1. Introduction
Breast cancer, the most frequently diagnosed cancer in women globally, accounted for up to 2 million new cases in recent years, making up 25% of all cancer cases in women ( 1 ). The complexity of breast cancer is highlighted by its high degree of heterogeneity, with current classifications based on three molecular markers: The estrogen receptor (ER), the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) ( 2 ). Therapeutic approaches and outcomes differ significantly among the various subtypes of breast cancer. The ER-negative (ER-) group, which includes the HER2-positive (HER2 + ) and triple-negative breast cancer (TNBC) subtypes, is less responsive to neoadjuvant chemotherapy compared with the ER-positive (ER + ) group ( 3 , 4 ).
In the past decades, numerous studies utilizing genome sequencing of breast cancers have revealed increasing numbers, up to thousands, of somatic mutations during the onset and progression of cancer ( 5 ). However, only a minor proportion of these mutations inherently provide a growth advantage to cancer cells, and are referred to as 'driver mutations' ( 6 ). Some of the driver mutations frequently observed in a particular DNA segment are known as 'hotspot mutations' and serve as targets for diagnosis and drug development ( 7 ). Finding a 'neoantigen', a tumor-specific antigen present exclusively in tumors, is needed to elicit an antitumor immune response. So far, most studies of neoantigen-targeted immunotherapies have focused on private neoantigens that are patient-specific. Such studies are time-consuming and costly. Neoantigens found in multiple patients with the same type of cancer, namely shared or public neoantigens, could be utilized in a broader spectrum of patients with cancer and aid corresponding cost savings. In the present review, an overview of neoantigens was provided and the public ones in clinical use were highlighted as immunotherapeutic targets in breast cancer treatment.
2. Breast cancer incidence, classification and management
Globally, breast cancer is the most common cancer in women and the leading cause of cancer death among women ( 1 ). In 2020, the estimated number of new breast cancer cases was 2,261,419, accounting for 12% of all new cancer cases, and the estimated number of deaths was 684,996 individuals, ~7% of all cancer deaths worldwide ( 1 , 8 ). There are several histological subtypes of invasive breast cancer, of which infiltrating ductal carcinoma is the most common, accounting for ~80% of invasive breast cancers, infiltrating lobular carcinoma accounts for 8%, ductal lobular carcinomas make up another 7%, and other less common histologic subtypes comprising medullary, metaplastic, mucinous and papillary carcinomas ( 9 ).
Breast cancer is an extremely heterogeneous disease caused by a diversity of genetic alterations that result in various biological and clinical behaviors within cancers themselves and in differences in disease progression and therapeutic response between patients ( 10 , 11 ). Based on the expression profiles of ER, PR, HER2 and Ki-67, four major molecular subtypes have been classified: Luminal A, luminal B, HER-2-enriched and basal-like. Each subtype has a different prognosis and potential therapeutic target ( 12 , 13 ). The luminal subtype is the most common subtype and is characterized by the expression of ER and other genes associated with resemblance to luminal epithelial cells. Cancer type luminal A is characterized by high ER + , PR + , HER2 - , and low Ki-67 expression and comprises ~40-50% of all breast cancers, while luminal B, which accounts for 20%, is classified by high ER + , low PR, HER2 -/+ and high Ki-67 ( 14 ). Luminal A cancers present as low grade with a favorable prognosis, whereas luminal B cancers tend to be high-grade with poor prognosis ( 15 , 16 ). The HER2-enriched subtype makes up ~15% of all invasive breast cancer and is characterized by upregulation of HER2 expression and no expression of ER-related genes (ER - /PR - /HER2 - ) ( 12 , 17 ). HER2-enriched tumors tend to manifest a high-grade and more aggressive form with decreased disease-free survival and overall survival (OS) rates compared with subtypes that do not overexpress HER2. However, this subtype responds well to monoclonal antibody-targeted HER2 therapy, which may improve survival outcomes ( 18 ). The fourth subtype, the basal-like subtype or TNBC, accounts for 15% of all breast cancer subtypes and has the least favorable prognosis; relapses may occur within five years after diagnosis ( 19 ). TNBC is associated with positive expression of cytokeratin 5, 14, and 17 genes in mammary basal cells and high expression of proliferation-related genes, but no expression of ER, PR and HER2 ( 20 ).
Management of patients with breast cancer is diverse and varies according to each patient's specific condition. The primary aim of treating early-stage breast cancer is to prevent its progression to invasive breast cancer. This involves a range of management strategies, such as surgery, radiation therapy, and, for suitable patients, adjuvant endocrine therapy to minimize the risk of cancer recurrence ( 21 ). Several studies of early-stage breast cancer have demonstrated that incorporating whole breast radiation after surgery reduces the recurrence of breast cancer ( 22 , 23 ). However, this approach does not significantly impact longer-term metastasis-free survival ( 24 ). Several drugs targeting the overexpressed or mutated genes have been used in the treatment of breast cancers ( 25 ). For example, the US Food and Drug Administration (FDA) has approved the use of tamoxifen to reduce the risk of ER + breast cancer recurrence ( 26 ), and buparlisib has been shown to be safe and efficacious in HER2 - , PIK3CA-mutated, advanced, or metastatic breast cancer ( 27 ). However, some targeting drugs did not significantly improve progression-free survival (PFS), and their dosing is limited by toxicity, which potentially limits their efficacy ( 28 ). Immunotherapy is a newer form of treatment that helps the immune system fight cancer. It is now frequently used in certain subtypes of advanced breast cancer ( 29 ). Atezolizumab, a human monoclonal antibody against programmed cell death-ligand 1 (PD-L1), has shown efficacy in enhancing PFS when used in combination with nab-paclitaxel for first-line chemotherapy in patients with metastatic TNBC or in cases of recurrent TNBC that are inoperable ( 30 ). The development and early successes in active immunotherapy techniques have led to therapeutic cancer vaccines. The first cancer vaccine, approved by the FDA in 2010, was for treating metastatic prostate cancer ( 31 ). However, the availability of specific immunotherapies or cancer vaccines for the treatment of breast cancer remains limited.
3. Tumor antigens
Immunotherapy to escalate the host's immune response has become a reputable pillar of cancer treatment, aiming to improve the therapeutic outcome of patients with certain types of hematological and solid tumors ( 32 ). Stimulation is achieved by using tumor antigens directly presentable by cancer cells to the host adaptive immune system ( 33 ). Strategies for targeting tumor antigens include cancer vaccines, which stimulate the immune system to produce an immune response against specific tumor antigens, and adoptive T-cell therapy, which involves modifying T-cells from a patient's blood to recognize specific tumor antigens and then infusing them back into the patient's body to attack the cancer cells ( 34 , 35 ).
Tumor antigens can be processed and presented with the major histocompatibility complex (MHC) on the cell membrane and recognized by receptors on the cell surface of T-cells to elicit an antitumor immune response ( 36 ). The properties of tumor antigens can differ depending on the specific antigen and the type of cancer. Common properties of tumor antigens include: Overexpression-tumor antigens are usually expressed at higher levels in cancer cells than in normal cells, which can make them more detectable by the immune system; mutation-some tumor antigens are mutated versions of normal proteins, which can render cancer cells more distinct from the normal cells and more vulnerable to immune attack; specificity-tumor antigens are specific to certain types of cancer, or even to certain subtypes of cancer which means that therapies targeting these tumor antigens can be less toxic than more broad-spectrum cancer treatments ( 37 ); and heterogeneity-when different cancer cells have unique properties and antigens it becomes more difficult to develop effective immunotherapies that target a broad range of tumor cells ( 38 ).
There are two main types of tumor antigens: Tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). TAAs are self proteins that are highly expressed in cancer cells but typically found at minimal levels in normal cells ( 39 ). TAAs naturally arise through genetic amplification or post-translational modification, leading to the aberrant expression of proteins that are then no longer shielded from the MHC-processing machinery and consequently acquire immunogenic properties ( 40 ). TAA categories are based on the pattern of expression in normal cells, including overexpressed antigens, oncofetal antigens and cancer-testis antigens. The overexpressed antigens are proteins present in higher levels in cancer cells compared with normal tissues due to amplification of their DNA or mRNA and ultimately protein levels. Examples of overexpressed antigens include HER2/neu in breast cancer or ovarian cancer ( 41 ) and mesothelin in brain metastasis tumors ( 42 ). Oncofetal antigens are normal proteins that are expressed at high levels during fetal development and increase in adult cancer, but not in normal adult tissues. Examples of these antigens are MART-1/Melan-A in melanoma ( 43 ) and carcinoembryonic antigen in colorectal cancer ( 44 ). Cancer-testis antigens or tumor germline antigens are proteins that are normally highly expressed only in germ cells of ovaries, testis and placenta but are also expressed in cancer cells. Examples are New York esophageal squamous cell carcinoma 1 ( 45 ) and melanoma antigen gene protein ( 46 ).
Even though TAAs are great potential targets for cancer immunotherapy, there are several difficulties in their use. The heterogeneity of cancer cells can lead to variability in the mutation and expression of TAAs across different tumor types, stages and patients. This heterogeneity can make it difficult to develop a single immunotherapy effective for all patients with a particular type of cancer ( 47 ). TAAs are typically removed from the immune repertoire by central and peripheral tolerance mechanisms, so they are not recognized as foreign by the immune system. This results in an immune tolerance that prevents the immune system from attacking the cancer cells ( 48 ). Thus, a cancer vaccine that uses these antigens may not be potent enough. In addition, some normal tissues may share epitopes with or express low levels of TAAs, which can lead to autoimmune reactions and on-target off-tumor toxicities when targeted by immunotherapy. To mitigate this effect, and to further improve the efficacy and safety of TAA-targeted immunotherapies, several approaches have been taken, including selection of only the highly expressed targeting TAA, adjustment of the affinity and avidity of the chimeric receptor in chimeric antigen receptor T-cells to respond only to cells expressing a high level of TAA ( 49 ), and the use of immune checkpoint inhibitors (ICIs) in combination with the TAA vaccine ( 50 ). Further development of these strategies may strengthen the promise shown by TAAs as targets for cancer immunotherapy.
