The role of radiation therapy and systemic therapies in elderly with breast cancer
Review Article

The role of radiation therapy and systemic therapies in elderly with breast cancer

Valerio Nardone1, Sara Falivene1, Francesca Maria Giugliano1, Marcella Gaetano1, Pasqualina Giordano2, Matteo Muto3, Bruno Daniele2, Cesare Guida1

1Unit of Radiation Oncology, 2Unit of Medical Oncology, Ospedale del Mare, Naples, Italy; 3Unit of Radiation Oncology, Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Valerio Nardone. Unit of Radiation Oncology, Ospedale del Mare, Via E. Russo 1, Napoli, Italy. Email:

Abstract: The focus of this review deals with the management of elderly patients with early stage breast cancer, discussing the role of systemic therapies [endocrine therapy (ET), chemotherapy, novel agents] and radiation therapy (RT). Several studies have evaluated in elderly low risk patients the possibility of omitting the RT but, at the same time, higher locoregional relapse (LR) rates without significant impact on overall survival (OS) were observed in all studies when RT was excluded. Technological improvements [intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), high dose brachy therapy (HDBT)] are very useful in order to reduce cosmetic outcome and improve quality of life of frail patients. The optimal sequence of ET, concomitant or sequential to RT, is currently under investigation, and specifically in the elderly it is questioned the possible choice of prolonged therapy after standard 5 years. Data regarding chemotherapy suggesting no benefit of OS in endocrine responsive diseases, whereas endocrine non-responsive breast cancer still showed a better outcome. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen is recognized as the standard protocol, although age-dependent increase in therapy related mortality was reported. Neoadjuvant chemotherapy in elderly showed a lower ratio of pathological complete response in comparison to younger patients, but triple negative breast cancer patients showed a good prognosis regarding OS, comparable to younger patients. The risk of cardiotoxicity seems to increase with age, so the use trastuzumab in this setting is much debated. Currently, other anti-HER2 agents (pertuzumab, lapatinib) are used in neoadjuvant setting, but the data on elderly are still premature. Novel molecules are rapidly changing the clinical management of breast cancer patients but are tested especially in locally advanced and metastatic setting. Among these, particularly interesting are inhibitors of CDK4 and 6, alpelisib (PI3K enzymes mutations), immune checkpoint (PD1, PDL1, CTLA4) inhibitors, atezolizumab. Elderly patients are under-represented in clinical trials, although ageing can be frequently correlated with a decrease in the effectiveness of the immune system. For elderly women, treatment decisions should be individually decided, taking into account the geriatric assessment and limited life expectancy and tumor characteristics.

Keywords: Elderly; breast cancer; radiation therapy (RT); adjuvant therapies; novel drugs

Submitted May 31, 2019. Accepted for publication Jun 26, 2019.

doi: 10.21037/tcr.2019.07.04


In the clinical management of cancer patients, it is of paramount importance to achieve optimal loco-regional control of disease, but at the same time trying to minimize the complications (1).

This recommendation is even stricter in the treatment of elderly patients.

Age represent the major risk factor for breast cancer, and a significant ratio of this disease is diagnosed in women >70 years (2). At the same time, many elderly women with early stage breast cancer die of other causes (up to 80% in node negative women and 60% in women with positive axillary nodes) (3).

The correct evaluation of the global health status is of paramount importance in older patients, so to avoid aggressive unnecessary treatment in frail patients and to prevent under treatments in fit elderly that can jeopardize the survival (4).

In this particular subset of patients, the scientific literature presents many pitfalls, due to the discrepancies between real life and clinical trials in terms of age and health status of patients (5).

Aim of this review is to depict the optimal adjuvant therapies in the management of elderly patients with breast cancer, focusing on the role of systemic therapies (hormonal therapy, chemotherapy, novel agents) and radiation therapy (RT), through a review of the available literature and the discussion of the various aspects of the clinical management of this defined subset of cancer patients.


It is mandatory in order to correctly stratify breast cancer patients to analyze the hormone receptor status, as well as the HER2 expression. Further stratification relies on anatomic and pathologic characteristics such as size, grading, N status, angiolymphatic invasion.

