1. Introduction
Thanks to treatment implementations [ 1 ], metastatic breast cancer (MBC) has shown an improvement of outcomes in the last years. However, prognosis is still critical [ 2 ], with reported 27% 5-year survival rates [ 3 ]. Incidence of MBC interests 25–28% as de novo metastatic, while the rate of metastatic recurrence is reported in 20–30% of patients in western countries—and can be even higher in low- to medium-income countries [ 4 ]. Over time, the risk of becoming metastatic increases, and the data describe a cumulative risk of 4.8% (4.7–4.8) at one year, 5.6% (5.5–5.6) at two years, 6.9% (6.8–7.0) at five years and 8.4% (8.3–8.5) at ten years [ 5 ].
Bone metastasis commonly occurs in solid tumors; 36% of the incidence is from breast cancer [ 5 ], with a tendency of incidence in luminal subtypes [ 6 ]. In the surveillance epidemiology end result (SEER) database, a retrospective analysis based on subtype and incidence of distant metastasis, data on the first site of relapse show that bone metastases commonly involve luminal subtypes (ER+/HER2− 58.52% and in ER+/HER2+ subtype 47.28% of incidence) [ 6 ]. The ER−/HER2+ subtype has a higher proportion of liver metastases (31.72%), while the triple negative (TN) subtype is more affected by lung involvement (32.09%), with an incidence of bone metastases of 34.49% and 36.39%, respectively [ 6 ]. In a retrospective study by Molnar IA et al., the luminal A subtype presented a tendency of isolated bone metastases in 59% of cases [ 7 ]. In breast cancer, bone metastasis can occur in a de novo or recurrent setting, with a pluri- or oligometastatic presentation and may or may not be associated with other sites of involvement, so the spectrum of prognoses can differ greatly [ 6 , 8 , 9 ].
Etiopathology of bone metastasis is based on multicellular unit (osteoblasts, osteoclasts, bone lining cells, osteocytes) disruption with release of growing factors (TGF-B, FGF, PDGF, IGF) that promotes increase of tumor cell growth and compromise of secondary bone architecture [ 5 , 10 ]. In particular, biologic theory hypnotizes that, in sclerotic lesions, the tumor produces growth factors and induces osteoblast differentiation with the inhibition of bone resorption, while, in lytic lesions, tumor-derived factors enhance pro-osteoclastogenic differentiation and activity with consequently bone resorption [ 11 ].
Due to the release of chemical mediators, bone metastases are a common cause of cancer pain, with increasing of pressure in the bone, microfractures, stretching of the periosteum, reactive muscle spasm, nerve root infiltration, compression of the nerve due to collapse of the bone [ 12 ].
Skeletal-related events (SRE) are complications of bone metastasis growth and consist of pathologic fractures, spinal cord compressions and the necessity of radiotherapy for pain/impending fracture or surgery to bone. SRE can compromise performance status, with a reduction of quality of life, poor survival outcomes and also limited access to systemic therapies [ 13 ].
Thanks to new emerging diagnostic imaging and systemic therapies [ 14 ], alongside the most compromised presentations of bone metastases in breast cancer, we are assisting even more with oligometastatic presentations (de novo or inducted) [ 8 ]. Early detection of metastases—and possibly using targeting agents—can enhance disease control over time [ 2 , 15 , 16 ]. Associated with systemic therapeutic options, local treatments such as radiotherapy (RT), are possible options for the implementation of local controls—with both palliative and eradication intents [ 17 , 18 ]. The radiobiological aim of radiotherapy is to cause an interruption of the vicious biomolecular pain cycle with not only pain relief, but also decreasing the local tumor burden in more radiosensitive tumor subtypes [ 19 ]. It has been clinically demonstrated that patients obtain an immediate relief of symptoms in 2–4 weeks [ 11 , 20 , 21 ], and radiologically demonstrated that, for intent-to-eradicate treatments, local controls at 1 and 2 years can achieve 90.3% and 82.4% success with excellent safety [ 22 ]. For this reason, oligometastatic/oligoprogressive patients are even more challenging because physicians can imbricate local treatments such as radiotherapy with new systemic drugs to achieve higher progression-free survival—and in general, improve overall survival. In these settings, radiotherapy can also promote eradication of subclones resistant to systemic therapy.
Here we propose a review of diagnostic imaging for the early detection of bone metastasis in breast cancer, their use for radiotherapy targeting and local therapy options with a focus on radiotherapy possibilities in terms of dose and volumes and integration of chemoradiotherapy to improve clinical outcomes. The final purpose is to offer a practical guide for multidisciplinary management of patients with bone metastases from breast cancer.
2. Diagnostic Imaging for Bone Metastasis from Breast Cancer
The metastatic spread from a primary breast tumor can occur at an early, pre-symptomatic stage. Disseminated cells can lie dormant for years before becoming clinically evident [ 23 ]. In some studies [ 24 , 25 ], it has been shown that during the metastatic process of breast tumors, disseminated cancer cells at early stages of tumor evolution successfully establish themselves in the bone marrow [ 23 ]. Based on this theory, adjuvant systemic therapy (chemotherapy, target therapy and/or hormone therapy), is always administered when indicated.
In terms of correctly identifying subsetting and prognosis, it is challenging for physicians to precociously identify bone metastasis during staging and follow-up. Even more diagnostic and functional imaging are moving towards this goal. Today, with innovations in morphologic and functional exams, novel technologies offer possibilities to detect early bone metastases. Imaging is considered fundamental not only for diagnosis, but also as necessary to identify target lesions in local treatments.
2.1. Morphologic Imaging
Morphologic exams, including radiographs or computed tomography (CT), are based on changes in bone density. Based on metastasis behavior, (lytic, sclerotic or mixed) metastases can present different pattern at imaging.
To be detected at CT exams, bone metastases need to be at least one cm with a loss of density around 25–50%. Usually breast cancer bone metastasis are lytic, but during treatments, due to response with osteoblastic reaction, they can become peripherally osteosclerotic. CT also allows to define soft-tissue invasion outside bone. Moreover, morphologic exams are fundamental to define critical site of bone metastasis which are at risk for SRE.
Magnetic resonance imaging . Conventional MRI sequences with T1, T2 and DWI studies, allow to detect breast cancer bone metastases with a sensitivity reported since to 100% [ 26 ] and a specificity of 90%, so they are used in case of doubt and are very useful for early detection. The pattern of MRI behavior of bone metastases usually determines low T1-signal, T2 hyperintensity and DWI signal restriction [ 27 ]. MRI allows visualizing lesions with high precision, and it is also useful to study integrity of spinal cord and eventually condition of its compression. For bone study, MRI is performed without contrast, but for study of spinal cord or surrounding soft tissue, contrast is required. Recently, whole-body MRI (WB-MRI) has been developed for study of entire bone compartment, but its utility for clinical practice is still under investigation—especially for early detection of bone metastasis [ 28 ]. In any case, its application could be interesting for early detection of oligometastatic patients. In literature, data on WB-MRI also provide a quantitative measure of treatment response in skeletal metastases and its sensitivity and specificity are superior to skeletal scintigraphy [ 29 , 30 ].
2.2. Functional Imaging
Bone scintigraphy. Functional imaging finds a role in staging, restaging and, during follow-up in detecting bone metastasis in breast cancer. The osteotropic agent used for skeletal imaging is metastable technetium 99 (99mTc) labeled diphosphonates for bone scintigraphy.
99mTc-radiolabeled diphosphonates has been in use since 1970s and thanks to its effectiveness and low cost, it is worldwide dedicated to first-level staging. Reported sensitivity and specificity are 78 and 48%, respectively [ 27 , 31 ]. Bone scintigraphy usually detects bone turnover, so metastasis with a prevalent lytic behavior can be considered as false negative. An alteration, not exclusively cancer-related, in 5–10% bone can cause accumulation of agents on bone scans, though this can be also a confounding factor with a benign pathology such as degenerative disease. For this reason, a second-level exam can be required in borderline cases. Another limitation of bone scan is represented from absence of volumetric evaluation and poor spatial resolution (<1 cm). An implementation of a bone scan is represented by single photon emission CT (SPECT/CT), in which the same radionuclide used for conventional skeletal scintigraphy is injected during acquisition of additional axial slices, with the possibility to have volumetric evaluation.
Positron emission tomography (PET) . PET is superior to the bone scan in terms of spatial resolution with acquisition of tomographic images. It also provides information about treatment response and prognosis [ 32 ]. Most employed radiopharmaceutical agents for skeletal investigation are 18F labeled sodium fluoride (18F NaF) and 18F labeled fluorodeoxyglucose (18F FDG). Due to fluoride ions collocation in the remodeling skeletal areas, 18F-NaF PET is particularly sensible to osteoblastic activity. 18F-NaF PET presents a high sensibility (100%) and specificity of 97% and it is more efficacy to detect bone metastases than 18F FDG, though it is still to be defined the setting of patients in which it could be useful [ 27 ]. About breast cancer, indolent subtypes with bone tropism such as luminal or lobular cancer, could be considered for specific protocols with 18F-NaF PET. Moreover, these subtypes with slower cellular growth and consequent lower uptake of glucose, present a poor sensibility of 18-FDG PET/CT and their spread could be missed.