TSAs are detected as foreign non-self proteins that are presented exclusively on cancer cell surfaces and are particularly potent in eliciting an immune response ( 51 ). TSAs primarily originate from mutations in passenger genes, with only a small fraction originating from mutations in driver genes, and are heterogeneous between, and within, patients. The identifying common passenger gene mutations may generate immunogenic TSAs acting as the shared neoantigens among patients. Moreover, the variability of TSAs within individual patients may impact the efficacy of personalized treatments tailored to target specific antigens while minimizing adverse effects associated with non-specific targeting.
Since TSAs are solely expressed in cancer cells, they are ideal targets for cancer immunotherapy. Numerous TSAs are oncovirus antigens, viral proteins derived from oncogenic cancer viruses that have integrated into the genome in cancer cells and induce cell transformation and tumorigenesis ( 52 ). These include the E6 and E7 proteins from human papillomavirus that elicit strong antigen-specific T-cell responses in cervical cancer and head and neck cancer ( 53 ). Another important group of TSAs comprises neoantigens: A specific type of tumor antigen resulting from genetic and epigenetic aberrations that arise during cancer initiation and progression ( 54 ). Multiple types of mutations can give rise to neoantigens when they occur in protein-coding regions and appear as non-synonymous polymorphisms. Well-defined sources of neoantigens are somatic missense mutations that can generate single nucleotide variants (SNVs) and insertions or deletions (INDELs). These may create new open reading frames by frameshifts, as well as other genomic alterations, including gene fusions ( 55 ). Frameshift mutations may be more immunogenic than missense mutations due to the lack of similarity to normal protein sequences and an increased probability of generating neoantigens ( 56 ). Interestingly, neoantigens derived from gene fusions are now highlighted for immunotherapeutic treatments, especially in cancers that have low tumor mutational burden (TMB) and less immune infiltration ( 57 ).
4. Genetic mutations associated with breast cancer development
Although inherited genetic mutations are associated with a high risk for breast cancer development, <15% of women with breast cancer come from families with a history of breast cancer diagnosis ( 58 ). The majority of breast cancer development in women who do not have a family history of breast cancer may originate from somatic mutations. The important genetic mutations in breast cancer are as follows, and the mechanisms of action are summarized in Fig. 1 .
BRCA1 and BRCA2
In total, ~20% of women with a family history of breast cancer have mutations in breast cancer susceptibility genes 1 or 2 ( BRCA1 or BRCA2 ) ( 59 ). BRCA1 and BRCA2 proteins are tumor suppressors that are crucial for homologous recombinant (HR)-mediated repair of DNA double-strand breaks (DSBs). They protect the integrity of the genome in proliferating cells to prevent tumorigenesis ( 60 ). BRCA1 involvement with DSBs requires recruitment of DNA repair protein RAD51 homolog 1 (RAD51) to the sites of DNA damage through interactions with partner and localizer of BRCA2 (PALB2), a stabilizer of the replication fork, and BRCA2 ( 61 ). The BRCA mutations impair HR-mediated repair of DSBs, raising the risk of developing inherited and sporadic breast cancer ( 62 , 63 ). Although BRCA mutations can be inherited and are found in a certain breast cancer family histories, Metcalfe et al ( 64 ) have reported no difference in the incidence of BRCA gene mutation carriers with or without a family history of breast cancer ( 64 ).
PIK3CA
PIK3CA gene encodes the p110α protein isoform, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) involved in cell proliferation, protein synthesis and DNA repair. In the PI3K signaling pathway, the activation of tyrosine kinase receptors by growth factors leads to the direct interaction of the receptor with the p85 regulatory subunit, and p110 subunit, resulting in the recruitment of PI3K to the membrane ( 65 ). The phosphorylation of AKT, downstream mediators, and mTOR activation promote cell growth and inhibit apoptosis ( 66 ). Systematically reviewed and compiled evidence from multiple studies indicates that PIK3CA mutation status is associated with shorter PFS and OS in clinical trials involving HR + /HER2breast cancer ( 67 ).
TP53
TP53 is a tumor suppressor gene that encodes the p53 protein. This protein is located in the nucleus and binds directly to DNA involved in the control of the cell cycle and cell differentiation, regulation of DNA repair, and cellular senescence in response to radiation and chemotherapy; binding prevents cancer formation ( 68 ). TP53 mutations arise mainly in the DNA binding domain, resulting in transcriptional inactivation of the p53 protein in stress responses ( 69 ). The TP53 gene mutation occurs in numerous types of cancer, including breast cancer ( 70 ). However, the magnitude of activation that arises from p53 mutation, and the specific transactivated targets of mutated p53, vary by cancer cell type ( 71 ). Wild-type p53 and its activity can indicate favorable prognoses in cancer ( 72 ); it has been indicated that patients with breast cancer with mutant tumor p53 have poorer survival than those with wild-type tumor p53 ( 70 ).
ESR1
ESR1 , the ER 1 gene, is the gene that encodes ER, which belongs to the nuclear hormone receptor superfamily. ER functions as a ligand-activated transcription factor and is composed of multiple domains crucial for the binding of hormones and DNA ( 73 ). In metastatic breast cancer, mutations of ESR1 mostly occur within the ER ligand-binding domain (LBD) and lead to changes in ER function. This affects the response to hormone therapy and can result in the development of hormone-resistant breast cancer ( 74 ). Numerous studies have shown that ESR1 mutations are constitutively active and are resistant to the ER antagonists tamoxifen and fulvestrant ( 75 , 76 ).
AKT1
AKT1 , v-akt murine thymoma viral oncogene homolog 1, belongs to the serine-threonine kinase family and is pivotal in various cellular processes ( 77 ). AKT1 is a downstream effector of PI3K, becoming activated by localizing to the membrane after inositol-3,4,5-triphosphate (PIP3) phosphorylation by PI3K. The pleckstrin homology domain of AKT1 binds to PIP3, exposing the activation sites of AKT1 for phosphorylation of serine 473 and threonine 308 ( 77 ). The process is often implicated in proliferation, survival and angiogenesis pathways recurrently activated in numerous cancers, including breast cancer ( 78 ).
Other genes
Other gene mutations are involved with breast cancer development; for example, the phosphatase and tensin homolog ( PTEN ) gene serves as a tumor suppressor that regulates various biological functions such as cell cycle progression, cell proliferation and apoptosis regulation through negative regulation of PI3K and AKT pathways ( 79 ). The alterations or mutations of PTEN promote proliferation, migration and invasion, leading to breast cancer development and metastasis ( 80 ). Partner and localizer of BRCA2 (PALB2) plays a role together with BRCA2 in DSB repair ( 81 ). Mutations that result in a loss of function in PALB2 are associated with the occurrence of hereditary breast cancer ( 82 ). ATM , ataxia-telangiectasia mutated, is a tumor suppressor gene that plays a role in repairing damaged DNA by triggering repair mechanisms in response to the DNA damage. Data collected by Gao et al ( 83 ) indicated that ATM missense mutations increase the risk of breast cancer; notably, the V2424G (c. 7271 T>G) missense variant exhibits the highest association with breast cancer in all subtypes ( 83 ). In addition, the CHEK2 gene encodes checkpoint kinase 2 (CHK2) protein, a serine/threonine kinase involved in DSBs repair mechanisms. Failure of kinase functions associated with missense mutation or deletion is found in various types of cancer and frequently in breast cancer ( 84 ). The mediator of DNA damage checkpoint 1 gene (MDC1) encodes the MDC1 scaffold protein which plays a crucial role in regulating precise DNA repair in DNA damage response ( 85 ). Loss of the MDC1 protein may serve as an indicator of recurrent metastases in patients with breast cancer ( 86 ), and mutations in the MDC1 gene have been associated with poor prognoses among patients with breast cancer ( 87 ). Hence, mutations of MDC1 may also give rise to plausible neoantigens. Numerous additional mutated genes associated with an increased risk of breast cancer development have been identified and reported ( 88 , 89 ).
5. Mutational landscape in breast cancer
The frequency of somatic mutations varies substantially within and between cancer classes, ranging from ~0.001 mutations per megabase (Mut/Mb) to over 400 Mut/Mb ( 90 ). TMB indicates the total number of non-synonymous mutations (NSMs) per coding area of a cancer genome and varies widely between individual patients and cancer types; breast cancer exhibits a noticeably lower TMB than other cancers, such as melanoma and lung cancer ( 54 , 91 ). No significant difference in OS or PFS between the high TMB (>5 Mut/Mb) and low TMB (≤5 Mut/Mb) groups have been reported, but high TMB may be associated with more prolonged survival of patients undergoing ICI-based treatment ( 92 ). Among breast cancer subtypes, the highest median number of NSMs was found in patients with TNBC (63, range 2-765 NSMs), followed by HER2 + (39, range 1-1206), and the lowest median in ER + /PR + /HER2 - patients (32, range 1-2,860) ( 93 ). The association between high TMB and NSMs in TNBC indicates that TNBC is the most suitable subtype of breast cancer for high neoantigen loading.