Several models have been developed in order to estimate outcomes, and a validated model is available online ( (6) to estimate disease-free survival (DFS) and overall survival (OS) at 10 years and to measure the expected gain of adjuvant systemic therapies (endocrine and chemotherapy) (7).

It is noteworthy, though, that the accuracy of the estimates for older patients is not very robust, as the algorithm relies on the 1998 meta-analysis of adjuvant trials, in which older patients were under-represented. Currently other methods of tailored medicine are available, through the analysis of individual tumor gene expression profiles. There are many different assays, analyzing a total of 21 genes (8), 50 genes (9) and 70 genes (10), all of them generally validated in older breast cancer patients.

Finally, in this subset of patients, it is mandatory to perform a multidimensional geriatric assessment, even with the collaboration of a Geriatrist (11), that can be particularly important in frail patients (12). There are different screening test that can be used to identify patients that would benefit from a more intensive geriatric evaluation (13,14).

We will briefly discuss in different paragraph the different choices of therapies in our selected subgroup of breast cancer patients.


While RT has an established role in the adjuvant setting of treatment of breast cancer, the omission of RT in a particular subgroup of elderly is still a matter of debate.

Several studies have evaluated, in patients older than 65 years treated with conservative surgery, low risk (pT1-2N0-1M0) the possibility of omitting the RT (see Table 1) (15-24). At the same time, it’s noteworthy that higher local recurrence rates were observed in all studies when RT was excluded.

Table 1
Table 1 Studies that have analyzed the role of adjuvant whole breast radiation therapy (WBRT) versus observation (no RT) in elderly patients
Full table

The overall 5-year survival rate results the same (not statistically significant difference) with adjuvant RT. Some authors (16) concluded that there is clinical evidence of avoiding adjuvant radiotherapy for patients over 75 years with T1–T2 cancer treated with quadrantectomy with a clear excision margin.

Herskovic et al. (23) in a retrospective explorative analysis of a large database of over 60.000 patients showed a 5-year overall survival rate of 93.0% in the adjuvant RT group and 83.6% (P=0.0001) in the non-adjuvant RT group. Improved survival is associated with adjuvant RT and endocrine therapy (ET) for older women with early-stage hormone receptor e positive HER2-negative breast cancer.

For frail elderly women, treatment decisions should be individually decided considering geriatric assessment and limited life expectancy and tumor characteristics.

In recent decades, several randomized trials evaluated the role of hypo fractionated RT delivered over a period of 3 weeks vs. standard fractionated RT (5 weeks) revealing equivalence in local control and survival without increased toxicity (25-27).

Moreover, APBI is a conservative approach with irradiation of a smaller volume (only the lumpectomy bed plus a 1- to 2-cm margin vs. whole breast) in less time. Different APBI methods are available, such as brachytherapy (28,29), intraoperative (30) or external beam radiotherapy.

In order to reduce discomfort of a long treatment of radiotherapy, especially in elderly frail women, APBI is of a special interest in this setting.

Each of these techniques is different from one another in terms of degree of invasiveness, radiation delivery, experience of radiation oncologist, and time of treatment.

Today APBI is not the gold standard but it was largely used in clinical trial and also in clinical practice especially in low risk elderly women in terms of efficacy, quality of life outcomes, and cost-effectiveness vs. whole breast standard RT.

Lately, technological improvements in modern radiotherapy are very useful in order to reduce cosmetic outcome. Intensity-modulated RT (IMRT) or volumetric modulated arc therapy (VMAT) results to give advantages over three-dimensional conformal RT in terms of a better homogeneity of dose distribution within the target volume and a reduction in high doses to organs at risk (31).

Although the advantage of these new techniques IMRT are still not considered a standard of care as they have no impact on local control or patients’ quality of life (32,33).

Some studies noted a fair aesthetic outcome after IMRT that results feasible and well tolerated in elderly breast cancer patients (see Table 2) (28,29,34-37).

Table 2
Table 2 Special radiation therapy techniques adopted in treating elderly patients
Full table

Concluding this paragraph, while the previous cited clinical trials have provided information regarding the omission of adjuvant RT for women with favorable characteristics, they still contain many limitations.

First, CALGB and Fyles trials do not include information regarding HER2 status and oncotype score, as they were not available. Similarly, the PRIME II and ABCSG Study trials did not specifically include or exclude HER2-positive patients, or patients who received chemotherapy. Most importantly, the previous trials could be not statistically powered enough to detect a potential OS benefit for adjuvant RT in favorable-risk patients (15,19,21,22,38-40).