18-FDG PET/CT is instead considered useful in case of locally advanced or metastatic disease for staging, evaluate treatment response and prognosis [ 33 ]. Accumulation of its agent is in high turnover areas. The sensitivity and specificity of 18F-FDG PET for detection of bone metastasis is 98% and 56%, respectively, even if it can be different according to subtypes [ 27 ]. Indication for use in follow-up is still controversial.
Hybrid images . A recent review by Cook G et al. [ 29 ] reported that molecular and hybrid imaging has an increasing role in early detecting of bone metastases and in monitoring response at early time points. In this sense, functional imaging as emission computed tomography (SPECT/CT), positron emission tomography/CT (PET/CT) or PET/MRI in breast cancer could find a role in identified early patients not responder to systemic therapies for shifting to further line of treatment with a benefit on disease control and cost/effectiveness of health systems. This advantage is based on combination of morphologic, physiologic and metabolic aspect for skeletal evaluation. Comparing the data in literature, the advantages of PET/MRI are still few and studies are focused on finding the best setting of patients [ 34 ].
2.3. Diagnostic Imaging for Treatment Planning of Radiotherapy
Morphologic imaging is useful for identify bone lesions and soft tissue invasion. In palliative radiotherapy treatments of bulky metastases, CT scan simulation allows radiotherapist contouring also of soft tissue surrounding. In some cases, co-registration with diagnostic CT scan with contrast can be helpful for distinguish healthy soft tissue from that interested by spread of disease outside bone metastases. MRI is useful for treatments with radical intent because it allows higher precision in gross tumor volume (GTV) and spinal cord contouring. Increased accuracy is always associated with higher local control and less side effects. MRI is usually required for stereotactic body radiotherapy (SBRT), in which target of the treatment is the lesion with a millimetric margin and dose are high. Functional imaging is less strictly used for contouring of bone metastasis in breast cancer and hold a function of supporting detecting of lesion at co-registration.
2.4. Biopsy on Bone Metastasis: When Imaging Is Not Enough
Metastatic presentation—especially in case of relapse—usually required a biopsy for prognostic factors study to confirm nature of disease and setting of systemic therapies. More often, in case of de novo metastatic patients, soft-tissue or primary tumor undergo pathologic study, while in case of relapse, especially for isolated bone presentation, a biopsy of lesion can become mandatory. Other conditions in which biopsy can be mandatory are necessities of differential diagnosis. The differential diagnosis for bone metastases includes chondrosarcoma, primary malignant lymphoma of the bone, multiple myeloma, post-radiation sarcoma and osteomyelitis. A distinction between acute osteoporotic fractures versus metastatic fractures should be made on radiographic imaging. In osteoporosis, the cortical bone may appear preserved, while in secondary lesions, cortical bone is typically destructed. Another possible differential diagnosis is sarcoidosis, because lesions cannot be reliably distinguished from metastatic lesions on routine MRI studies [ 35 ]. 18F-FDG PET/CT is highly sensitive in detecting granulomatous bone marrow infiltration, but an increased 18F-FDG uptake can mimic metastatic disease, reducing the specificity of 18-FDG PET/CT when both sarcoidosis and a tumor which may develop bone metastases occur in the same patient [ 36 ].
3. Radiotherapy Treatments Options and New Drugs
Radiotherapy effect on bone metastasis. In-human pathologic data of radiotherapy damage on bone metastases are few. In general, RT effect is mediated by sublethal damage from free radical generated by water molecules or, in case of high doses, also direct lethal damage on DNA [ 37 ]. In fact, higher doses for fraction, as in stereotactic radiotherapy (SBRT), can promote direct cytotoxic, endothelial disruption with vascular death [ 38 , 39 ] ( Figure 1 ). On bone metastases, final effect of RT damage is reduction of pain (by interruption of biomolecular pain modulation mechanisms), interruption of osteolysis mechanisms and decrease of tumor burden [ 40 ]. Radiotherapy with palliative intent causes an interruption on neuromodulatory algic mechanism by early depletion of inflammatory cells, thanks to inhibition of the inflammatory cells [ 12 ]. Main trigger of pain modulation by bone metastases are nerve growth factor (NGF), bradykinin, serotonin, adenosine triphosphate, H+, lipids (prostaglandin E2) and degenerin family of ion channels [ 12 ].
Decrease of osteolysis is mediated by osteoclasts apoptosis, as in vitro data showed [ 41 ]. Radiotherapy can also promote reossification process from 3–6 weeks from the end of radiotherapy and reaches highest degree within six months [ 11 ]; ossification process is realized in 65% to 85% of lytic metastases in unfractured bone [ 12 ].
In a study by Steverink et al. [ 42 ], on ten biopsy of vertebral metastasis who underwent a single preoperative SBRT of 18 Gy, a change of tissue in 21 h, as necrosis development, happened in 83% of sample. A consistent reduction of mitotic activity and vessel density (especially in renal cell metastases who are enriched of vessels) was also reported. On these samples, pathologic analysis underlined a persistence of T-cell and natural kill cell density after SBRT. Probably, in a further phase, immune-related reactions starts against antigens exposed by tumor cell damage.
From radiobiological data on primary tumor, in which lesions since to four centimeters were treated with definitive radiotherapy, 3-year local control of 81 and 100% were achieved with doses of 70–80 Gy and >80 Gy, respectively [ 43 ]. Some authors speculate that a large single fraction could be more advantageous on breast cancer, compared with prolonged fractionated radiotherapy [ 44 ]. For the tissue damage caused, radiotherapy can be considered crucial as local ablative treatment in oligometastatic breast cancer setting especially when a BED > 75 Gy [ 45 ].
Dose and volumes of radiotherapy treatments. Dose and volume prescriptions are chosen according to aim of treatment. In palliative setting, radiotherapy aims to control symptoms and local growing of disease. It is usually combined with antalgic drugs modulation and orthopedic multidisciplinary evaluation can be required for setup and mobilizing patients during RT. Palliative RT volumes usually include all the bone compartment and extra compartment invasion of lesion, with sub-centimetric margins. Historically, these treatments are administered with 3D conformal treatment plan with one or more fields of therapy, but at the present day, especially in case of retreatment, even more sophisticated techniques such as intensity modulated radiotherapy (IMRT) or volumetric modulated arch therapy (VMAT) can be chose for optimizing dose distribution, avoiding missing target and preserving organ at risk, especially spinal cord. Palliative radiotherapy is brief with administration of 8–20 Gy in 1–5 daily fractions (Fr), to obtain a pain relief or, in some cases, control of neurological impairment in some weeks [ 20 , 21 ] ( Table 1 a). In a metanalysis of Chow E et al. it is reported that efficacy of single-fraction RT and multi-fractions (since to 30 Gy in 10 Fr) are equivalent in terms of pain control, but rate of retreatment are 2.5-fold higher in single-fraction arms [ 46 ]. Patients who underwent surgery for SRE can benefit of adjuvant radiotherapy on surgery bed and residual disease. A prospective study on bone metastases with spinal cord compression showed that responsiveness of breast cancer tumor (that presents intermediate radiosensitivity) is linked to schedule of 30 Gy given with 10 Fr, while dose escalation is not related to an improvement of outcomes [ 47 ].
In oligometastatic settings, treatments with radical purpose are usually given in few days, but total doses reach a higher biologic equivalent dose (BED), of at least 75 Gy [ 45 , 48 , 49 ] ( Table 1 b). For these treatments, higher sophisticated techniques are usually used to conform volumes and stereotactic body radiotherapy technique (SBRT) is often applied for sparing organ at risk and give higher doses on the core of GTV. SBRT requires strictly system of immobilization and co-registration with MRI is mandatory to detect bone lesion and for spinal cord identification [ 50 ].
In literature, few retrospective and prospective series reported data on oligometastatic breast cancer, but results show that a treatment direct to metastases (surgery or radiotherapy) is significantly related to survival outcomes at 10–20 years [ 17 , 18 ]. Patients who are candidate to these treatments need to be carefully selected in terms of prognosis [ 55 ]. In general, breast cancer is a favorable prognostic factor for OS in oligometastatic patients who underwent SBRT (HR, 0.12; 95% CI, 0.07–0.37) [ 56 ]. Another prognostic factors that has been found related to OS in a retrospective SBRT for oligometastatic analysis was BED > 75 Gy [ 48 ]. In a study by Milano MT et al. survival outcomes of SBRT in 48 oligometastatic breast cancer treated for extracranial metastases showed that bone-only oligometastatic present a younger age, usually are hormone-responders and synchronous with diagnosis [ 17 ]. In this study, OS and freedom from widespread metastases (FFWM) were better in bone-only group (12 patients); these patients underwent RT with a median EQD2 of 57.3 Gy [38.3–70]. In a Phase II prospective trials, oligometastatic breast cancer patients were treated on all metastatic sites with SBRT (30–45 Gy in 3 Fr) or IMRT (60 Gy in 25 Fr). Results showed that 60 on 92 metastatic lesions were in the bone and 80% of patients included were Luminal A. In this study, 1- and 2-year PFS was 75% and 53%, respectively; two-year LC and OS were 97% and 95%, respectively, while only one bone lesion on 60 relapsed in spine (but was treated with 17 Gy in 3 Fr) [ 52 ].