The mutations that provide a clonal selective advantage to cancer cells, are strongly associated with oncogenesis, and play a causative role in the development and progression of cancer are known as 'driver genes' ( 94 ). Some driver mutations are inherited in the germline, but the majority of them arise in somatic cells during the lifetime of a patient with cancer, along with numerous 'passenger mutations' that are not linked to cancer development ( 94 ). Several driver gene mutations in breast cancer have been reported ( 95 , 96 ). The most frequent or hotspot mutations of the driver genes in breast cancer are summarized in Table I .
BRCA mutations include germline and somatic mutations. Germline mutations in BRCA1 and BRCA2 genes drive carcinogenesis in ~20% of patients with early-onset breast cancer and only 1-4% of post-menopausal patients ( 97 , 98 ). Somatic mutations in BRCA account for 15-30% of all BRCA1 and BRCA2 mutations and are found in 3% of all breast cancer cases ( 99 ). BRCA1 mutation is found in 61% of TNBC, while 70% of luminal B subtypes show BRCA2 mutations ( 100 , 101 ). However, the HER2-enriched subtype exhibits a low percentage of BRCA1 and BRCA2 mutations ( 101 , 102 ). The most common mutation type of BRCA1 is frameshift mutation, whereas missense mutations are the most common in BRCA2 ( 103 , 104 ). The highest mutation found for BRCA1 was c.68_69delAG (c.185delAG) followed by c.5266dupC (c.5382insC), whereas the most frequent mutation for BRCA2 was c.6174delT (c.5946delT).
PIK3CA somatic mutations are higher in luminal tumors, ~40% of luminal breast cancers, but they do not independently predict the outcome of endocrine therapy ( 105 , 106 ). Most PIK3CA mutations are situated in the helical domains (exon 9) and kinase domain (exon 20), which are located in three hotspot NSMs: PIK3CA E542K (c.70273G>A) and PIK3CA E545K (c.70282G>A) in exon 9 and PIK3CA H1047R (c.86276A>G) in exon 20 ( 107 ). Measurements of the frequencies of PIK3CA mutations in patients with primary breast cancer revealed that PIK3CA E545K was found in 8.1%, representing 63.6% of the exon 9 mutations, whereas PIK3CA H1047R was detected in 14%, corresponding to 91.7% of the exon 20 mutations ( 108 ). The findings were consistent with those of Zhou et al ( 96 ). Other hotspot mutations of PIK3CA in breast cancer have been reported from several studies, such as PIK3CA N345K and PIK3CA C420R in exon4, PIK3CA E726K in exon 13, and PIK3CA H1047L in exon 20 ( 96 , 105 , 108 - 110 ).
TP53 has been observed as the most frequently mutated gene, and accounts for 30-45% of the Cancer Genome Atlas (TCGA) and Guangdong Provincial People's Hospital (GDPH) cohorts ( 95 ). Among breast cancer subtypes, HER2-enriched and TNBC tumors contained more TP53 mutations (60-80%) than luminal A and B subtypes (10-30%) ( 54 , 95 , 96 ). In total, ~50% of TP53 mutations were missense mutations, and 50 and 60% of TP53 mutations were missense mutations ( 95 , 111 ). The most frequent hotspot TP53 somatic mutation identified in TCGA cohorts by several research groups was TP53 R175H , while TP53 R248Q/W and TP53 R273C/H were the most frequent mutation sites in the GDPH cohort ( 95 , 111 - 113 ). The mutations included classic hot spots, such as TP53 G245D , TP53 R273C ,and TP53 Y220S , which have been detected in breast cancer ( 112 , 114 , 115 ).
Certain patients with ER + breast cancer have metastatic disease progression due to hormone therapy resistance caused by missense mutations in the LBD of the ESR1 gene ( 116 , 117 ). In 2013, at least two groups reported that the location is a likely hotspot for activating the LBD ESR1 mutations that mediate clinical resistance to hormone therapy, such as mutations ESR1 L536S , ESR1 Y537S and ESR1 D538G ( 96 , 118 , 119 ). Moreover, a study of circulating tumor DNA in patients with ER + breast cancer revealed that 58% of ESR1 E380Q could be detected in the plasma DNA of metastatic patients ( 118 ).
AKT1 mutations have also been described in breast cancer, especially in the ER + subtype. The most frequent hotspot mutation was AKT1 E17K , found in ~3-8% of breast cancer ( 120 - 122 ). Mutations in MDC1 were found in ~0.6-2.6% of breast cancers ( 123 ); however, the information available on its hotspot mutations is limited.
6. Neoantigen landscape in breast cancer
Neoantigens are potential targets for vaccine development and adoptive therapy ( 124 , 125 ). Most neoantigens arise from the unique somatic mutations that are typically found in cancers in which there is more than one somatic mutation per Mb. TMB is predictive of neoantigens which result in cancer immunogenicity. Barroso-Sousa et al ( 126 ) found that patients with breast cancer who have a high mutational load contain a higher neoantigen burden that correlates with increased cytolytic activity and granzyme A ( GZMA ) and perforin 1 ( PRF1 ) gene expression. These data support the relationship in breast cancer between TMB and higher neoantigen burden favoring antitumor immune responses.
Narang et al ( 93 ) reported that the number of potential neoantigens was highest in TNBC (43% of NSMs). TNBC with a high neoantigen load exhibited increased sensitivity to chemotherapeutic drugs, as well as a favorable response to immunotherapy, mainly through the upregulation of program death-1 (PD-1) signaling signature genes during treatment with ICIs ( 127 ). Neoantigen prediction tools exist to identify HLA-restricted neoantigens that can bind to HLA class I and class II ( 128 ). Ren et al ( 129 ) predicted distribution across HLA genotypes of neoantigens found in individual patients with breast cancer. The neoantigens restricted to HLA class I were 0 to 1,953 from SNVs, 0 to 17,743 from INDELs, and 0 to 7,255 from gene fusions. For HLA class II-restricted neoantigens, the range was 0 to 3,728 from SNVs, 0 to 45,883 from INDELs, and 0 to 20,383 from gene fusions ( 129 ). Interestingly, >1% of neoantigens predicted from their cohort were driver genes. These included MAP3K1 (746 neoantigens; 167 HLA class I and 579 HLA class II), TP53 (252 neoantigens; 46 HLA class I, and 206 HLA class II), GATA3 (58 neoantigens; 8 HLA class I and 50 HLA class II) and PIK3CA (37 neoantigens; 6 HLA class I and 31 HLA class II) ( 129 ). Notably, the neoantigens were categorized into two types based on the level of their individual uniqueness and accessibility: The private and the public neoantigens.
Private neoantigens in breast cancer . Private neoantigens are mutated antigens that are unique and diverse among patients ( 130 ). Most private neoantigens originate from either passenger mutations or non-recurring driver mutations, which result in tumor heterogeneity with expression of neoantigens unique to individual patients ( 131 ). Therefore, therapeutic approaches that target private neoantigens are personalized to suit the unique characteristics of each patient and are referred to as personalized therapy. The authors' group has recently reported personalized neoantigens identified in two patients with breast cancer using whole-genome sequencing and whole-transcriptomic analysis ( 132 ). The predicted HLA-binding affinity of these neoantigens was confirmed to ensure the capacity of these neoantigens to activate T-cells with high cytotoxicity against breast cancer cells. However, such approaches are controversial because clinical outcomes in patients with breast cancer vary considerably owing to the variability in the immune status of patients, the cancer surroundings, and the genetic makeup of the cancers themselves ( 133 ). Several clinical studies targeting private neoantigens in breast cancer have been reported ( Table II ) and provide valuable insights into the development of personalized neoantigen-based immunotherapy.
A clinical study of a private neoantigen-based vaccine against TNBC has been reported. Zhang et al ( 134 ) identified neoantigens in patients with TNBC with distinct HLA phenotypes. PALB2 (SPVTEIRT D L) and ROBO3 (R V AGSMSSL) were predicted with HLA-B * 07:02, and PTPRS (RQLEVP W PYI) and ZDHHC16 (ALGALTVW L ) were predicted with HLA-A * 02:01) ( 134 ). After stimulating each patient's peripheral blood mononuclear cells with neoantigens, increased neoantigen-specific immune responses were obtained, and there was no cross-reaction with the corresponding wild-type peptides. These neoantigens entered a Phase I clinical trial ( NCT02348320 ) as a neoantigen polyepitope DNA vaccine applied to patients by electroporation. The presence of T-cells that specifically target neoantigens was induced in both the pre-and post-vaccination phases, and at 36-month follow-up, the median of responding patients was 87.5% [95% confidence interval (CI): 72.7-100%] compared with 49% (95% CI: 36.4-65.9%) of institutional historical control patients ( 135 ).
In a clinical trial, NCT04105582 , a total of 25 neoantigen peptides from patients with TNBC were administered in autologous dendritic cells (DCs) over 16 weeks. The aforementioned study proved the safety and immunogenicity of these vaccines. In another clinical trial, NCT04879888 , DC vaccines pulsed with synthetic neoantigen peptides are being tested in nine patients with TNBC. The trial's primary goal is to ensure safety, with a secondary focus on evaluating the vaccine's immunogenicity using interferon-γ (IFNγ) ELISPOT. However, these trials have not examined the stability of the neoantigen peptides. Disis et al ( 136 ) reported that ~60% of patients with breast cancer who receive a DNA vaccine had persistent DNA at week 16 following vaccination. Currently, no trial results have been made available. In another clinical study, Morisaki et al ( 137 ) identified neoantigens in primary cancer cells from the pleural fluid of a patient with TNBC. In total, 2/10 of predicted neoantigens had a high binding affinity for HLA-A * 02:06: GEMIN2 (AQCPDV L V) and PARP10 (SISCHV F CL). Both caused a significant increase in the response of IFNγ-producing T-cells to autologous cancer cells observed after inducing cytotoxic T lymphocytes with peptide-pulsed autologous DCs ( 137 ). However, the aforementioned study also reported that AKT1, ARAP3, NOTCH3, PIK3CA and SLC35E2 contained identical non-synonymous SNVs without testing immunogenicity. Additionally, there are other ongoing clinical trials to evaluate personalized neoantigen-based immunotherapy in breast cancer ( Table II ).
