC Cancer 23 , 198 . 36864384 10.1186/s12885-023-10637-4 PMC9979422

Suski JM , Braun M , Strmiska V and Sicinski P ( 2021 ) Targeting cell-cycle machinery in Cancer . Cancer Cell 39 , 759 – 778 . 33891890 10.1016/j.ccell.2021.03.010 PMC8206013

Tang Z , Zeng Q , Li Y , Zhang X , Ma J , Suto MJ , Xu B and Yi N ( 2017 ) Development of a radiosensitivity gene signature for patients with soft tissue sarcoma . Oncotarget 8 , 27428 – 27439 . 28404969 10.18632/oncotarget.16194 PMC5432346

Thomas G , Eisenhauer E , Bristow RG , Grau C , Hurkmans C , Ost P , Guckenberger M , Deutsch E , Lacombe D , Weber DC and European Organisation for Research and Treatment of Cancer (EORTC) ( 2020 ) The European Organisation for Research and Treatment of Cancer, state of science in radiation oncology and priorities for clinical trials meeting report . European Journal of Cancer (Oxford, England: 1990) 131 , 76 – 88 . 32305726 10.1016/j.ejca.2020.02.050

Tie J ( 2023 ) Triaging suspected cancer with a multi-Cancer early detection blood test . The Lancet Oncology 24 , 710 – 711 . 37352874 10.1016/S1470-2045(23)00288-7

Tie J , Cohen JD , Lahouel K , Lo SN , Wang Y , Kosmider S , Wong R , Shapiro J , Lee M , Harris S , Khattak A , Burge M , Harris M , Lynam J , Nott L , Day F , Hayes T , McLachlan SA , Lee B , Ptak J , Silliman N , Dobbyn L , Popoli M , Hruban R , Lennon AM , Papadopoulos N , Kinzler KW , Vogelstein B , Tomasetti C , Gibbs P and DYNAMIC Investigators ( 2022 ) Circulating tumor DNA analysis guiding adjuvant therapy in stage II Colon Cancer . The New England Journal of Medicine 386 , 2261 – 2272 . 35657320 10.1056/NEJMoa2200075 PMC9701133

Tivey A , Church M , Rothwell D , Dive C and Cook N ( 2022 ) Circulating tumour DNA - looking beyond the blood . Nature Reviews. Clinical Oncology 19 , 600 – 612 . 10.1038/s41571-022-00660-y PMC9341152 35915225

Tonelli MR and Shirts BH ( 2017 ) Knowledge for precision medicine: Mechanistic reasoning and methodological pluralism . JAMA 318 , 1649 – 1650 . 29052713 10.1001/jama.2017.11914

Topol EJ ( 2014 ) Individualized medicine from Prewomb to tomb . Cell 157 , 241 – 253 . 24679539 10.1016/j.cell.2014.02.012 PMC3995127

Van Cutsem E , Köhne C-H , Hitre E , Zaluski J , Chang Chien C-R , Makhson A , D’Haens G , Pintér T , Lim R , Bodoky G , Roh JK , Folprecht G , Ruff P , Stroh C , Tejpar S , Schlichting M , Nippgen J and Rougier P ( 2009 ) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer . The New England Journal of Medicine 360 , 1408 – 1417 . 19339720 10.1056/NEJMoa0805019

van Tilburg CM , Pfaff E , Pajtler KW , Langenberg KPS , Fiesel P , Jones BC , Balasubramanian GP , Stark S , Johann PD , Blattner-Johnson M , Schramm K , Dikow N , Hirsch S , Sutter C , Grund K , von Stackelberg A , Kulozik AE , Lissat A , Borkhardt A , Meisel R , Reinhardt D , Klusmann J-H , Fleischhack G , Tippelt S , von Schweinitz D , Schmid I , Kramm CM , von Bueren AO , Calaminus G , Vorwerk P , Graf N , Westermann F , Fischer M , Eggert A , Burkhardt B , Wößmann W , Nathrath M , Hecker-Nolting S , Frühwald MC , Schneider DT , Brecht IB , Ketteler P , Fulda S , Koscielniak E , Meister MT , Scheer M , Hettmer S , Schwab M , Tremmel R , Øra I , Hutter C , Gerber NU , Lohi O , Kazanowska B , Kattamis A , Filippidou M , Goemans B , Zwaan CM , Milde T , Jäger N , Wolf S , Reuss D , Sahm F , von Deimling A , Dirksen U , Freitag A , Witt R , Lichter P , Kopp-Schneider A , Jones DTW , Molenaar JJ , Capper D , Pfister SM and Witt O ( 2021 ) The pediatric precision oncology INFORM registry: Clinical outcome and benefit for patients with very high-evidence targets . Cancer Discovery 11 , 2764 – 2779 . 34373263 10.1158/2159-8290.CD-21-0094 PMC9414287