In another study of 2015 by Yoo GS et al. 50 patients with bone metastases who underwent RT for a median dose of 30 Gy (20–60 Gy) were retrospectively studied. The analysis of Yoo GS showed that patients treated with a BED of at least 50 Gy presented better 5-year LC and OS [ 51 ]. In a prospective cohort of 50 patients with breast cancer, 68 spine bone metastasis were treated with a single fraction radiosurgery for a total mean dose of 19 Gy (15–22.5 Gy) with a 96% of pain control and local control at 15 months of 100% [ 44 ]. In a mixed cohort of 22 oligometastatic and oligoprogressive patients, 32% were affected from breast cancer and were treated with doses from 35 to 50 Gy in 5 Fr, to spinal and non-spinal metastases, respectively [ 53 ]. Local control achieved was 91% at 1-year, with median PFS and OS, respectively of 10.1 and 37.3 months, while PFS stratified for OP and OM group were 6.6 and 10.6 months, respectively.
Some patients are not candidate to stereotactic radiosurgery (SRS), for presence of more than three lesions or for proximity to spinal canal and an intermediate solution to achieve a better local control is to administer a simultaneous integrated boost (SIB) on GTV, treating whole vertebra with palliative dose and fractionation. In a cohort of 12 patients, of which only one was affected by breast angiosarcoma (with a different radiosensitive respect breast carcinoma), treatment with a SIB of 40 Gy and 30 Gy on whole vertebra given in 10 Fr showed a 1-year LC of 93% [ 54 ].
At the present time, there is a great inhomogeneity in dose prescription especially for extraspinal bone metastasis and the need of consensus guidelines supported by evidences is necessary [ 57 , 58 ].
Cytotoxic chemotherapy and radiotherapy . Systemic therapy is still the fundamental treatment for all molecular subtypes in the management of MBC with bone metastases [ 33 , 59 ]. Drug choice is influenced by immunophenotype, previous treatment and tumor spread [ 33 , 59 ]. In TNBC or hormone-resistance MBC anthracycline- or taxane-based regimens are preferred treatment [ 60 , 61 ]. Recently, therapeutic options after anthracycline- and in case of taxane-resistant disease were increased. In fact, some cytotoxic drugs after first line chemotherapy treatment are become available. In the last years, eribulin [ 62 ] and nanoparticle albumin-bound paclitaxel [ 63 ], in monotherapies administration, were added to therapeutic options that have long been available as capecitabine, vinorelbine, cyclophosphamide, gemcitabine and pegylated liposomal doxorubicin [ 64 , 65 ]. In addition, combination therapies such as paclitaxel plus gemcitabine or carboplatin plus gemcitabine could represent an alternative option, but sequential monotherapy is usually preferable in MBC setting [ 62 , 63 ]. Generally, bone metastases had the low response rates to chemotherapy. For this reason and for the need of a rapid pain relief, these systemic treatments are often imbricated with palliative radiant treatment. In oligometastatic setting, to imbricate radiant treatments with cytotoxic treatment it can be considered to achieve a better disease control, discussing case by case. In both cases, considering the significant risk of myelosuppression of both treatments, radiotherapy is almost never concomitant with systemic treatment. The clinicians must merge these treatments to avoid the overlap of the specific nadirs of bone marrow toxicity. The sequence of these treatments is dictated by the need to prioritize a systemic control of disease versus a locoregional control (oligoprogressive) or the pain control.
Hormonal therapy and radiotherapy. In MBC patients, bone metastases more often derived from HR-positive tumors as previously described [ 7 ]. In this case hormonal therapy (ET) is the preferred choice in most cases, except for rapidly progressive disease or in case of visceral crisis, where cytotoxic drugs remain the preferred option [ 59 ]. In recent years, the introduction of everolimus (M-TOR inhibitor) [ 66 ] and alpelisib (PI3KCA inhibitor) [ 67 ] in hormone refractory disease and CDK4/6 inhibitors [ 14 , 68 ] in both hormone-sensitive and hormone-refractory disease has made hormonal sequence more complex and often longer.
Target therapy in ER+HER2− setting and radiotherapy. Recently, target therapies became even more common in ER+/HER− metastatic setting. In addition, frequent presence of bone metastases has also determined the need to imbricate these systemic therapies with palliative or radical RT. Hormonal treatment alone, characterized by an excellent toxicity profile, not arises problem for combination with radiotherapy, association with target therapy instead entails timing issue for imbrication. No prospective studies, addressed to establish the best combination schedule between target therapy and RT, are currently ongoing. Continuous and semicontinuous therapeutic schedules for these target therapy, implying necessity of treatment discontinuation in case of necessity to decrease cumulative toxicity. As regards everolimus and alpelisib, in the absence of clinical data, no biologic contraindications can be postulated at the basis of the need for drug suspension during radiant treatment. Vice versa, for using of CDK4/6 inhibitors (ribociclib, palbociclib or abemaciclib) that act directly on the cell cycle, it is evident that optimization of the combination with radiant treatments appears to be a goal to be achieved. In pivotal studies of CDK4/6 inhibitors, radiotherapy is allowed before systemic therapies beginning and it is preferable to avoid concomitance [ 68 , 69 , 70 ]. In literature, few data are reported that showed feasibility of radiotherapy in concomitance with CDK4/6 inhibitors, with a possible side effects arising (for example there are some reports of GI toxicity with RT on bone metastasis during abemaciclib) [ 71 , 72 , 73 , 74 ]. Another interesting issue about radiotherapy and CDK4/6 inhibitor is time of association because these drugs cause a cell blockage in G1 phase with consequently possible radioresistance. At the end, hypothetic effect on immune system by CDK4/6 inhibitor could be implemented with ablative RT, and it is under investigation in Phase II protocol ongoing.
HER2 target therapy and radiotherapy. In preclinical studies in vivo and in vitro, it is clearly identified that HER2−overexpression is a factor of radioresistance in breast cancer [ 75 , 76 , 77 , 78 ]. It seems that the PI3-K/Akt pathway, increase of antiapoptotic transcription factors (NF-KB and c-myc), Fak protein [ 79 ] or STAT3-survivin signaling [ 80 ] are implicated in the mechanisms of radioresistance of HER2 positives breast tumors.
Recently, in clinical practice, since from trastuzumab (the first anti-HER2 monoclonal antibody) many treatments have been developed that are revolutionizing the systemic therapy of HER2 positive disease. Various anti-HER2 TKIs such as lapatinib, neratinib and tucatinib and new anti-HER2 monoclonal antibodies such as pertuzumab and T-DM1 have been introduced in recent years.
Concerning the trastuzumab, some authors [ 81 , 82 ] described HER2−dependent sensitization to radiation-induced apoptosis by trastuzumab in a panel of breast cancer cell lines. This radiosensitizing effect was not associated with toxicities as demonstrated in preclinical model [ 83 ]. Furthermore, in MBC patients, concomitant administration of trastuzumab with radiotherapy does not increase major toxicity, particularly cardiac.
Moreover, for lapatinib and T-DM1, there are preclinical study with xenograft of HER2−positive breast cancer cells where the radiosensitizing effect of these drugs is confirmed [ 84 , 85 , 86 ]. Even in small clinical trials lapatinib and T-DM1 given at standard dose (respectively 1500 mg/day per os and 3.6 mg/kg intravenously every three weeks) in combination with RT were well tolerated [ 87 , 88 ]. However, it is important to note that a significant number of cases of radionecrosis was reported with concomitant T-DM1 and SRS for brain metastases in HER2−positive MBC.
Overall, the available data show a good efficacy profile and poor toxicity for the combinations between anti-HER2 therapy and radiotherapy, however these data often concern small numbers of patients, many are retrospective or do not directly compare the concomitant association.
PARP inhibitors and radiotherapy. Poly(ADP-ribose) polymerase (PARP) proteins catalyze the polymerization of poly(ADP-ribose) on proteins. This reversible post-translational modification of proteins—also called parylation—has been implicated in many cellular mechanisms, notably DNA repair. PARP detects single-strand breaks (SSBs) and—through its parylation activity—recruits proteins that mediate DNA repair such as XRCC1, which stabilize the DNA break. DNA polymerase performs complementary base synthesis, and DNA ligase III ligates the ends of the DNA [ 89 ]. Ultimately, the auto-parylation of PARP releases it from the SSB site. PARP activity is enhanced in many tumors [ 90 ]. Thus, the inhibition of PARP activity is being used increasingly as a therapeutic strategy especially in MBC with BRCA mutations. Two PARPis are recently showed an interesting efficacy in BRCA mt MBC (olaparib and talazoparib). Radiosensitizer molecules are used to enhance the effects of radiation on tumors, improving the antitumor response with lower toxicity. PARPis are potential radiosensitizers, based on their ability to enrich unrepaired DNA damage [ 91 ]. In tumor models comprehending breast cancer, PARPis have had good efficacy as radiosensitizers, with an enhanced of cellular death. Their effects included inhibition of tumor cell proliferation, decreased cellular survival, delayed tumor growth and improved survival in mice [ 92 ]. However, the radiosensitizing effect of this combination raises concerns about its toxicity, the secondary hematological effects of PARPis, such as myelosuppression [ 93 ], could amplify when combined with pelvic or large-field spinal radiation. Taken together these consideration, the rationale for the concomitant use of PARPi and radiotherapy is strong, however, in light of the bone marrow toxicity profile, in the absence of prospective trials with verified dosage of the drug, we do not recommend the concomitant use of these treatment with radiotherapy.