Public neoantigens in breast cancer
Cancer-driver mutations, which are typically found in oncogenes or specific tumor suppressor genes, often occur in genomic hotspots. These hotspots lead to changes in protein function and are frequently observed across different patients ( 138 ). The mutated peptides produced by these genetic alterations, when presented by HLA alleles, can generate neoantigens that are common among individuals with the same genetic changes and HLA types ( 139 ). This phenomenon marks these neoantigens as shared among cancer patients, giving rise to 'public' neoantigens ( 140 ). Setting aside R157H, other p53 mutants could serve as neoantigens, such as TP53 Y220C found in breast cancer. The TP53 Y220C neoepitopes, VVP C EPPEV, RNTFRHSVVVP C E and NTFRHSVVVP C EPPE, were recognized by HLA-A * 02:01-, HLA-DRB1 * 04:01 and HLA-DRB3 * 02:02-expressing tumor-infiltrating lymphocytes (TILs), respectively ( 141 ). Consequently, the results of current research support efforts to create off-the-shelf anticancer therapies based on the public or shared neoantigens, which could potentially benefit a broad group of patients with breast cancer.
In breast cancer, most shared target antigens have been reported as TAAs; for example, a Phase I/II clinical trial of autologous DC transfected with the cDNA of mucin (MUC1) in patients with advanced breast cancer ( 142 ). The trial demonstrated the feasibility and safety of this vaccine approach and demonstrated immunologic responses in patients who had previously received treatment and had advanced-stage disease ( 142 ). In situ testing of a HER2-pulsed DC vaccine in 27 patients with HER2/neu-overexpressing ductal carcinoma was well-tolerated and demonstrated reduction or elimination of HER2/neu expression ( 143 ).
Previously, a small number of public neoantigens were explored in breast cancer ( Table III ). Pettitt et al ( 144 ) analyzed the prediction of an out-of-frame sequence resulting from common founder BRCA2 reversion (c.5946delT: RENLSRYQMLHYKTQ) that can be presented by numerous HLA class I alleles such as HLA-A * 0101, HLA-A * 3303, HLA-B * 3501, HLA-B * 4001, HLA-C * 0602 and HLA-C * 1203 ( 144 ). The results showed a revertant neoepitope sequence that can be presented with a high probability by the MHC class I across the general population and therefore provides an option for targeting public neoantigens ( 144 ).
Ruangapirom et al ( 145 ) predicted the immunogenicity of common hotspot mutations found in BRCA1-related breast cancer. They predicted elements with high binding affinity for various alleles of MHC class I in peptides of 9-12 amino acids: PIK3CA H1047R , PIK3CA E542K , PIK3CA E545K , PIK3CA N345K and TP53 Y220C ( 145 ). Although these common neoantigens were predicted based on in silico analysis, the findings suggested the potential use of public neoantigen targets in vaccines for the population with breast cancer. Iiizumi et al ( 146 ) provided in vitro validation of neoantigens frequently found in breast cancer, such as PIK3CA H1047R , that were predicted to bind with HLA-A * 0201, HLA-A * 2402, HLA-DRB1 * 0405 and HLA-DRB1 * 0901. They elicited both CD4 + and CD8 + responses in 16.7% of healthy donors ( 146 ). Moreover, Chandran et al ( 147 ) verified the spontaneous immunogenicity of PIK3CA public neoantigens in eight patients with breast cancer harboring PIK3CA H1047L . In total, two of these neoantigens were able to successfully retrieve from a patient a TCR that conferred a response to targets that carried the PIK3CA H1047L mutation. This confirmed that the PIK3CA public neoantigen can trigger an immune response and drive in vivo clonal expansion in a subset of patients with breast cancer.
Previous research has indicated that TP53 hotspot mutations can be utilized in a shared neoantigen-based cancer vaccine to treat breast cancers ( 148 , 149 ). Lo et al ( 148 ) described the identification and characterization of HLA-A * 0201-restricted TCRs that react with TP53 R175H and recognize various cancer cell lines, including breast cancer endogenously expressing TP53 R175H . When a patient with the HLA-A * 0201 allele and chemorefractory breast cancer was treated by adoptive transfer using TP53 R175H -TCR-engineered autologous peripheral blood lymphocytes, a significant reduction in subcutaneous tumor deposits occurred, and all skin lesions wholly resolved by day 60 after cell therapy ( 149 ). This finding may indicate a suitable shared neoantigen target for the treatment of patients whose cancers convey HLA-A * 0201 and contain a TP53 R175H mutation ( 148 ). Kim et al ( 149 ) and Zacharakis et al ( 150 ) reported that patients with breast cancer who received adoptive transfer of ex vivo -expanded autologous TILs targeting TP53 Y220C exhibited a partial response. There was complete resolution of two right subpectoral lymph nodes, subcutaneous breast nodules, and substantial regression of the primary breast tumor with response durations of 6 months ( 150 ). The summary of hotspot mutations recognized as public neoantigens sharing among patients with breast cancer is shown in Fig. 2 .
7. Clinical utilization of public neoantigens for breast cancer treatment
Despite multiple studies that have identified shared neoantigens in breast cancer and demonstrated their ability to stimulate anti-tumor immune responses in vitro , clinical investigations that have focused on exploiting the immunogenicity of the associated shared neoantigens in breast cancer are limited. Ongoing clinical trials testing the immunogenicity of shared neoantigen vaccines are in non-small cell lung, colorectal and pancreatic cancer (Clinical trial NCT03953235 ). The aforementioned study has been measuring PFS and OS for ~4 years (2019-2023). There remains a crucial necessity for further clinical investigation into the implications and outcomes of these shared neoantigens within breast cancer. The broader application across a diverse spectrum of cancer patients suggests that they may be promising targets for off-the-shelf immunotherapy.
8. Conclusion
Cancer mutations are patient-specific, giving neoantigens a highly personalized character. Yet, some neoepitopes are consistently found across multiple patients with cancer, making them shared neoantigens. These common neoantigens hold promise for treating a substantial number of patients who share several specific HLA types, offering viable targets for off-the-shelf cancer immunotherapies. Current clinical research into breast cancer predominantly investigates personalized neoantigens, whereas the study of shared neoantigens in breast cancer is limited due to the low proportion of neoantigen burden, limited studies of hotspot mutations in breast cancer, and the challenges in locating patients who have both a specific HLA allele and a particular common neoantigen. The true potential of broad HLA-specific public neoantigen prediction remains to be fully explored through clinical trials involving diverse patient groups with various HLA types. This presents a significant challenge for the development of broadly applicable ready-to-use immunotherapies for cancers in general and for patients with breast cancer in particular.
Acknowledgements
The authors would like to thank Dr Jan Davies, Faculty of Graduate Studies, Mahidol University, for English editing.
Availability of data and materials
Not applicable.