Vo KT , Sabnis AJ , Williams PM , Roy-Chowdhuri S , Patton DR , Coffey B , Reid JM , Piao J , Saguilig L , Alonzo TA , Berg SL , Jaju A , Fox E , Hawkins DS , Mooney MM , Takebe N , Tricoli JV , Janeway KA , Seibel N and Parsons DW ( 2022 ) Ulixertinib in patients with tumors with MAPK pathway alterations: Results from NCI-COG pediatric MATCH trial arm J (APEC1621J) . Journal of Clinical Oncology 40 , 3009 – 3009 .

Wallace BD , Wang H , Lane KT , Scott JE , Orans J , Koo JS , Venkatesh M , Jobin C , Yeh LA , Mani S and Redinbo MR ( 2010 ) Alleviating cancer drug toxicity by inhibiting a bacterial enzyme . Science (New York, N.Y.) 330 , 831 – 835 . 21051639 10.1126/science.1191175 PMC3110694

Wang J , Wang H and Qian H ( 2018 ) Biological effects of radiation on Cancer cells . Military Medical Research 5 , 20 . 29958545 10.1186/s40779-018-0167-4 PMC6026344

Webb AJ , Harper E , Rattay T , Aguado-Barrera ME , Azria D , Bourgier C , Brengues M , Briers E , Bultijnck R , Chang-Claude J , Choudhury A , Cicchetti A , De Ruysscher D , De Santis MC , Dunning AM , Elliott RM , Fachal L , Gómez-Caamaño A , Gutiérrez-Enríquez S , Johnson K , Lobato-Busto R , Kerns SL , Post G , Rancati T , Reyes V , Rosenstein BS , Seibold P , Seoane A , Sosa-Fajardo P , Sperk E , Taboada-Valladares B , Valdagni R , Vega A , Veldeman L , Ward T , West CM , Symonds RP , Talbot CJ and REQUITE Consortium ( 2022 ) Treatment time and circadian genotype interact to influence radiotherapy side-effects. A prospective European validation study using the REQUITE cohort . eBioMedicine 84 , 104269 . 36130474 10.1016/j.ebiom.2022.104269 PMC9486558

Wegman P , Vainikka L , Stål O , Nordenskjöld B , Skoog L , Rutqvist L-E and Wingren S ( 2005 ) Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast Cancer patients . Breast Cancer Research 7 , R284 – R290 . 15987423 10.1186/bcr993 PMC1143572

Weinstein JN , Collisson EA , Mills GB , Shaw KM , Ozenberger BA , Ellrott K , Shmulevich I , Sander C and Stuart JM ( 2013 ) The cancer genome atlas Pan-Cancer analysis project . Nature Genetics 45 , 1113 – 1120 . 24071849 10.1038/ng.2764 PMC3919969

Werbrouck C , Evangelista CCS , Lobón-Iglesias M-J , Barret E , Le Teuff G , Merlevede J , Brusini R , Kergrohen T , Mondini M , Bolle S , Varlet P , Beccaria K , Boddaert N , Puget S , Grill J , Debily M-A and Castel D ( 2019 ) TP53 pathway alterations drive radioresistance in diffuse intrinsic pontine gliomas (DIPG) . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 25 , 6788 – 6800 . 31481512 10.1158/1078-0432.CCR-19-0126