Immunotherapy and radiotherapy . Although immunotherapy has shown antitumor activity against several advanced tumors in recent years, at the present day for breast cancer data showed in TN promising results. In fact, atezolizumab plus nab-paclitaxel in PD-L1 positive metastatic TN population has shown an increase of PFS and OS respect chemotherapy alone [ 94 ]. The spread of bone metastases activates many immunosuppressive pathways. Therefore, the immunophenotype of bone metastases could represent a different pattern of response to immunotherapy when compared to visceral disease. Though checkpoint inhibitors have shown significant efficacy in many tumors including TN breast cancer with visceral metastases, their specific performance in bone metastases is not well understood and it may be poor. Although we currently have not clinical data, radiotherapy on bone metastases could make these localizations of disease more immunogenic and optimize the effectiveness of inhibitory checkpoints. Given these considerations, studying how and when to combine these treatments is an important goal of clinical research in the coming years.
Further perspectives. At the present time there is an increasing interest in oligometastatic breast cancer, especially in good prognosis setting (Luminal subtype, single lesion, bone metastasis only). Ongoing trials are investigating possible therapeutic patterns in this sense. In April 2020, a Medline on ClinicalTrial.gov showed that six trials were active for oligometastatic while only one trial was active for oligo progression.
A Phase II trial (CLEAR, NCT03750396 in Table 2 ) is dedicated to oligometastatic recurrent patients (all parenchyma) with ER+/HER2− who underwent a radical local approach [surgery, radiotherapy (57–97.5 Gy/6–10 Fraction) or radiofrequency] during first systemic line to test PFS. Another trial ( NCT02364557 ) is recruiting patients with limited MBC, randomizing them between systemic therapies (according to standard of care) and systemic therapies with association of stereotactic radiosurgery in one, three or five fractions at the discretion of the treating physician, to test PFS and OS. A Phase III study, STEREO-SEIN Trial, ( NCT02089100 ) is testing the role of curative SBRT in de novo oligometastatic breast cancer (no triple negative subtypes), randomizing patients between systemic therapies (according to standard of care) and systemic therapies with association of stereotactic radiosurgery. In another trial ( NCT03808337 ), supported by Memorian Sloan Kettering Cancer Center, is recruiting metastatic non-small cell lung cancer or triple negative breast cancer, with randomization between standard systemic therapies vs. receiving SBRT (with a minimum BED more than or equal to 48 Gy 10 ) to all sites of metastasis, concurrently with systemic therapies. In another Phase I/II trial by NCI ( NCT00182793 ), patients with Stage IV Metastatic and Stage IIIB/C Breast Cancer were enrolled to receive bone marrow ablation with chemotherapy and autologous-autologous tandem hematopoietic stem cell transplantation and concurrent RT on site of disease. In this study, oligometastatic patients, received helical-tomotherapy RT on site of metastases with standard fractionation. In CIMER study ( NCT04220476 ), a Phase II study, patients with oligometastatic BC, luminal subtypes, who are candidates to first-line with CDK4/6 inhibitors will be randomizing between receiving first-line of treatment vs. underwent also immune-SBRT every 48 h on all sites of metastases with a total dose of 50 Gy in 5 Fr.
At the present time only one trial ( NCT03808662 ) is testing oligoprogressive setting in NSCLS and TNBC patients, randomizing them between standard of care and SBRT 9–10 Gy × 3 or 10 Gy × 5 fractions given every other day to all oligoprogressive sites.
4. Co-Adjuvant Systemic Therapies and Focal Alternatives to Radiotherapy
Bone target agents. To control skeletal disease, some other focal therapies have been developed and used in clinical practice, such as systemic therapeutic agents. First, bone target therapies which are systemic agents used to control skeletal disease frailty, even if in case of bone metastases. Behind oncological systemic therapies for breast cancer, two main groups are available, antiresorptive drugs and bone-seeking radiopharmaceuticals. Antiresorptive drugs aim to control both bone metastases incidence in adjuvant setting and their advantage in breast cancer is well consolidated [ 11 ]. Bisphosphonates and denosumab are commonly used in clinical practice and their therapeutic effect is based on targeting locoregional tissue cells to activate not only blocking of resorption mechanism, but also activating antitumor response by immune system activation.
Radiopharmaceuticals. Radiopharmaceuticals drugs are principally used for pain relief in palliative setting with involvement of more than one skeletal site [ 95 ]. Therapeutic bone-seeking radiopharmaceuticals can be divided into two principal chemical classes: cationic or calcium-analog (phosphorus-32, strontium-89 chloride and radium-223 chloride) which are incorporated as calcium in bone regions thank to mineralization process and anionic or noncalcium-analog (Samarium-153 lexidronam and rhenium-186 etidronate) bone-seekers with different mechanism of uptake into bone by chelating mechanism to organic phosphates. In literature, few experiences are reported on breast cancer patients. First of all, experiences with strontium-89 chloride (89 Sr) showed 75% of pain relief at two-three weeks from end of treatment [ 96 ]. Some other series reported results of use of rhenium-186 etidronate (186 Re–HEDP) on metastatic breast cancer patients with implementation of quality of life of 58% and pain relief of 60% [ 97 , 98 ]. To preserve bone marrow function, recent develop of alfa-emitter that present a short radiation range, has been applied also to metastatic breast cancer. radium-223 chloride (223 Ra) was administered in a Phase I study on 10 breast cancer metastatic patients with results of a pain relief since to 60% and absence of G3 bone marrow events [ 99 ]. In another study, breast cancer patients with predominant bone disease underwent 223 Ra therapy with metabolic activity reduction of lesions and a good safety profile [ 100 ]. CARBON trial, registered o 2016, is investigating a possible combination of 223 Ra and capecitabine in terms of safety and disease control for metastatic breast cancer patients with bone involvement [ 101 ]. Limitations of radiopharmaceuticals is their myelosuppressive persistent effect and indication to use principally in the palliative setting. No data are in favor of their use in preventive or oligometastatic setting in absence of symptoms.
Surgery . Bone metastases cause an impairment in bone density and architecture that has a negative impact on mechanical performance of bone, especially for support and motorial function [ 102 ]. Surgery can be considered both for excisional and palliative intention. Excisional surgery includes wide procedures, hemipelvectomy, wide resection with prosthesis, curettage and cementing, while palliative surgery includes internal and external fixation [ 103 ]. Although bone is only one possible site of metastatic lesions and local control on bone metastatic sites has a little effect on global status of disease, excisional intention of surgery can be considered in case of confined disease (oligometastatic, one parenchyma involved), to improve quality of live [ 103 ]. Surgery needs also healing time respect other therapies for local control and its indication needs to consider also systemic therapies ongoing and their time of suspension. Many target therapies for metastatic breast cancer can require a stop for side effects in terms of bone marrow suppression, to avoid post-surgery complications. Moreover, some drugs are cytostatic, and this can increase time for healing. Delaying systemic therapy in oligometastatic patients can reduce global disease control. A proper algorithm for establishing a diagnosis and evaluation of prognostic factors would help in planning the surgical intervention. In a study of Durr et al. a series of 70 patients with breast cancer bone metastases were treated with surgery and of the 19 patients with solitary bone lesions, only 26.3% (5 patients) were alive and free of disease at a mean follow-up of 35 months [ 104 ]. This retrospective study found that only two independent factors for survival were extent of disease and duration of symptoms from bone lesions, so they concluded that orthopedic surgery in patients with bone metastases secondary to breast cancer, wide resection is not likely to be necessary [ 104 ]. In another study by Szendroi et al. an algorithm based on staging, prognostic factors and patients’ condition for classification and surgical treatment of bone metastases was proposed. Patients with solitary metastasis and good prognostic factors can be considered for surgery with radical intent or minimal surgery (palliative) followed by radiotherapy, while patients with multiple metastases are candidate in case of impending fractures to palliative surgery, if global conditions are acceptable [ 105 ].
Palliative surgery usually is required for fracture or risk of fracture and/or neurological vertebrae symptoms in patients that present a systemic compromising with a prognosis of at least 6–8 weeks, to implement quality of life.