This last point is supported by the Early Breast Cancer Trialists’ Collaborative Group Oxford meta-analysis, which found that 1 breast cancer death could be avoided for every 4 local recurrences prevented over 15 years. The absolute risk reduction in cancer mortality risk was 5.4% at 15 years in that analysis (41).


In patients with endocrine responsive breast cancer, hormonal therapy has provided evidence to increase both disease free survival and overall survival (42,43).

The optimal sequence of hormonal therapies is currently under investigation, and specifically in the elderly it is questioned the possible choice of prolonged therapy after 5 years of hormonal therapy.

Two studies have compared tamoxifen (TAM) versus aromatase inhibitor (AI) as first choice of adjuvant therapy in postmenopausal women (44,45), and they found that AI arm showed fewer recurrences, although no differences in survival were reported.

At the same time, a significant increase of fractures was reported in older patients undergoing letrozole (11.6%) versus tamoxifen (5.4%).

Cardiovascular events of high grade, similarly, were increased in letrozole arm (2.4%) versus tamoxifen arm (1.4%), although the overall low incidence (46). Hypertension and prior cardiac events were recognized as risk factors, and the risk seems to be greater in the range 65–74 years (44,47).

Conversely, the use of tamoxifen could increase the risk of endometrial cancer and thromboembolic complications, and increasing age is an independent risk for these complications (48). For this reason, generally, AI is the preferred option as first choice of hormonal therapy in elderly patients (49).

Several trials have analyzed the various combinations of HT in elderly patients, with comparable results (see Table 3) (45,50-53).

Table 3
Table 3 Studies that have analyzed various combinations of adjuvant hormone therapies in elderly patients with breast cancer
Full table

At the same time, the Clinician should also take in consideration the comorbidities and should discuss with older patients the optimal choice of adjuvant hormonal therapies, due to the different toxicities of AI and TAM.

The concurrent use of hormonal agents and radiotherapy have been analyzed in the meta-analysis of Li et al. (54), that found no difference in any of the clinical endpoint (toxicity, local recurrence, distant metastases and overall survival) for the concurrent approach. Although this study does not present a subgroup analysis for the elderly patients, the median age of concurrent approach was older than sequential approach.

The avoidance of some “invasive” treatment in elderly, with a minimalistic approach, on the other hand, is currently under investigation in many trials.

Specifically, the ET when used as a sole agent to treat breast cancer is defined as primary endocrine therapy (PET) and is greatly used in clinical practice for elderly patients (2), reaching over 60% of patients over 80 years in UK.

The Cochrane review of Hind et al. found no overall survival benefit in comparison to surgery for patients older than 75 years, although a worse local control (55). The study by Fennessy et al. compared TAM versus surgery and TAM, and found a significant benefit for surgery in the subgroup 70–75 years, a trend towards a benefit for the subgroup 75–80 and no benefit of survival for patients older than 80 years, although the numbers were small (56). Mustacchi et al. analyzed in a randomized multicenter controlled GRETA trial the same approach with TAM versus surgery and TAM (57). Similarly, after a follow up of 80 months, they did not found a significant difference in OS for patients older than 70 years.

Another approach is to treat only with hormonal therapy, avoiding adjuvant radiotherapy after surgery. Chesney et al. have published recently a meta-analysis of four randomized controlled trials in a subset of elderly breast cancer patients (>70 years). They concluded that radiotherapy can reduce local recurrences (breast and axilla), but it does not impact distant recurrence or overall survival in this particular subgroup (58). Wickberg et al. (59), similarly, analyzed a cohort of 603 breast cancer women (age >65 years), and found that breast conservative surgery and ET without RT seem to be a safe treatment option, with only 1.2% recurrence at five years.


As the magnitude of the effect of chemotherapy in terms of recurrences and survival generally decrease with elderly patients, the decision whether to use systemic cytotoxic therapy in the management of breast cancer in older patients is very complex (41), especially if comorbidities that can exacerbate the toxicity of chemotherapy are present (60).