Authors' contributions
NS designed and wrote the manuscript. CT, PT and PY provided the research direction. NS and CT edited the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
1 Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A Bray F Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 71 209 249 2021 10.3322/caac.21660 33538338
2 Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours Nature 490 61 70 2012 10.1038/nature11412 23000897 PMC3465532
3 Rouzier R Perou CM Symmans WF Ibrahim N Cristofanilli M Anderson K Hess KR Stec J Ayers M Wagner P Breast cancer molecular subtypes respond differently to preoperative chemotherapy Clin Cancer Res 11 5678 5685 2005 10.1158/1078-0432.CCR-04-2421 16115903
4 Bhargava R Beriwal S Dabbs DJ Ozbek U Soran A Johnson RR Brufsky AM Lembersky BC Ahrendt GM Immunohistochemical surrogate markers of breast cancer molecular classes predicts response to neoadjuvant chemotherapy: A single institutional experience with 359 cases Cancer 116 1431 1439 2010 10.1002/cncr.24876 20131351
5 Nik-Zainal S Davies H Staaf J Ramakrishna M Glodzik D Zou X Martincorena I Alexandrov LB Martin S Wedge DC Landscape of somatic mutations in 560 breast cancer whole-genome sequences Nature 534 47 54 2016 10.1038/nature17676 27135926 PMC4910866
6 Pon JR Marra MA Driver and passenger mutations in cancer Annu Rev Pathol 10 25 50 2015 10.1146/annurev-pathol-012414-040312 25340638
7 Chen T Wang Z Zhou W Chong Z Meric-Bernstam F Mills GB Chen K Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types BMC Genomics 17 Suppl 2 S394 2016 10.1186/s12864-016-2727-x PMC4928158 27356755
8 Siegel RL Miller KD Fuchs HE Jemal A Cancer statistics, 2022 CA Cancer J Clin 72 7 33 2022 10.3322/caac.21708 35020204
9 Li CI Uribe DJ Daling JR Clinical characteristics of different histologic types of breast cancer Br J Cancer 93 1046 1052 2005 10.1038/sj.bjc.6602787 16175185 PMC2361680
10 Caswell-Jin JL Lorenz C Curtis C Molecular heterogeneity and evolution in breast cancer Annu Rev Cancer Biol 5 79 94 2021 10.1146/annurev-cancerbio-060220-014137
11 Wagner J Rapsomaniki MA Chevrier S Anzeneder T Langwieder C Dykgers A Rees M Ramaswamy A Muenst S Soysal SD A single-cell atlas of the tumor and immune ecosystem of human breast cancer Cell 177 1330 1345.e18 2019 10.1016/j.cell.2019.03.005 30982598 PMC6526772
12 Tsang JYS Tse GM Molecular classification of breast cancer Adv Anat Pathol 27 27 35 2020 10.1097/PAP.0000000000000232 31045583
13 Goldhirsch A Wood WC Coates AS Gelber RD Thürlimann B Senn HJ Panel members Strategies for subtypes-dealing with the diversity of breast cancer: Highlights of the St. Gallen international expert consensus on the primary therapy of early breast cancer 2011 Ann Oncol 22 1736 1747 2011 10.1093/annonc/mdr304 21709140 PMC3144634
14 Li J Chen Z Su K Zeng J Clinicopathological classification and traditional prognostic indicators of breast cancer Int J Clin Exp Pathol 8 8500 8505 2015 26339424 PMC4555752
15 Prat A Cheang MCU Martín M Parker JS Carrasco E Caballero R Tyldesley S Gelmon K Bernard PS Nielsen TO Perou CM Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer J Clin Oncol 31 203 209 2013 10.1200/JCO.2012.43.4134 23233704 PMC3532392
16 Maisonneuve P Disalvatore D Rotmensz N Curigliano G Colleoni M Dellapasqua S Pruneri G Mastropasqua MG Luini A Bassi F Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes Breast Cancer Res 16 R65 2014 10.1186/bcr3679 24951027 PMC4095689
17 Tang P Tse GM Immunohistochemical surrogates for molecular classification of breast carcinoma: A 2015 update Arch Pathol Lab Med 140 806 814 2016 10.5858/arpa.2015-0133-RA 27472239
18 Dawood S Broglio K Buzdar AU Hortobagyi GN Giordano SH Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: An institutional-based review J Clin Oncol 28 92 98 2010 10.1200/JCO.2008.19.9844 19933921 PMC2799236
19 Badve S Dabbs DJ Schnitt SJ Baehner FL Decker T Eusebi V Fox SB Ichihara S Jacquemier J Lakhani SR Basal-like and triple-negative breast cancers: A critical review with an emphasis on the implications for pathologists and oncologists Mod Pathol 24 157 167 2011 10.1038/modpathol.2010.200 21076464
20 Prat A Pineda E Adamo B Galván P Fernández A Gaba L Díez M Viladot M Arance A Muñoz M Clinical implications of the intrinsic molecular subtypes of breast cancer Breast 24 Suppl 2 S26 S35 2015 10.1016/j.breast.2015.07.008 26253814
21 Gradishar WJ Moran MS Abraham J Aft R Agnese D Allison KH Anderson B Burstein HJ Chew H Dang C Breast cancer, version 3.2022, NCCN clinical practice guidelines in oncology J Natl Compr Canc Netw 20 691 722 2022 10.6004/jnccn.2022.0030 35714673
22 EORTC Breast Cancer Cooperative Group EORTC Radiotherapy Group Bijker N Meijnen P Peterse JL Bogaerts J Van Hoorebeeck I Julien JP Gennaro M Rouanet P Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: Ten-year results of European organisation for research and treatment of cancer randomized phase III trial 10853-A study by the EORTC breast cancer cooperative group and EORTC radiotherapy group J Clin Oncol 24 3381 3387 2006 10.1200/JCO.2006.06.1366 16801628
23 McCormick B Winter K Hudis C Kuerer HM Rakovitch E Smith BL Sneige N Moughan J Shah A Germain I RTOG 9804: A prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation J Clin Oncol 33 709 715 2015 10.1200/JCO.2014.57.9029 25605856 PMC4334775
24 Holmberg L Garmo H Granstrand B Ringberg A Arnesson LG Sandelin K Karlsson P Anderson H Emdin S Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast J Clin Oncol 26 1247 1252 2008 10.1200/JCO.2007.12.7969 18250350
25 Bhushan A Gonsalves A Menon JU Current state of breast cancer diagnosis, treatment, and theranostics Pharmaceutics 13 723 2021 10.3390/pharmaceutics13050723 34069059 PMC8156889
26 Cuzick J Sestak I Bonanni B Costantino JP Cummings S DeCensi A Dowsett M Forbes JF Ford L LaCroix AZ Selective oestrogen receptor modulators in prevention of breast cancer: An updated meta-analysis of individual participant data Lancet 381 1827 1834 2013 10.1016/S0140-6736(13)60140-3 23639488 PMC3671272
27 Rodon J Braña I Siu LL De Jonge MJ Homji N Mills D Di Tomaso E Sarr C Trandafir L Massacesi C Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors Invest New Drugs 32 670 681 2014 10.1007/s10637-014-0082-9 24652201
28 Krop IE Mayer IA Ganju V Dickler M Johnston S Morales S Yardley DA Melichar B Forero-Torres A Lee SC Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): A randomised, double-blind, placebo-controlled, phase 2 trial Lancet Oncol 17 811 821 2016 10.1016/S1470-2045(16)00106-6 27155741 PMC5524539
29 Schneble E Jinga DC Peoples G Breast cancer immunotherapy Maedica (Bucur) 10 185 191 2015 28275416 PMC5327815
30 Kang C Syed YY Atezolizumab (in combination with nab-paclitaxel): A review in advanced triple-negative breast cancer Drugs 80 601 607 2020 10.1007/s40265-020-01295-y 32248356
31 Kantoff PW Schuetz TJ Blumenstein BA Glode LM Bilhartz DL Wyand M Manson K Panicali DL Laus R Schlom J Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer J Clin Oncol 28 1099 1105 2010 10.1200/JCO.2009.25.0597 20100959 PMC2834462
32 Hu ZI Ho AY McArthur HL Combined radiation therapy and immune checkpoint blockade therapy for breast cancer Int J Radiat Oncol Biol Phys 99 153 164 2017 10.1016/j.ijrobp.2017.05.029 28816141
33 Boon T Cerottini JC Van den Eynde B van der Bruggen P Van Pel A Tumor antigens recognized by T lymphocytes Annu Rev Immunol 12 337 365 1994 10.1146/annurev.iy.12.040194.002005 8011285
34 Butterfield LH Cancer vaccines BMJ 350 h988 2015 10.1136/bmj.h988 25904595 PMC4707521
35 Perica K Varela JC Oelke M Schneck J Adoptive T cell immunotherapy for cancer Rambam Maimonides Med J 6 e0004 2015 10.5041/RMMJ.10179 25717386 PMC4327320
36 Ilyas S Yang JC Landscape of tumor antigens in T cell immunotherapy J Immunol 195 5117 5122 2015 10.4049/jimmunol.1501657 26589749 PMC4656134
37 Srinivasan R Wolchok JD Tumor antigens for cancer immunotherapy: Therapeutic potential of xenogeneic DNA vaccines J Transl Med 2 12 2004 10.1186/1479-5876-2-12 15090064 PMC419720
38 Benvenuto M Focaccetti C Izzi V Masuelli L Modesti A Bei R Tumor antigens heterogeneity and immune response-targeting neoantigens in breast cancer Semin Cancer Biol 72 65 75 2021 10.1016/j.semcancer.2019.10.023 31698088
39 Alatrash G Crain AK Molldrem JJ Chapter 7-tumor-associated antigens Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation Socié G Zeiser R Blazar BR 2nd edition Academic Press 107 125 2019 10.1016/B978-0-12-812630-1.00007-4