Interventional Radiology. Interventional radiology includes different therapeutic techniques all with the aim of stabilization of the bone and improvement in quality of life [ 106 ]. Percutaneous techniques include vertebroplasty that allow to inject surgical cement in the vertebral body with immediate and analgesic effect in few days—and more recently—cementoplasty, that stabilize also of extraspinal lesion, for example long bone sites. Other percutaneous technique, such as embolization (with pure alcohol and contrast), radiofrequency (with a hot needle since to 65 °C) and cryoablation (with a generation of temperature −100 °C) can also cause tumoral cell destruction and need to be carefully used in case of proximity with nerve and vascular structures. Endovascular techniques cause a loss of blood flow inside bone lesions and this can reduce pain by reducing of pain modulators circulation. In case of big masses these techniques reduce systemic reaction of cytokines release. Endovascular techniques are embolization that uses microparticles or liquid agents and chemoembolization that uses antimitotic drugs (adriamycin and platinum derivatives) with also antitumoral effect.
Respect surgery procedures, interventional radiology present rapid healing time, but further prospective studies need to test their application in specific sub settings of metastatic breast cancer patients.
5. Implication for Clinicians
According to time, disease presentation and prognosis, bone metastases from breast cancer patients can be addressed to different pathways of care, for optimize symptoms management and outcomes. It is mandatory to identify patients who are at risk to develop bone metastases to tailoring diagnostic exams and therapeutic intervention. In a study by Colleoni et al. the highest cumulative incidences of bone metastases at any time were among patients who had four or more involved axillary nodes at the time of diagnosis (14.9% at two years and 40.8% at 10 years) and among patients who had as their first event a local or regional recurrence or a recurrence in soft tissue, without any other overt metastases (21.1% at two years from first recurrence and 36.7% at 10 years) [ 107 ]. Hence, it is important to tailor follow-up in patients that can be considered at high risk of relapse.
The therapeutic pathway can be tailored for each patient, and often requires multidisciplinary interventions, since from individuation of patients at risk already during follow-up. Negative prognostic factors for developing bone metastases reported in literature are: tumor size (>5 cm), higher tumor grade, tumor subtypes (lobular carcinoma), number of positive lymph nodes, extent of disease, duration of the symptoms, age > 60 years and hemoglobin less than 11 g/L, while positive prognostic factors found were estrogen receptor positivity, solitary bone presentation, bisphosphonate treatment.
Based on this literature review, we summed up all available results in an algorithm for practical use. The algorithm begins with identification of presence of metastases. This is fundamental, both at staging and follow-up patients should be investigated with tailored approach and studied with diagnostic exam according to their risk of metastases development and symptoms.
At confirmation of metastases, according to literature results and in consideration of the need to classify the type of bone metastasis presentations to optimize the treatment, we can divide them, in the sequent subgroups: De novo or recurrent metastatic breast cancer: based on time of metastases presentation; Oligometastatic or plurimetastatic breast cancer: based on the presence of five metastatic sites or more; Bone-only or visceral metastatic breast cancer: based on parenchymal involvement.
After qualitative and quantitative definition of metastatic disease, patients need to be stratified in prognostic group to chose best therapeutic options. In literature are reported as prognostic factors, age, ECOCG, comorbidities, immunophenotype, previous treatments. In fact, a TN old patient with isolated bone metastases will have a different prognosis of a luminal A plurimetastatic young patients.
According to prognostic subgroups’ organization, here we report an algorithm pathway for radical and palliative setting management of these patients ( Figure 2 ). In this algorithm, patients with good prognosis are candidate to insertion of radical local therapies with definitive intent (radical radiotherapy SBRT/SRS, intervention radiology, surgery) on bone metastases during systemic therapies, but concomitance with drugs it is still under investigation (for achieve a better disease control). Patients with intermediate prognosis are the most heterogeneous group so for their management it is important to considered also prognostic factors (ER expression, age, performance status). They are addressed principally to maintain their systemic therapies and local treatments are introduced in case of symptoms and not compromised systemic situation. Patients with poor prognosis are candidate to therapies (systemic or local) that have the purpose to preserve quality of life, so also treatment of their bone lesions with radiotherapy or other techniques is considered with this intent.
6. Conclusions
Bone metastasis is a condition that unfortunately still affects patients with breast cancer, also limiting quality of life. Among these patients, oligometastatic breast cancer with only bone presentation represent a subgroup with favorable prognosis and in which escalation of diagnostic imaging methods, systemic therapies and imbrication with SBRT can be related with survival. Use of few or single-fraction SBRT can allow physician to administered BED of 75 Gy and to treat, with a radical intent, patient who present good prognosis.
Despite the considerations that can be drawn from currently available data, large pooled analysis and prospective trials are required to individuate best therapeutic algorithms, also considering new target therapies and the need of imbrication these treatment with radiotherapy to improve QoL and survival of our patients.
Author Contributions
F.M., A.O. and V.M. analyzed literature and chose the study design. V.M. provided paper elaboration and submission. All authors read and approved the final manuscript.
Funding
The APC was funded by © 2020 Novartis Italia
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Andre F. Slimane K. Bachelot T. Dunant A. Namer M. Barrelier A. Kabbaj O. Spano J.F. Marsiglia H. Rouzier R. Breast Cancer with Synchronous Metastases: Trends in Survival during a 14-Year Period JCO 2004 22 3302 3308 10.1200/JCO.2004.08.095 15310773
2. Sledge G.W. Curing Metastatic Breast Cancer JOP 2016 12 6 10 10.1200/JOP.2015.008953 26759458
3. American Cancer Society Survival Rates for Breast Cancer Available online: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html (accessed on 20 April 2020)
4. Harbeck N. Penault-Llorca F. Cortes J. Gnant M. Houssami N. Poortmans P. Ruddy K. Tsang J. Cardoso F. Breast cancer Nat. Rev. Dis. Primers 2019 5 66 10.1038/s41572-019-0111-2 31548545
5. Hernandez R.K. Wade S.W. Reich A. Pirolli M. Liede A. Lyman G.H. Incidence of bone metastases in patients with solid tumors: Analysis of oncology electronic medical records in the United States BMC Cancer 2018 18 44 10.1186/s12885-017-3922-0 29306325 PMC5756362
6. Wu Q. Li J. Zhu S. Wu J. Chen C. Liu Q. Wei W. Zhang Y. Sun S. Breast cancer subtypes predict the preferential site of distant metastases: A SEER based study Oncotarget 2017 8 27990 10.18632/oncotarget.15856 28427196 PMC5438624
7. Molnár I.A. Molnár B.Á. Vízkeleti L. Fekete K. Tamás J. Deák P. Szundi C. Székely B. Moldvay J. Vári-Kakas S. Breast carcinoma subtypes show different patterns of metastatic behavior Virchows Arch. 2017 470 275 283 10.1007/s00428-017-2065-7 28101678