At the same time, the bio molecular characteristics associated with a worse outcome are the same markers of increased benefit from systemic therapy (nodal status, negative hormonal receptors). Conversely, shorter remaining life expectancy, positive estrogen receptor as well as the necessity of decreasing chemotherapy doses due to comorbidities require to seriously consider the effective necessity of a systemic approach (61,62).

Actually, data regarding older women are limited (41), suggesting no benefit of survival in endocrine responsive diseases, whereas endocrine non responsive breast cancer still showed a better outcomes (63,64).

In regards of the chemotherapy regimen, the combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is recognized as the standard protocol, although age-dependent increase in therapy related mortality was reported (65). Capecitabine has shown to be inferior to standard CMF or Adriamycin cyclophosphamide combination (AC) (66), although the enrollment was discontinued early, so that these results need to be interpreted with great caution. Anthracycline, at the same time, carry on an increased risk of heart failure in the treatment of elderly people (67), thus docetaxel and carboplatin combination could represent an alternative regimen (68).

The large meta-analysis of Early Breast Cancer Trialists’ Collaborative Group (69) concluded that taxane and/or anthracycline-based regimens reduced breast cancer mortality by, on average, about one-third. Their data, though, are limited in patients older than 70 years. The SEER registries analysis, conversely, has demonstrated a benefit of survival in elderly patients with non-endocrine positive breast cancer, and this gain in OS was higher if the axillary nodes were positive (64).

A recent pooled analysis by von Waldenfels et al. analyzed individual patients data from eight randomized controlled trials in order to investigate the outcome after neoadjuvant chemotherapy in elderly patients (>65 years) (70). They concluded that elderly showed a lower ratio of pathological complete response in comparison to younger patients, but triple negative breast cancer patients showed a good prognosis regarding overall survival, comparable to younger patients. This approach, thus, could be useful in a selected elderly population.

The combination with RT, at the same time, is still poorly investigated in elderly. A recent work by Huang et al. has analyzed radiotherapy concurrent versus adjuvant standard anthracycline based chemotherapy, concluding that the concurrent strategy was superior to the sequential administration in loco-regional recurrence-free survival for node positive patients, although with an high risk of lymphedema (71). There are, unfortunately, no information regarding the age of patients enrolled in the meta-analysis, so that these results cannot be safely assumed for older breast cancer patients.

Other approaches in order to determine the frailty of elderly patients undergoing chemotherapy are currently under investigation. Bailur et al. have recently performed an analysis of the immune profiling in breast cancer patients receiving chemotherapy. This profiling was correlated with unexpected hospitalizations, and could be useful to select the most appropriate tailored strategy (72).

Concluding this paragraph, actually there are insufficient data to extrapolate chemotherapy recommendations in older women, thus the treatment needs to be individualized, taking into consideration the comorbidities and the bio molecular characteristics of the disease.

Targeted agents

Trastuzumab is a humanized monoclonal antibody with a selective specificity for the extracellular domain of HER2, that has shown an improvement in both DFS and OS, although with an increase of heart failures (73).

Unfortunately, in this particular subgroup of patients, the frequency of HER2 positivity tends to decrease with age. At the same time, the first trials evaluating this drug did not include elderly women. The Finnish trial included women <66 years, whereas the median age in the HERA trial was 49 years (73-75). Additionally, the risk of cardio toxicity seems to increase with age (>60 years), so that the decision whether to use trastuzumab in elderly patients is much debated.

The physiopathology of cardio toxicity of this drug is classified as a chemotherapy related cardiac dysfunction of type II (CRCD II) and induce a reduced contractility of myocyte cells, through the blockade of HER2 signaling of cardiomyocytes (76).

It is usually reversible with discontinuation of the treatment, and it differs with cardiac dysfunction of type I, usually induced by anthracyclines, that is related to the total dose and induces irreversible loss of myocyte cells.

Several studies have investigated the use of trastuzumab in elderly (77-79), finding significant association with clinical variables and comorbidities (age, adjuvant chemo, history of cardiac disease, diabetes, renal failure).

Usually, adjuvant trastuzumab was used for one year, although improvement of outcomes was observed with only 9 weeks of treatment (80,81), an approach that must be further validated but could be interesting for our particular subset.