40 Tawara I Kageyama S Miyahara Y Fujiwara H Nishida T Akatsuka Y Ikeda H Tanimoto K Terakura S Murata M Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS Blood 130 1985 1994 2017 10.1182/blood-2017-06-791202 28860210
41 Baxevanis CN Gritzapis AD Tsitsilonis OE Katsoulas HL Papamichail M HER-2/neu-derived peptide epitopes are also recognized by cytotoxic CD3(+)CD56(+) (natural killer T) lymphocytes Int J Cancer 98 864 872 2002 10.1002/ijc.10251 11948464
42 Zhenjiang L Rao M Luo X Sandberg E Bartek J Jr Schoutrop E von Landenberg A Meng Q Valentini D Poiret T Mesothelin-specific immune responses predict survival of patients with brain metastasis EBioMedicine 23 20 24 2017 10.1016/j.ebiom.2017.08.024 28888924 PMC5605370
43 Pittet MJ Valmori D Dunbar PR Speiser DE Liénard D Lejeune F Fleischhauer K Cerundolo V Cerottini JC Romero P High frequencies of naive Melan-A/MART-1-specific CD8(+) T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals J Exp Med 190 705 716 1999 10.1084/jem.190.5.705 10477554 PMC2195613
44 Lesterhuis WJ De Vries IJ Schreibelt G Schuurhuis DH Aarntzen EH De Boer A Scharenborg NM Van De Rakt M Hesselink EJ Figdor CG Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA mRNA for vaccination of colorectal cancer patients Anticancer Res 30 5091 5097 2010 21187495
45 Parvanova I Rettig L Knuth A Pascolo S The form of NY-ESO-1 antigen has an impact on the clinical efficacy of anti-tumor vaccination Vaccine 29 3832 3836 2011 10.1016/j.vaccine.2011.03.073 21470580
46 Mohsenzadegan M Razmi M Vafaei S Abolhasani M Madjd Z Saeednejad Zanjani L Sharifi L Co-expression of cancer-testis antigens of MAGE-A6 and MAGE-A11 is associated with tumor aggressiveness in patients with bladder cancer Sci Rep 12 599 2022 10.1038/s41598-021-04510-2 35022469 PMC8755713
47 Lawrence MS Stojanov P Polak P Kryukov GV Cibulskis K Sivachenko A Carter SL Stewart C Mermel CH and Roberts SA Mutational heterogeneity in cancer and the search for new cancer-associated genes Nature 499 214 218 2013 10.1038/nature12213 23770567 PMC3919509
48 Makkouk A Weiner GJ Cancer immunotherapy and breaking immune tolerance: New approaches to an old challenge Cancer Res 75 5 10 2015 10.1158/0008-5472.CAN-14-2538 25524899 PMC4286422
49 Wang Y Buck A Piel B Zerefa L Murugan N Coherd CD Miklosi AG Johal H Bastos RN Huang K Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects Mol Cancer 23 56 2024 10.1186/s12943-024-01952-w 38491381 PMC10943873
50 Sanderson K Scotland R Lee P Liu D Groshen S Snively J Sian S Nichol G Davis T Keler T Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and montanide ISA 51 for patients with resected stages III and IV melanoma J Clin Oncol 23 741 750 2005 10.1200/JCO.2005.01.128 15613700
51 Wölfel T Hauer M Schneider J Serrano M Wölfel C Klehmann-Hieb E De Plaen E Hankeln T Meyer zum Büschenfelde KH Beach D A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma Science 269 1281 1284 1995 10.1126/science.7652577 7652577
52 Plummer M de Martel C Vignat J Ferlay J Bray F Franceschi S Global burden of cancers attributable to infections in 2012: A synthetic analysis Lancet Glob Health 4 e609 e616 2016 10.1016/S2214-109X(16)30143-7 27470177
53 Trimble CL Morrow MP Kraynyak KA Shen X Dallas M Yan J Edwards L Parker RL Denny L Giffear M Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: A randomised, double-blind, placebo-controlled phase 2b trial Lancet 386 2078 2088 2015 10.1016/S0140-6736(15)00239-1 26386540 PMC4888059
54 Castle JC Uduman M Pabla S Stein RB Buell JS mutation-derived neoantigens for cancer immunotherapy Front Immunol 10 1856 2019 10.3389/fimmu.2019.01856 31440245 PMC6693295
55 Capietto AH Hoshyar R Delamarre L Sources of cancer neoantigens beyond single-nucleotide variants Int J Mol Sci 23 10131 2022 10.3390/ijms231710131 36077528 PMC9455963
56 Roudko V Bozkus CC Orfanelli T McClain CB Carr C O'Donnell T Chakraborty L Samstein R Huang KL Blank SV Shared immunogenic poly-epitope frameshift mutations in microsatellite unstable tumors Cell 183 1634 1649.e17 2020 10.1016/j.cell.2020.11.004 33259803 PMC8025604
57 Yang W Lee KW Srivastava RM Kuo F Krishna C Chowell D Makarov V Hoen D Dalin MG Wexler L Immunogenic neoantigens derived from gene fusions stimulate T cell responses Nat Med 25 767 775 2019 10.1038/s41591-019-0434-2 31011208 PMC6558662
58 Colditz GA Kaphingst KA Hankinson SE Rosner B Family history and risk of breast cancer: Nurses' health study Breast Cancer Res Treat 133 1097 1104 2012 10.1007/s10549-012-1985-9 22350789 PMC3387322
59 Couch FJ Nathanson KL Offit K Two decades after BRCA: Setting paradigms in personalized cancer care and prevention Science 343 1466 1470 2014 10.1126/science.1251827 24675953 PMC4074902
60 Narod SA Foulkes WD BRCA1 and BRCA2: 1994 And beyond Nat Rev Cancer 4 665 676 2004 10.1038/nrc1431 15343273
61 Roy R Chun J Powell SN BRCA1 and BRCA2: Different roles in a common pathway of genome protection Nat Rev Cancer 12 68 78 2011 10.1038/nrc3181 22193408 PMC4972490
62 Russo A Calò V Agnese V Bruno L Corsale S Augello C Gargano G Barbera F Cascio S Intrivici C BRCA1 genetic testing in 106 breast and ovarian cancer families from Southern Italy (Sicily): A mutation analyses Breast Cancer Res Treat 105 267 276 2007 10.1007/s10549-006-9456-9 17221156
63 Armstrong N Ryder S Forbes C Ross J Quek RG A systematic review of the international prevalence of BRCA mutation in breast cancer Clin Epidemiol 11 543 561 2019 10.2147/CLEP.S206949 31372057 PMC6628947
64 Metcalfe KA Lubinski J Gronwald J Huzarski T McCuaig J Lynch HT Karlan B Foulkes WD Singer CF Neuhausen SL The risk of breast cancer in BRCA1 and BRCA2 mutation carriers without a first-degree relative with breast cancer Clin Genet 93 1063 1068 2018 10.1111/cge.13191 29206279
65 Liu P Cheng H Roberts TM Zhao JJ Targeting the phosphoinositide 3-kinase pathway in cancer Nat Rev Drug Discov 8 627 644 2009 10.1038/nrd2926 19644473 PMC3142564
66 Sun K Luo J Guo J Yao X Jing X Guo F The PI3K/AKT/mTOR signaling pathway in osteoarthritis: A narrative review Osteoarthritis Cartilage 28 400 409 2020 10.1016/j.joca.2020.02.027 32081707
67 Fillbrunn M Signorovitch J André F Wang I Lorenzo I Ridolfi A Park J Dua A Rugo HS PIK3CA mutation status, progression and survival in advanced HR + /HER2-breast cancer: A meta-analysis of published clinical trials BMC Cancer 22 1002 2022 10.1186/s12885-022-10078-5 36131248 PMC9490901
68 Tonnessen-Murray CA Lozano G Jackson JG The regulation of cellular functions by the p53 protein: Cellular senescence Cold Spring Harb Perspect Med 7 a026112 2017 10.1101/cshperspect.a026112 27881444 PMC5287062
69 Hamroun D Kato S Ishioka C Claustres M Béroud C Soussi T The UMD TP53 database and website: Update and revisions Hum Mutat 27 14 20 2006 10.1002/humu.20269 16278824
70 Ungerleider NA Rao SG Shahbandi A Yee D Niu T Frey WD Jackson JG Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment Breast Cancer Res 20 115 2018 10.1186/s13058-018-1044-5 30285883 PMC6167800
71 Kato S Han SY Liu W Otsuka K Shibata H Kanamaru R Ishioka C Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis Proc Natl Acad Sci USA 100 8424 8429 2003 10.1073/pnas.1431692100 12826609 PMC166245
72 Soussi T Béroud C Assessing TP53 status in human tumours to evaluate clinical outcome Nat Rev Cancer 1 233 240 2001 10.1038/35106009 11902578
73 Parker MG Arbuckle N Dauvois S Danielian P White R Structure and function of the estrogen receptor Ann N Y Acad Sci 684 119 126 1993 10.1111/j.1749-6632.1993.tb32276.x 8317825
74 Pejerrey SM Dustin D Kim JA Gu G Rechoum Y Fuqua SAW The impact of ESR1 mutations on the treatment of metastatic breast cancer Horm Cancer 9 215 228 2018 10.1007/s12672-017-0306-5 29736566 PMC9680193
75 Jeselsohn R Buchwalter G De Angelis C Brown M Schiff R ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer Nat Rev Clin Oncol 12 573 583 2015 10.1038/nrclinonc.2015.117 26122181 PMC4911210
76 Lei JT Shao J Zhang J Iglesia M Chan DW Cao J Anurag M Singh P He X Kosaka Y Functional annotation of ESR1 gene fusions in estrogen receptor-positive breast cancer Cell Rep 24 1434 1444.e7 2018 10.1016/j.celrep.2018.07.009 30089255 PMC6171747
77 Siddika T Balasuriya N Frederick MI Rozik P Heinemann IU O'Donoghue P Delivery of active AKT1 to human cells Cells 11 3834 2022 10.3390/cells11233834 36497091 PMC9738475
78 George B Gui B Raguraman R Paul AM Nakshatri H Pillai MR Kumar R AKT1 transcriptomic landscape in breast cancer cells Cells 11 2290 2022 10.3390/cells11152290 35892586 PMC9332453