8. Guckenberger M. Lievens Y. Bouma A.B. Collette L. Dekker A. deSouza N.M. Dingemans A.C. Fournier B. Hurkmans C. Lecouvet F.E. Characterisation and classification of oligometastatic disease: A European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation Lancet Oncol. 2020 21 e18 e28 10.1016/S1470-2045(19)30718-1 31908301
9. Eisenhauer E. Therasse P. Bogaerts J. Schwartz L.H. Sargent D. Ford R. Dancey J. Arbuck S. Gwyther S. Mooney M. New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1) Eur. J. Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774
10. Mundy G. Mechanisms of Bone Metastasis Cancer 1997 80 1546 1556 10.1002/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I 9362421
11. D’Oronzo S. Coleman R. Brown J. Silvestris F. Metastatic bone disease: Pathogenesis and therapeutic options J. Bone Oncol. 2019 15 100205 10.1016/j.jbo.2018.10.004 30937279 PMC6429006
12. Vakaet L.A.L. Boterberg T. Pain control by ionizing radiation of bone metastasis Int. J. Dev. Biol. 2004 48 599 606 10.1387/ijdb.041817lv 15349834
13. Manfrida S. Masiello V. Cellini F. Adducci E. Polidori L. Longo S. Cannelli G. Balducci M. Rossi M. Valentini V. IMproved MAnagement (IM-MA study) in cancer-related pain: The value of a joint approach by an integrated team of radiotherapist and anesthetist Support Care Cancer 2019 27 505 512 10.1007/s00520-018-4335-6 29980908
14. Cristofanilli M. Turner N.C. Bondarenko I. Ro J. Im S.A. Masuda N. Colleoni M. DeMichele A. Loi S. Verma S. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol. 2016 17 425 439 10.1016/S1470-2045(15)00613-0 26947331
15. Ghezzi P. Magnanini S. Rinaldini M. Berardi F. Di Biagio G. Testare F. Tavoni N. Schittulli F. D’Amico C. Pedicini T. Impact of Follow-up Testing on Survival and Health-Related Quality of Life in Breast Cancer Patients A Multicenter Randomized Controlled Trial JAMA 1994 271 1587 1592 10.1001/jama.1994.03510440047031 8182811
16. Rosselli Del Turco M. Palli D. Cariddi A. Ciatto S. Pacini P. Distante V. Intensive Diagnostic Follow-up After Treatment of Primary Breast Cancer. A Randomized Trial JAMA 1994 271 1593 1597 10.1001/jama.271.20.1593 7848404
17. Milano M.T. Katz A.W. Zhang H. Huggins C.F. Aujla K.S. Okunieff P. Oligometastatic breast cancer treated with hypofractionated stereotactic radiotherapy: Some patients survive longer than a decade Radiother. Oncol. 2019 131 45 51 10.1016/j.radonc.2018.11.022 30773186
18. Kobayashi T. Ichiba T. Sakuyama T. Arakawa Y. Nagasaki E. Aiba K. Nogi H. Kawase K. Takeyama H. Toriumi Y. Possible clinical cure of metastatic breast cancer: Lessons from our 30-year experience with oligometastatic breast cancer patients and literature review Breast Cancer 2012 19 218 237 10.1007/s12282-012-0347-0 22532161
19. Mundy G. Metastasis to bone: Causes, consequences and therapeutic opportunities Nat. Rev. Cancer 2002 2 584 593 10.1038/nrc867 12154351
20. Chow E. Wu J. Hoskin P. Coia L. Bentzen S. Blitzer P. International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases Radiother. Oncol. 2002 64 275 280 10.1016/S0167-8140(02)00170-6 12242115
21. Chow E. Hoskin P. Mitera G. Zeng L. Lutz S. Roos D. Hahn C. van der Linden Y. Hartsell W. Kumar E. Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases Int. J. Radiat. Oncol. Biol. Phys. 2012 82 1730 1737 10.1016/j.ijrobp.2011.02.008 21489705
22. Zeng K.L. Tseng C.-L. Soliman H. Weiss Y. Sahgal A. Myrehaug S. Stereotactic Body Radiotherapy (SBRT) for Oligometastatic Spine Metastases: An Overview Front. Oncol. 2019 9 337 10.3389/fonc.2019.00337 31119099 PMC6504814
23. Schwartz R.S. Erban J.K. Timing of Metastasis in Breast Cancer N. Engl. J. Med 2017 376 2486 2488 10.1056/NEJMcibr1701388 28636861
24. Hosseini H. Obradović M.M.S. Hoffmann M. Harper K.L. Sosa M.S. Werner-Klein M. Nanduri L.K. Werno C. Ehrl C. Maneck M. Early dissemination seeds metastasis in breast cancer Nature 2016 540 552 558 10.1038/nature20785 27974799 PMC5390864
25. Harper K. Sosa M.S. Entenberg D. Hosseini H. Cheung J.F. Nobre R. Avivar-Valderas A. Nagi C. Girnius N. Davis R.J. Mechanism of early dissemination and metastasis in Her2+ mammary cancer Nature 2016 540 588 592 10.1038/nature20609 27974798 PMC5471138
26. Ghanem N. Uhl M. Brink I. Schäfer O. Kelly T. Moser E. Langer M. Diagnostic value of MRI in comparison to scintigraphy, PET, MS-CT and PET/CT for the detection of metastases of bone Eur. J. Radiol. 2005 55 41 55 10.1016/j.ejrad.2005.01.016 15950100
27. O’Sullivan G.J. Imaging of bone metastasis: An update WJR 2015 7 202 10.4329/wjr.v7.i8.202 26339464 PMC4553252
28. Di Gioia D. Stieber P. Schmidt G.P. Nagel D. Heinemann V. Baur-Melnyk A. Early detection of metastatic disease in asymptomatic breast cancer patients with whole-body imaging and defined tumour marker increase Br. J. Cancer 2015 112 809 818 10.1038/bjc.2015.8 25647014 PMC4453962
29. Cook G. Goh V. Molecular imaging of bone metastases and their response to therapy J. Nucl. Med. 2020 61 799 806 10.2967/jnumed.119.234260 32245899
30. Stecco A. Trisoglio A. Soligo E. Berardo S. Sukhovei L. Carriero A. Whole-Body MRI with Diffusion-Weighted Imaging in Bone Metastases: A Narrative Review Diagnostics 2018 8 45 10.3390/diagnostics8030045 PMC6163267 29987207
31. Costelloe C.M. Rohren E.M. Madewell J.E. Hamaoka T. Theriault R.L. Yu T.K. Lewis V.O. Ma J. Stafford R.J. Tari A. Imaging bone metastases in breast cancer: Techniques and recommendations for diagnosis Lancet Oncol. 2009 10 9 10.1016/S1470-2045(09)70088-9 19482249
32. Taralli S. Lorusso M. Scolozzi V. Masiello V. Marazzi F. Calcagni M.L. Response evaluation with 18F-FDG PET/CT in metastatic breast cancer patients treated with Palbociclib: First experience in clinical practice Ann. Nucl. Med. 2019 33 193 200 10.1007/s12149-018-01323-8 30569442
33. National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Breast Cancer version 2 National Comprehensive Cancer Network Plymouth Meeting, PA, USA 2020
34. Yang H.-L. Liu T. Wang X.-M. Xu Y. Deng S.-M. Diagnosis of bone metastases: A meta-analysis comparing 18FDG PET, CT, MRI and bone scintigraphy Eur. Radiol. 2011 21 2604 2617 10.1007/s00330-011-2221-4 21887484
35. Moore S.L. Kransdorf M.J. Schweitzer M.E. Murphey M.D. Babb J.S. Can Sarcoidosis and Metastatic Bone Lesions Be Reliably Differentiated on Routine MRI? Am. J. Roentgenol. 2012 198 1387 1393 10.2214/AJR.11.7498 22623553
36. Soussan M. Augier A. Brillet P.-Y. Weinmann P. Valeyre D. Functional Imaging in Extrapulmonary Sarcoidosis: FDG-PET/CT and MR Features Clin. Nucl. Med. 2014 39 e146 e159 10.1097/RLU.0b013e318279f264 23579973
37. Foerster R. Cho B.C.J. Fahim D.K. Gerszten P.C. Flickinger J.C. Grills I.S. Jawad M.S. Kersh C.R. Létourneau D. Mantel F. Histopathological Findings After Reirradiation Compared to First Irradiation of Spinal Bone Metastases with Stereotactic Body Radiotherapy: A Cohort Study Neurosurgery 2019 84 435 441 10.1093/neuros/nyy059 29547929
38. Alongi F. Arcangeli S. Filippi A.R. Ricardi U. Scorsetti M. Review and Uses of Stereotactic Body Radiation Therapy for Oligometastases Oncologist 2012 17 1100 1107 10.1634/theoncologist.2012-0092 22723509 PMC3425528
39. Costa S. Reagan M.R. Therapeutic Irradiation: Consequences for Bone and Bone Marrow Adipose Tissue Front. Endocrinol. 2019 10 587 10.3389/fendo.2019.00587 PMC6727661 31555210
40. Goblirsch M. Mathews W. Lynch C. Alaei P. Gerbi B.J. Mantyh P.W. Clohisy D.R. Radiation Treatment Decreases Bone Cancer Pain, Osteolysis and Tumor Size Radiat. Res. 2004 161 228 234 10.1667/RR3108 14731066
41. Zhang J. Wang Z. Wu A. Nie J. Pei H. Hu W. Wang B. Shang P. Li B. Zhou G. Differences in responses to X-ray exposure between osteoclast and osteoblast cells J. Radiat. Res. 2017 58 791 802 10.1093/jrr/rrx026 28541506 PMC5710662