West C , Azria D , Chang-Claude J , Davidson S , Lambin P , Rosenstein B , De Ruysscher D , Talbot C , Thierens H , Valdagni R , Vega A and Yuille M ( 2014 ) The REQUITE project: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in Cancer survivors . Clinical Oncology (Royal College of Radiologists (Great Britain)) 26 , 739 – 742 . 25267305 10.1016/j.clon.2014.09.008

West Catharine , Rosenstein BS , Alsner J , Azria D , Barnett G , Begg A , Bentzen S , Burnet N , Chang-Claude J , Chuang E , Coles C , De Ruyck K , De Ruysscher D , Dunning A , Elliott R , Fachal L , Hall J , Haustermans K , Herskind C , Hoelscher T , Imai T , Iwakawa M , Jones D , Kulich C , EQUAL-ESTRO , Langendijk J-H , O’Neils P , Ozsahin M , Parliament M , Polanski A , Rosenstein B , Seminara D , Symonds P , Talbot C , Thierens H , Vega A , West Catherine and Yarnold J ( 2010 ) Establishment of a Radiogenomics consortium . International Journal of Radiation Oncology, Biology, Physics 76 , 1295 – 1296 . 20338472 10.1016/j.ijrobp.2009.12.017

Wu S , Xu J , Li G and Jin X ( 2022 ) Integrating radiosensitivity gene signature improves glioma outcome and radiotherapy response prediction . Medicina (Kaunas, Lithuania) 58 , 1327 . 36295489 10.3390/medicina58101327 PMC9609360

Xu C , Tang X , Qu Y , Keyoumu S , Zhou N and Tang Y ( 2016 ) UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal Cancer . Cancer Chemotherapy and Pharmacology 78 , 119 – 130 . 27220761 10.1007/s00280-016-3057-z

Ye Y , Xiang Y , Ozguc FM , Kim Y , Liu C-J , Park PK , Hu Q , Diao L , Lou Y , Lin C , Guo A-Y , Zhou B , Wang L , Chen Z , Takahashi JS , Mills GB , Yoo S-H and Han L ( 2018 ) The genomic landscape and Pharmacogenomic interactions of clock genes in Cancer chronotherapy . Cell Systems 6 , 314 – 328 .e2. 29525205 10.1016/j.cels.2018.01.013 PMC6056007

Yi Y , Lu W , Shen L , Wu Y and Zhang Z ( 2023 ) The Gut microbiota as a booster for radiotherapy: Novel insights into radio-protection and radiation injury . Experimental Hematology & Oncology 12 , 48 . 37218007 10.1186/s40164-023-00410-5 PMC10201781

Zhao SG , Chang SL , Spratt DE , Erho N , Yu M , Ashab HA-D , Alshalalfa M , Speers C , Tomlins SA , Davicioni E , Dicker AP , Carroll PR , Cooperberg MR , Freedland SJ , Karnes RJ , Ross AE , Schaeffer EM , Den RB , Nguyen PL and Feng FY ( 2016 ) Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate Cancer: A matched, retrospective analysis . The Lancet. Oncology 17 , 1612 – 1620 . 27743920 10.1016/S1470-2045(16)30491-0

Zhong H and Prentice RL ( 2010 ) Correcting ‘Winner’s curse’ in odds ratios from genomewide association findings for Major complex human diseases . Genetic Epidemiology 34 , 78 – 91 . 19639606 10.1002/gepi.20437 PMC2796696

Zhou W , Gurubhagavatula S , Liu G , Park S , Neuberg DS , Wain JC , Lynch TJ , Su L and Christiani DC ( 2004 ) Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung Cancer patients treated with platinum-based chemotherapy . Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 10 , 4939 – 4943 . 15297394 10.1158/1078-0432.CCR-04-0247

Zhou Y and Lauschke VM ( 2022 ) The genetic landscape of Major drug metabolizing cytochrome P450 genes—An updated analysis of population-scale sequencing data . The Pharmacogenomics Journal 22 , 284 – 293 . 36068297 10.1038/s41397-022-00288-2 PMC9674520

Zhou J , Wang J , Zhang X and Tang Q ( 2021 ) New insights into Cancer chronotherapies . Frontiers in Pharmacology 12 , 741295 . 34966277 10.3389/fphar.2021.741295 PMC8710512