79 Keniry M Parsons R The role of PTEN signaling perturbations in cancer and in targeted therapy Oncogene 27 5477 5485 2008 10.1038/onc.2008.248 18794882
80 Chen J Sun J Wang Q Du Y Cheng J Yi J Xie B Jin S Chen G Wang L Systemic deficiency of PTEN accelerates breast cancer growth and metastasis Front Oncol 12 825484 2022 10.3389/fonc.2022.825484 35372075 PMC8971716
81 Sy SMH Huen MSY Zhu Y Chen J PALB2 regulates recombinational repair through chromatin association and oligomerization J Biol Chem 284 18302 18310 2009 10.1074/jbc.M109.016717 19423707 PMC2709360
82 Antoniou AC Casadei S Heikkinen T Barrowdale D Pylkäs K Roberts J Lee A Subramanian D De Leeneer K Fostira F Breast-cancer risk in families with mutations in PALB2 N Engl J Med 371 497 506 2014 10.1056/NEJMoa1400382 25099575 PMC4157599
83 Gao LB Pan XM Sun H Wang X Rao L Li LJ Liang WB Lv ML Yang WZ Zhang L The association between ATM D1853N polymorphism and breast cancer susceptibility: A meta-analysis J Exp Clin Cancer Res 29 117 2010 10.1186/1756-9966-29-117 20799949 PMC2936337
84 Apostolou P Papasotiriou I Current perspectives on CHEK2 mutations in breast cancer Breast Cancer (Dove Med Press) 9 331 335 2017 28553140 10.2147/BCTT.S111394 PMC5439543
85 Stewart GS Wang B Bignell CR Taylor AMR Elledge SJ MDC1 is a mediator of the mammalian DNA damage checkpoint Nature 421 961 966 2003 10.1038/nature01446 12607005
86 Patel AN Goyal S Wu H Schiff D Moran MS Haffty BG Mediator of DNA damage checkpoint protein 1 (MDC1) expression as a prognostic marker for nodal recurrence in early-stage breast cancer patients treated with breast-conserving surgery and radiation therapy Breast Cancer Res Treat 126 601 607 2011 10.1007/s10549-010-0960-6 20521098
87 Liu C Chang H Li XH Qi YF Wang JO Zhang Y Yang XH Network meta-analysis on the effects of DNA damage response-related gene mutations on overall survival of breast cancer based on TCGA database J Cell Biochem 118 4728 4734 2017 10.1002/jcb.26140 28513990
88 Wang YA Jian JW Hung CF Peng HP Yang CF Cheng HS Yang AS Germline breast cancer susceptibility gene mutations and breast cancer outcomes BMC Cancer 18 315 2018 10.1186/s12885-018-4229-5 29566657 PMC5863855
89 Breast Cancer Association Consortium Dorling L Carvalho S Allen J González-Neira A Luccarini C Wahlström C Pooley KA Parsons MT Fortuno C Breast cancer risk genes-association analysis in more than 113,000 women N Engl J Med 384 428 439 2021 10.1056/NEJMoa1913948 33471991 PMC7611105
90 Alexandrov LB Nik-Zainal S Wedge DC Aparicio SA Behjati S Biankin AV Bignell GR Bolli N Borg A Børresen-Dale AL Signatures of mutational processes in human cancer Nature 500 415 421 2013 10.1038/nature12477 23945592 PMC3776390
91 Vogelstein B Papadopoulos N Velculescu VE Zhou S Diaz LA Jr Kinzler KW Cancer genome landscapes Science 339 1546 1558 2013 10.1126/science.1235122 23539594 PMC3749880
92 Ke L Li S Cui H The prognostic role of tumor mutation burden on survival of breast cancer: A systematic review and meta-analysis BMC Cancer 22 1185 2022 10.1186/s12885-022-10284-1 36397030 PMC9673350
93 Narang P Chen M Sharma AA Anderson KS Wilson MA The neoepitope landscape of breast cancer: Implications for immunotherapy BMC Cancer 19 200 2019 10.1186/s12885-019-5402-1 30832597 PMC6399957
94 Stratton MR Campbell PJ Futreal PA The cancer genome Nature 458 719 724 2009 10.1038/nature07943 19360079 PMC2821689
95 Zhang G Wang Y Chen B Guo L Cao L Ren C Wen L Li K Jia M Li C Characterization of frequently mutated cancer genes in Chinese breast tumors: A comparison of Chinese and TCGA cohorts Ann Transl Med 7 179 2019 10.21037/atm.2019.04.23 31168460 PMC6526269
96 Zhou S Liu S Zhao L Sun HX A comprehensive survey of genomic mutations in breast cancer reveals recurrent neoantigens as potential therapeutic targets Front Oncol 12 786438 2022 10.3389/fonc.2022.786438 35387130 PMC8978336
97 Carraro DM Koike Folgueira MAA Garcia Lisboa BC Ribeiro Olivieri EH Vitorino Krepischi AC de Carvalho AF de Carvalho Mota LD Puga RD do Socorro Maciel M Michelli RA Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: A portrait of early-onset breast cancer in Brazil PLoS One 8 e57581 2013 10.1371/journal.pone.0057581 23469205 PMC3586086
98 Kurian AW BRCA1 and BRCA2 mutations across race and ethnicity: Distribution and clinical implications Curr Opin Obstet Gynecol 22 72 78 2010 10.1097/GCO.0b013e328332dca3 19841585
99 Winter C Nilsson MP Olsson E George AM Chen Y Kvist A Törngren T Vallon-Christersson J Hegardt C Häkkinen J Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic Ann Oncol 27 1532 1538 2016 10.1093/annonc/mdw209 27194814 PMC4959927
100 Staaf J Glodzik D Bosch A Vallon-Christersson J Reuterswärd C Häkkinen J Degasperi A Amarante TD Saal LH Hegardt C Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study Nat Med 25 1526 1533 2019 10.1038/s41591-019-0582-4 31570822 PMC6859071
101 Larsen MJ Kruse TA Tan Q Lænkholm AV Bak M Lykkesfeldt AE Sørensen KP Hansen TV Ejlertsen B Gerdes AM Thomassen M Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling PLoS One 8 e64268 2013 10.1371/journal.pone.0064268 23704984 PMC3660328
102 De Talhouet S Peron J Vuilleumier A Friedlaender A Viassolo V Ayme A Bodmer A Treilleux I Lang N Tille JC Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes Sci Rep 10 7073 2020 10.1038/s41598-020-63759-1 32341426 PMC7184602
103 Linger RJ Kruk PA BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications FEBS J 277 3086 3096 2010 10.1111/j.1742-4658.2010.07735.x 20608970
104 Lavoro A Scalisi A Candido S Zanghì GN Rizzo R Gattuso G Caruso G Libra M Falzone L Identification of the most common BRCA alterations through analysis of germline mutation databases: Is droplet digital PCR an additional strategy for the assessment of such alterations in breast and ovarian cancer families Int J Oncol 60 58 2022 10.3892/ijo.2022.5349 35383859 PMC8997337
105 Sabine VS Crozier C Brookes CL Drake C Piper T van de Velde CJ Hasenburg A Kieback DG Markopoulos C Dirix L Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study J Clin Oncol 32 2951 2958 2014 10.1200/JCO.2013.53.8272 25071141
106 Meyer DS Brinkhaus H Müller U Müller M Cardiff RD mBentires-Alj M Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors Cancer Res 71 4344 4351 2011 10.1158/0008-5472.CAN-10-3827 21482677
107 Forbes SA Bindal N Bamford S Cole C Kok CY Beare D Jia M Shepherd R Leung K Menzies A COSMIC: Mining complete cancer genomes in the catalogue of somatic mutations in cancer Nucleic Acids Res 39 Database Issue D945 D950 2011 10.1093/nar/gkq929 20952405 PMC3013785
108 Mangone FR Bobrovnitchaia IG Salaorni S Manuli E Nagai MA PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients Clinics (Sao Paulo) 67 1285 1290 2012 10.6061/clinics/2012(11)11 23184205 PMC3488987
109 Arsenic R Treue D Lehmann A Hummel M Dietel M Denkert C Budczies J Comparison of targeted next-generation sequencing and sanger sequencing for the detection of PIK3CA mutations in breast cancer BMC Clin Pathol 15 20 2015 10.1186/s12907-015-0020-6 26587011 PMC4652376
110 Martínez-Sáez O Chic N Pascual T Adamo B Vidal M González-Farré B Sanfeliu E Schettini F Conte B Brasó-Maristany F Frequency and spectrum of PIK3CA somatic mutations in breast cancer Breast Cancer Res 22 45 2020 10.1186/s13058-020-01284-9 32404150 PMC7222307
111 Li X Chen X Wen L Wang Y Chen B Xue Y Guo L Liao N Impact of TP53 mutations in breast cancer: Clinicopathological features and prognosisImpact of TP53 mutations in breast CA Thorac Cancer 11 1861 1868 2020 10.1111/1759-7714.13467 32412177 PMC7327681
112 Behring M Vazquez AI Cui X Irvin MR Ojesina AI Agarwal S Manne U Shrestha S Gain of function in somatic TP53 mutations is associated with immune-rich breast tumors and changes in tumor-associated macrophages Mol Genet Genomic Med 7 e1001 2019 10.1002/mgg3.1001 31637877 PMC6900370
113 Perumal D Imai N Laganà A Finnigan J Melnekoff D Leshchenko VV Solovyov A Madduri D Chari A Cho HJ Mutation-derived neoantigen-specific T-cell responses in multiple myeloma Clin Cancer Res 26 450 464 2020 10.1158/1078-0432.CCR-19-2309 31857430 PMC6980765
114 Walerych D Napoli M Collavin L Del Sal G The rebel angel: Mutant p53 as the driving oncogene in breast cancer Carcinogenesis 33 2007 2017 2012 10.1093/carcin/bgs232 22822097 PMC3483014
115 Boyle DP McArt DG Irwin G Wilhelm-Benartzi CS Lioe TF Sebastian E McQuaid S Hamilton PW James JA Mullan PB The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer Histopathology 65 340 352 2014 10.1111/his.12398 24612173