42. Steverink J. Willems S.M. Philippens M.E.P. Kasperts N. Eppinga W.S.C. Versteeg A.L. van der Velden J.M. Faruqi S. Sahgal A. Early Tissue Effects of Stereotactic Body Radiation Therapy for Spinal Metastases Int. J. Radiat. Oncol. Biol. Phys. 2018 100 1254 1258 10.1016/j.ijrobp.2018.01.005 29439885
43. Arriagada R. Mouriesse H. Sarrazin D. Clark R. Deboer G. Analysis of tumor parameters, tumor dose and local control: The experience of the Gustave-Roussy Institute and the Princess Margaret Hospital Int. J. Radiat. Oncol. Biol. Phys. 1985 11 1751 1757 10.1016/0360-3016(85)90027-6 4044337
44. Gerszten P.C. Burton S.A. Welch W.C. Brufsky A.M. Lembersky B.C. Ozhasoglu C. Vogel W.J. Single-fraction radiosurgery for the treatment of spinal breast metastases Cancer 2005 104 2244 2254 10.1002/cncr.21467 16216003
45. Kwapisz D. Oligometastatic breast cancer Breast Cancer 2019 26 138 146 10.1007/s12282-018-0921-1 30324552
46. Chow E. Harris K. Fan G. Tsao M. Sze W.M. Palliative Radiotherapy Trials for Bone Metastases: A Systematic Review JCO 2007 25 1423 1436 10.1200/JCO.2006.09.5281 17416863
47. Rades D. Fehlauer F. Stalpers L.J. Wildfang I. Zschenker O. Schild S.E. Schmoll H.J. Karstens J.H. Alberti W. A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: Final results of a multicenter study Cancer 2004 101 2687 2692 10.1002/cncr.20633 15493037
48. De Vin T. Engels B. Gevaert T. Storme G. De Ridder M. Stereotactic radiotherapy for oligometastatic cancer: A prognostic model for survival Ann. Oncol. 2014 25 467 471 10.1093/annonc/mdt537 24355488
49. Tree A.C. Khoo V.S. Eeles R.A. Ahmed M. Dearnaley D.P. Hawkins M.A. Huddart R.A. Nutting C.M. Ostler P.J. van As N.J. Stereotactic body radiotherapy for oligometastases Lancet Oncol. 2013 14 e28 e37 10.1016/S1470-2045(12)70510-7 23276369
50. Cellini F. Manfrida S. Deodato F. Cilla S. Maranzano E. Pergolizzi S. Arcidiacono F. Di Franco R. Pastore F. Muto M. Pain REduction with bone metastases STereotactic radiotherapy (PREST): A phase III randomized multicentric trial Trials 2019 20 609 10.1186/s13063-019-3676-x 31661034 PMC6816218
51. Yoo G.S. Yu J.I. Park W. Huh S.J. Choi D.H. Prognostic factors in breast cancer with extracranial oligometastases and the appropriate role of radiation therapy Radiat. Oncol. J. 2015 33 301 10.3857/roj.2015.33.4.301 26756030 PMC4707213
52. Trovo M. Furlan C. Polesel J. Fiorica F. Arcangeli S. Giaj-Levra N. Alongi F. Del Conte A. Militello L. Muraro E. Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial Radiother. Oncol. 2018 126 177 180 10.1016/j.radonc.2017.08.032 28943046
53. Kam T.Y. Chan O.S.H. Hung A.W.M. Yeung R.M.W. Utilization of stereotactic ablative radiotherapy in oligometastatic & oligoprogressive skeletal metastases: Results and pattern of failure Asia-Pac. J. Clin. Oncol. 2019 15 14 19 10.1111/ajco.13115 30859749
54. Farooqi A. Bishop A.J. Narang S. Allen P.K. Li J. McAleer M.F. Tatsui C.E. Rhines L.D. Amini B. Wang X.A. Outcomes after Hypofractionated Dose-Escalation using a Simultaneous Integrated Boost Technique for Treatment of Spine Metastases Not Amenable to Stereotactic Radiosurgery Pract. Radiat. Oncol. 2019 9 e142 e148 10.1016/j.prro.2018.10.008 30385151
55. Mizumoto M. Harada H. Asakura H. Hashimoto T. Furutani K. Hashii H. Takagi T. Katagiri H. Takahashi M. Nishimura T. Prognostic factors and a scoring system for survival after radiotherapy for metastases to the spinal column: A review of 544 patients at Shizuoka Cancer Center Hospital Cancer 2008 113 2816 2822 10.1002/cncr.23888 18846565
56. Wong A.C. Watson S.P. Pitroda S.P. Son C.H. Das L.C. Stack M.E. Uppal A. Oshima G. Khodarev N.N. Salama J.K. Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT): Survival after SBRT for Oligometastases Cancer 2016 122 2242 2250 10.1002/cncr.30058 27206146
57. Nguyen T.D. Theobald S. Rougier P. Ducreux M. Lusinchi A. Bardet E. Eymard J.C. Conroy T. Francois E. Seitz J.F. Simultaneous high-dose external irradiation and daily cisplatin in unresectable, non-metastatic adenocarcinoma of the pancreas: A phase I–II study Radiother. Oncol. 1997 45 129 132 10.1016/S0167-8140(97)00116-3 9424002
58. Bonet M. García V. Farré N. Algara M. Farrús B. Fernandez J. Reyes V. Eraso A. Álvarez A. Cambra M.J. Radiation Therapy for Bone-Only Metastases in Breast Cancer Patients: A GOCO Survey of Current Clinical Practice Rep. Pract. Oncol. Radiother. 2020 25 113 116 10.1016/j.rpor.2019.12.019 31908604 PMC6938868
59. Cardoso F. Senkus E. Costa A. Papadopoulos E. Aapro M. André F. Harbeck N. Aguilar Lopez B. Barrios C.H. Bergh J. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) Ann. Oncol. 2018 29 1634 1657 10.1093/annonc/mdy192 30032243 PMC7360146
60. Radaideh S.M. Sledge G.W. Taxane vs. taxane: Is the duel at an end? A commentary on a phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: Results of the ERASME 3 study Breast Cancer Res. Treat. 2008 111 203 208 10.1007/s10549-007-9776-4 17990102
61. Sledge G.W. Neuberg D. Bernardo P. Ingle J.N. Martino S. Rowinsky E.K. Wood W.C. Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193) JCO 2003 21 588 592 10.1200/JCO.2003.08.013 12586793
62. Cortes J. O’Shaughnessy J. Loesch D. Blum J.L. Vahdat L.T. Petrakova K. Chollet P. Manikas A. Diéras V. Delozier T. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study Lancet 2011 377 914 923 10.1016/S0140-6736(11)60070-6 21376385
63. Gradishar W.J. Krasnojon D. Cheporov S. Makhson A.N. Manikhas G.M. Clawson A. Bhar P. Significantly Longer Progression-Free Survival With nab -Paclitaxel Compared with Docetaxel as First-Line Therapy for Metastatic Breast Cancer JCO 2009 27 3611 3619 10.1200/JCO.2008.18.5397 19470941
64. Albain K.S. Nag S. Calderillo-Ruiz G. Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival J. Clin. Oncol. 2004 22 510 10.1200/jco.2004.22.90140.510
65. Yardley D.A. Brufsky A. Coleman R.E. Conte P.F. Cortes J. Glück S. Nabholtz J.M. O’Shaughnessy J. Beck R.M. Ko A. Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): Study protocol for a randomized controlled trial Trials 2015 16 575 10.1186/s13063-015-1101-7 26673577 PMC4682258
66. Piccart M. Hortobagyi G.N. Campone M. Pritchard K.I. Lebrun F. Ito Y. Noguchi S. Perez A. Rugo H.S. Deleu I. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Overall survival results from BOLERO-2 Ann. Oncol. 2014 25 2357 2362 10.1093/annonc/mdu456 25231953 PMC6267855
67. André F. Ciruelos E. Rubovszky G. Campone M. Loibl S. Rugo H.S. Iwata H. Conte P. Mayer I.A. Kaufman B. Alpelisib for PIK3CA -Mutated, Hormone Receptor–Positive Advanced Breast Cancer N. Engl. J. Med. 2019 380 1929 1940 10.1056/NEJMoa1813904 31091374
68. Finn R.S. Martin M. Rugo H.S. Jones S. Im S.A. Gelmon K. Harbeck N. Lipatov O.N. Walshe J.M. Moulder S. Palbociclib and Letrozole in Advanced Breast Cancer N. Engl. J. Med. 2016 375 1925 1936 10.1056/NEJMoa1607303 27959613
69. Goetz M.P. Toi M. Campone M. Sohn J. Paluch-Shimon S. Huober J. Park I.H. Trédan O. Chen S.C. Manso L. MONARCH 3: Abemaciclib as Initial Therapy for Advanced Breast Cancer JCO 2017 35 3638 3646 10.1200/JCO.2017.75.6155 28968163
70. Tripathy D. Im S.A. Colleoni M. Franke F. Bardia A. Harbeck N. Hurvitz S.A. Chow L. Sohn J. Lee K.S. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial Lancet Oncol. 2018 19 904 915 10.1016/S1470-2045(18)30292-4 29804902
71. Figura N.B. Potluri T.K. Mohammadi H. Oliver D.E. Arrington J.A. Robinson T.J. Etame A.B. Tran N.D. Liu J.K. Soliman H. CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases J. Neurooncol. 2019 144 583 589 10.1007/s11060-019-03260-6 31399935
72. Messer J.A. Ekinci E. Patel T.A. Teh B.S. Enhanced dermatologic toxicity following concurrent treatment with palbociclib and radiation therapy: A case report Rep. Pract. Oncol. Radiother. 2019 24 276 280 10.1016/j.rpor.2019.03.001 30948930 PMC6429548
73. Chowdhary M. Sen N. Chowdhary A. Usha L. Cobleigh M.A. Wang D. Patel K.R. Barry P.N. Rao R.D. Safety and Efficacy of Palbociclib and Radiation Therapy in Patients with Metastatic Breast Cancer: Initial Results of a Novel Combination Adv. Radiat. Oncol. 2019 4 453 457 10.1016/j.adro.2019.03.011 31360799 PMC6639750
74. Ippolito E. Greco C. Silipigni S. Dell’Aquila E. Petrianni G.M. Tonini G. Fiore M. D’Angelillo R.M. Ramella S. Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: Preliminary assessment of toxicity Breast 2019 46 70 74 10.1016/j.breast.2019.05.001 31100573
75. Liang K. Lu Y. Jin W. Sensitization of breast cancer cells to radiation by trastuzumab Mol. Cancer Ther. 2003 2 1113 1120 14617784
76. Guo G. Wang T. Gao Q. Tamae D. Wong P. Chen T. Chen W.C. Shively J.E. Wong J.Y. Expression of ErbB2 enhances radiation-induced NF-κB activation Oncogene 2004 23 535 545 10.1038/sj.onc.1207149 14724581
77. Pietras R. Poen J. Gallardo D. Wongvipat P. Lee H. Slamon D. Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene Cancer Res. 1999 59 1347 1355 10096569
78. Hou J. Zhou Z. Chen X. Zhao R. Yang Z. Wei N. Ni Q. Feng Y. Yu X. Ma J. HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo Oncotarget 2016 7 45186 45198 10.18632/oncotarget.9870 27286256 PMC5216715
79. Lazaro G. Smith C. Goddard L. Jordan N. McClelland R. Barrett-Lee P. Nicholson R.I. Hiscox S. Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response Endocr. Relat. Cancer 2013 20 691 704 10.1530/ERC-13-0019 23900794
80. Kim J.-S. Kim H.A. Seong M.K. Seol H. Oh J.S. Kim E.K. Chang J.W. Hwang S.G. Noh W.C. STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers Oncotarget 2016 7 7055 7065 10.18632/oncotarget.6855 26755645 PMC4872768
81. Sato S. Kajiyama Y. Sugano M. Iwanuma Y. Sonoue H. Matsumoto T. Sasai K. Tsurumaru M. Monoclonal antibody to HER-2/neu receptor enhances radiosensitivity of esophageal cancer cell lines expressing HER-2/neu oncoprotein Int. J. Radiat. Oncol. Biol. Phys. 2005 61 203 211 10.1016/j.ijrobp.2004.05.017 15629613
82. Uno M. Otsuki T. Kurebayashi J. Sakaguchi H. Isozaki Y. Ueki A. Yata K. Fujii T. Hiratsuka J. Akisada T. Anti-HER2-antibody enhances irradiation-induced growth inhibition in head and neck carcinoma Int. J. Cancer 2001 94 474 479 10.1002/ijc.1493 11745431
83. Bese N.S. Umay C. Serdengecti S. Kepil N. Sut N. Altug T. Ober A. The impact of trastuzumab on radiation-induced pulmonary fibrosis: Results of an experimental study Med. Oncol. 2010 27 1415 1419 10.1007/s12032-009-9395-5 20041318
84. Sambade M.J. Kimple R.J. Camp J.T. Peters E. Livasy C.A. Sartor C.I. Shields J.M. Lapatinib in Combination with Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts Int. J. Radiat. Oncol. Biol. Phys. 2010 77 575 581 10.1016/j.ijrobp.2009.12.063 20457354 PMC2976524
85. Sambade M.J. Camp J.T. Kimple R.J. Sartor C.I. Shields J.M. Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf > MEK > ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK Radiother. Oncol. 2009 93 639 644 10.1016/j.radonc.2009.09.006 19853943 PMC2799330
86. Adams S.R. Yang H.C. Savariar E.N. Aguilera J. Crisp J.L. Jones K.A. Whitney M.A. Lippman S.M. Cohen E.E. Tsien R.Y. Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize Nat. Commun. 2016 7 13019 10.1038/ncomms13019 27698471 PMC5059467
87. Kimple R.J. Horton J.K. Livasy C.A. Shields J.M. Lawrence J.A. Chiu W.M. Ivanova A. Ollila D.W. Carey L.A. Halle J.S. Phase I Study and Biomarker Analysis of Lapatinib and Concurrent Radiation for Locally Advanced Breast Cancer Oncologist 2012 17 1496 10.1634/theoncologist.2012-0256 23006498 PMC3528381
88. Krop I.E. Suter T.M. Dang C.T. Dirix L. Romieu G. Zamagni C. Citron M.L. Campone M. Xu N. Smitt M. Feasibility and Cardiac Safety of Trastuzumab Emtansine After Anthracycline-Based Chemotherapy As (neo)Adjuvant Therapy for Human Epidermal Growth Factor Receptor 2–Positive Early-Stage Breast Cancer JCO 2015 33 1136 1142 10.1200/JCO.2014.58.7782 PMC5657012 25713436
89. Yu M.L.X. The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy Oncogene 2015 34 3349 3356 10.1038/onc.2014.295 25220415 PMC4362780
90. Scarpa E.S. Fabrizio G. di Girolamo M. A role of intracellular mono-ADP-ribosylation in cancer biology FEBS J. 2013 280 3551 3562 10.1111/febs.12290 23590234
91. Dulaney C. Marcrom S. Stanley J. Yang E.S. Poly(ADP-ribose) Polymerase Activity and Inhibition in Cancer Seminars in Cell & Developmental Biology Academic Press Cambridge, MA, USA 2017 144 153 10.1016/j.semcdb.2017.01.007 28087320
92. Lesueur P. Chevalier F. Austry J.B. Waissi W. Burckel H. Noël G. Habrand J.L. Saintigny Y. Joly F. Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: A systematic review of pre-clinical and clinical human studies Oncotarget 2017 8 69105 69124 10.18632/oncotarget.19079 28978184 PMC5620324
93. McLachlan J. George A. Banerjee S. The Current Status of PARP Inhibitors in Ovarian Cancer Tumori J. 2016 102 433 440 10.5301/tj.5000558 27716873
94. Schmid P. Adams S. Rugo H.S. Schneeweiss A. Barrios C.H. Iwata H. Diéras V. Hegg R. Im S.A. Shaw Wright G. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer N. Engl. J. Med. 2018 379 2108 2121 10.1056/NEJMoa1809615 30345906
95. Rubini G. Nicoletti A. Rubini D. Asabella A.N. Radiometabolic Treatment of Bone-Metastasizing Cancer: From 186 Rhenium to 223 Radium Cancer Biother. Radiopharm. 2014 29 1 11 10.1089/cbr.2013.1549 24180669
96. Fuster D. Herranz D. Vidal-Sicart S. Muñoz M. Conill C. Mateos J.J. Martín F. Pons F. Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients Nucl. Med. Commun. 2000 21 623 626 10.1097/00006231-200007000-00004 10994664
97. Lam M.G.E.H. de Klerk J.M.H. van Rijk P.P. 186Re-HEDP for metastatic bone pain in breast cancer patients Eur. J. Nucl. Med. Mol. Imaging 2004 31 S162 S170 10.1007/s00259-004-1539-4 15118846
98. Palmedo H. Bender H. Dierke-Dzierzon C. Carl U. Pain Palliation With rhenium-186 HEDP in Breast Cancer Patients With Disseminated Bone Metastases Clin. Nucl. Med. 1999 24 643 648 10.1097/00003072-199909000-00001 10478737
99. Nilsson S. Larsen R. Fossa S. First Clinical Experience With Alpha-Emitting radium-223 in the Treatment of Skeletal Metastases Clin. Cancer Res. 2005 11 4451 4459 10.1158/1078-0432.CCR-04-2244 15958630
100. Coleman R. Aksnes A.K. Naume B. Garcia C. Jerusalem G. Piccart M. Vobecky N. Thuresson M. Flamen P. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease Breast Cancer Res. Treat. 2014 145 411 418 10.1007/s10549-014-2939-1 24728613 PMC4025174
101. Coleman R. Brown J. Rathbone E. Flanagan L. Reid A. Kendall J. Howell S. Twelves C. Palmieri C. Anand A. CApecitabine plus Radium-223 (Xofigo TM ) in breast cancer patients with BONe metastases (CARBON): Study protocol for a phase IB/IIA randomised controlled trial Trials 2020 21 89 10.1186/s13063-019-3643-6 31941523 PMC6961242
102. Burke M. Atkins A. Kiss A. Akens M. Yee A. Whyne C. The impact of metastasis on the mineral phase of vertebral bone tissue J. Mech. Behav. Biomed. Mater. 2017 69 75 84 10.1016/j.jmbbm.2016.12.017 28040610
103. Manabe J. Kawaguchi N. Matsumoto S. Tanizawa T. Surgical treatment of bone metastasis: Indications and outcomes Int. J. Clin. Oncol. 2004 10 103 111 10.1007/s10147-005-0478-9 15864695
104. Durr H. Muller P. Lenz T. Surgical Treatment of Bone Metastases in Patients with Breast Cancer Clin. Orthop. Relat. Res. 2002 396 191 196 11859243
105. Szendrői M. Antal I. Szendrői A. Lazáry Á. Varga P.P. Diagnostic algorithm, prognostic factors and surgical treatment of metastatic cancer diseases of the long bones and spine EFORT Open Rev. 2017 2 372 381 10.1302/2058-5241.2.170006 29071122 PMC5644421
106. Chiras J. Shotar E. Cormier E. Clarençon F. Interventional radiology in bone metastases Eur. J. Cancer Care 2017 26 e12741 10.1111/ecc.12741 28873239
107. Colleoni M. O’Neill A. Goldhirsch A. Gelber R.D. Bonetti M. Thürlimann B. Price K.N. Castiglione-Gertsch M. Coates A.S. Lindtner J. Identifying Breast Cancer Patients at High Risk for Bone Metastases JCO 2000 18 3925 3935 10.1200/JCO.2000.18.23.3925 11099322