116 Weis KE Ekena K Thomas JA Lazennec G Katzenellenbogen BS Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein Mol Endocrinol 10 1388 1398 1996 8923465 10.1210/mend.10.11.8923465
117 Zhang QX Borg A Wolf DM Oesterreich S Fuqua SA An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer Cancer Res 57 1244 1249 1997 9102207
118 De Mattos-Arruda L Weigelt B Cortes J Won HH Ng CKY Nuciforo P Bidard FC Aura C Saura C Peg V Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: A proof-of-principle Ann Oncol 25 1729 1735 2014 10.1093/annonc/mdu239 25009010 PMC6276937
119 Toy W Shen Y Won H Green B Sakr RA Will M Li Z Gala K Fanning S King TA ESR1 ligand-binding domain mutations in hormone-resistant breast cancer Nat Genet 45 1439 1445 2013 10.1038/ng.2822 24185512 PMC3903423
120 Carpten JD Faber AL Horn C Donoho GP Briggs SL Robbins CM Hostetter G Boguslawski S Moses TY Savage S A transforming mutation in the pleckstrin homology domain of AKT1 in cancer Nature 448 439 444 2007 10.1038/nature05933 17611497
121 Rudolph M Anzeneder T Schulz A Beckmann G Byrne AT Jeffers M Pena C Politz O Köchert K Vonk R Reischl J AKT1 (E17K) mutation profiling in breast cancer: Prevalence, concurrent oncogenic alterations, and blood-based detection BMC Cancer 16 622 2016 10.1186/s12885-016-2626-1 27515171 PMC4982009
122 Wu W Chen Y Huang L Li W Tao C Shen H Effects of AKT1 E17K mutation hotspots on the biological behavior of breast cancer cells Int J Clin Exp Pathol 13 332 346 2020 32269671 PMC7137002
123 Xie R Yan Z Jing J Wang Y Zhang J Li Y Liu X Yu X Wu C Functional defects of cancer-associated MDC1 mutations in DNA damage repair DNA Repair (Amst) 114 103330 2022 10.1016/j.dnarep.2022.103330 35378404
124 Ott PA Hu Z Keskin DB Shukla SA Sun J Bozym DJ Zhang W Luoma A Giobbie-Hurder A Peter L An immunogenic personal neoantigen vaccine for patients with melanoma Nature 547 217 221 2017 10.1038/nature22991 28678778 PMC5577644
125 Tran E Robbins PF Lu YC Prickett TD Gartner JJ Jia L Pasetto A Zheng Z Ray S Groh EM T-cell transfer therapy targeting mutant KRAS in cancer N Engl J Med 375 2255 2262 2016 10.1056/NEJMoa1609279 27959684 PMC5178827
126 Barroso-Sousa R Jain E Cohen O Kim D Buendia-Buendia J Winer E Lin N Tolaney SM Wagle N Prevalence and mutational determinants of high tumor mutation burden in breast cancer Ann Oncol 31 387 394 2020 10.1016/j.annonc.2019.11.010 32067680
127 Zhu Y Meng X Ruan X Lu X Yan F Wang F Characterization of neoantigen load subgroups in gynecologic and breast cancers Front Bioeng Biotechnol 8 702 2020 10.3389/fbioe.2020.00702 32754579 PMC7370692
128 Richters MM Xia H Campbell KM Gillanders WE Griffith OL Griffith M Best practices for bioinformatic characterization of neoantigens for clinical utility Genome Med 11 56 2019 10.1186/s13073-019-0666-2 31462330 PMC6714459
129 Ren Y Cherukuri Y Wickland DP Sarangi V Tian S Carter JM Mansfield AS Block MS Sherman ME Knutson KL HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer Oncoimmunology 9 1744947 2020 10.1080/2162402X.2020.1744947 32523802 PMC7255108
130 Sahin U Türeci Ö Personalized vaccines for cancer immunotherapy Science 359 1355 1360 2018 10.1126/science.aar7112 29567706
131 Parkhurst MR Robbins PF Tran E Prickett TD Gartner JJ Jia L Ivey G Li YF El-Gamil M Lalani A Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers Cancer Discov 9 1022 1035 2019 10.1158/2159-8290.CD-18-1494 31164343 PMC7138461
132 Sueangoen N Grove H Chuangchot N Prasopsiri J Rungrotmongkol T Sanachai K Darai N Thongchot S Suriyaphol P Sa-Nguanraksa D Stimulating T cell responses against patient-derived breast cancer cells with neoantigen peptide-loaded peripheral blood mononuclear cells Cancer Immunol Immunother 73 43 2024 10.1007/s00262-024-03627-3 38349410 PMC10864427
133 Jain KK Personalized immuno-oncology Med Princ Pract 30 1 16 2021 10.1159/000511107 32841942 PMC7923844
134 Zhang X Kim S Hundal J Herndon JM Li S Petti AA Soysal SD Li L McLellan MD Hoog J Breast cancer neoantigens can induce CD8+ T-cell responses and antitumor immunity Cancer Immunol Res 5 516 523 2017 10.1158/2326-6066.CIR-16-0264 28619968 PMC5647648
135 Xiuli Z Goedegebuure SP Myers NB Vickery T McLellan MD Gao F Sturmoski MA Chen MY Kim SW Chen I Neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses in patients with triple negative breast cancer medRxiv: 2021.2011.2019.21266466 2021
136 Disis MLN Guthrie KA Liu Y Coveler AL Higgins DM Childs JS Dang Y Salazar LG Safety and outcomes of a plasmid DNA vaccine encoding the ERBB2 intracellular domain in patients with advanced-stage ERBB2-positive breast cancer: A phase 1 nonrandomized clinical trial JAMA Oncol 9 71 78 2023 10.1001/jamaoncol.2022.5143 36326756 PMC9634596
137 Morisaki T Kubo M Umebayashi M Yew PY Yoshimura S Park JH Kiyotani K Kai M Yamada M Oda Y Neoantigens elicit T cell responses in breast cancer Sci Rep 11 13590 2021 10.1038/s41598-021-91358-1 34193879 PMC8245657
138 Chang MT Asthana S Gao SP Lee BH Chapman JS Kandoth C Gao J Socci ND Solit DB Olshen AB Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity Nat Biotechnol 34 155 163 2016 10.1038/nbt.3391 26619011 PMC4744099
139 Neefjes J Jongsma ML Paul P Bakke O Towards a systems understanding of MHC class I and MHC class II antigen presentation Nat Rev Immunol 11 823 836 2011 10.1038/nri3084 22076556
140 Klebanoff CA Wolchok JD Shared cancer neoantigens: Making private matters public J Exp Med 215 5 7 2018 10.1084/jem.20172188 29269561 PMC5748868
141 Malekzadeh P Pasetto A Robbins PF Parkhurst MR Paria BC Jia L Gartner JJ Hill V Yu Z Restifo NP Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers J Clin Invest 129 1109 1114 2019 10.1172/JCI123791 30714987 PMC6391139
142 Pecher G Häring A Kaiser L Thiel E Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial Cancer Immunol Immunother 51 669 673 2002 10.1007/s00262-002-0317-z 12439613 PMC11034218
143 Sharma A Koldovsky U Xu S Mick R Roses R Fitzpatrick E Weinstein S Nisenbaum H Levine BL Fox K HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ Cancer 118 4354 4362 2012 10.1002/cncr.26734 22252842 PMC3330145
144 Pettitt SJ Frankum JR Punta M Lise S Alexander J Chen Y Yap TA Haider S Tutt ANJ Lord CJ Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance Cancer Discov 10 1475 1488 2020 10.1158/2159-8290.CD-19-1485 32699032 PMC7611203
145 Ruangapirom L Sutivijit N Teerapakpinyo C Mutirangura A Doungkamchan C Identification of shared neoantigens in BRCA1-related breast cancer Vaccines (Basel) 10 1597 2022 10.3390/vaccines10101597 36298462 PMC9609887
146 Iiizumi S Ohtake J Murakami N Kouro T Kawahara M Isoda F Hamana H Kishi H Nakamura N Sasada T Identification of novel HLA class II-restricted neoantigens derived from driver mutations Cancers (Basel) 11 266 2019 10.3390/cancers11020266 30813491 PMC6406322
147 Chandran SS Ma J Klatt MG Dündar F Bandlamudi C Razavi P Wen HY Weigelt B Zumbo P Fu SN Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA Nat Med 28 946 957 2022 10.1038/s41591-022-01786-3 35484264 PMC9117146
148 Lo W Parkhurst M Robbins PF Tran E Lu YC Jia L Gartner JJ Pasetto A Deniger D Malekzadeh P Immunologic recognition of a shared p53 mutated neoantigen in a patient with metastatic colorectal cancer Cancer Immunol Res 7 534 543 2019 10.1158/2326-6066.CIR-18-0686 30709841 PMC6685528
149 Kim SP Vale NR Zacharakis N Krishna S Yu Z Gasmi B Gartner JJ Sindiri S Malekzadeh P Deniger DC Adoptive cellular therapy with autologous tumor-infiltrating lymphocytes and T-cell receptor-engineered T cells targeting common p53 neoantigens in human solid tumors Cancer Immunol Res 10 932 946 2022 10.1158/2326-6066.CIR-22-0040 35749374 PMC9357191
150 Zacharakis N Huq LM Seitter SJ Kim SP Gartner JJ Sindiri S Hill VK Li YF Paria BC Ray S Breast cancers are immunogenic: Immunologic analyses and a phase II pilot clinical trial using mutation-reactive autologous lymphocytes J Clin Oncol 40 1741 1754 2022 10.1200/JCO.21.02170 35104158 PMC9148699
151 O'Connell MJ Selection and the cell cycle: Positive Darwinian selection in a well-known DNA damage response pathway J Mol Evol 71 444 457 2010 10.1007/s00239-010-9399-y 21057781
152 Su YC Lee WC Wang CC Yeh SA Chen WH Chen PJ Targeting PI3K/AKT/mTOR signaling pathway as a radiosensitization in head and neck squamous cell carcinomas Int J Mol Sci 23 15749 2022 10.3390/ijms232415749 36555391 PMC9778923