Currently, other anti-HER2 agents (pertuzumab, lapatinib) are used in neoadjuvant setting, but the data on elderly are still premature. In the “Aphinity” that investigated the use of double HER2 blocking with trastuzumab and pertuzumab, only 13% of the patients (315 patients) were older than 65 years, and the subset analysis did not show difference in DFS (82).

Concluding this paragraph, age should not be the only parameter in the decision-making process for women with HER2 positive breast cancer. At the same time, the prevention of cardiac risk among elderly breast cancer patients receiving trastuzumab is of paramount importance.

Novel agents

Novel molecules are rapidly changing the clinical management of breast cancer patients, although their use is currently limited to locally advanced and metastatic setting.

At the same time, there are many clinical trials enrolling early stage breast cancer patients in order to investigate the efficacy in earlier stage of disease, so in this paragraph we will briefly comment these approaches in elderly, with a particular emphasis on the combination with RT.

At this regard, the role of RT especially for oligometastatic breast cancer patients, has shown to be able to achieve long term progression free survival, without significant treatment related toxicities, as in other pathologies (83). Its investigation with the novel molecules will be necessary in the next future for the optimal management of breast cancer patients, elderly included.

Inhibitors of cycle-dependent kinases (CDK) 4 and 6 seem one of the most promising drug in this setting. Normal cell replication progresses are regulated by a number of proteins including cyclin-dependent-kinases (CDKs). CDK 4/6 inhibitors target the formation of the CDK 4/6-cyclin D1 complex and block the phosphorylation of Rb to effect cell cycle arrest (84).

Their efficacy has been tested in many clinical trials (85-88), and is currently used for post-menopausal, HER2-, advanced breast cancer in combination, either with AI or with Fulvestrant. At the same time, as with previous drugs, specific data regarding efficacy and safety in elderly are limited and mostly extrapolated by subgroup analysis of randomized controlled trials. According to these trials, CDK seem to have similar efficacy with a slight increase of toxicity (89).

The combination with RT is still investigational and is currently tested in clinical trials. There are only small series published (90-92), and a case report of severe radiation induced enter colitis in a patient undergoing palliative RT to bone metastases (93).

In the same setting, after treatment with AI, everolimus with exemestane has been shown to improve PFS as compared to exemestane alone (94), regardless of age.

Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR) pathway, an important intracellular signal that promotes cell growth and proliferation.

The toxicity of this drug included infections, rash, pneumonitis, stomatitis and hyperglycemia, and elderly patients seem to have similar incidence of these side effects, with more weight loss and anemia, but had more deaths on-treatment (95,96).

The combination with RT has been tested in different diseases, especially in glioblastoma (97-99), but currently there are no sufficient data to estimate risks and benefits of the concurrent approach, especially in breast cancer. Particular caution should be given when RT involves gastrointestinal tracts, due to case reports in literature.

On the other hand, the analysis of phosphatidylinositol 3-Kinase (PI3K) enzymes mutations, that occur in almost 40% of breast cancer patients, has led to the development of Alpelisib that was very recently approved by FDA in combination with fulvestrant, to treat post-menopausal women with hormone receptor positive, HER2 negative advanced or metastatic breast cancer following progression after endocrine-based regimen (SOLAR 1 trial). The cohort of PI3K mutated patients treated with Alpelisib had a PFS of 11 months versus 5.7 months (P<0.001). The most frequent adverse events were hyperglycemia, rash, diarrhea (100).

The median age in the SOLAR trial was 63 years (range, 25–87 years), but unfortunately there is not a subgroup analysis for the elderly patients. These drugs, thus, should be used with caution in elderly patients. The combination with RT, also, needs to be further studied, although PIK3CA seems to be a part of biological pathways impacting the radio sensitivity (101).

Immune checkpoint inhibitors, finally, represent an immunotherapy approach that include molecules targeting programmed cell death type I (PD1) or death ligand type I (PDL1) and cytotoxic T lymphocyte antigen 4 pathways (CTLA4). This strategy has demonstrated a dramatic efficacy for several cancer diseases and many drugs are currently used in oncological clinical practice. Elderly patients, again, are under-represented in clinical trials, although ageing can be frequently correlated with a decrease in the effectiveness of the immune system (102). These agents are usually better tolerated than cytotoxic chemotherapies and the side effects are mainly immune-related adverse events that can develop in different organs.

Few clinical trials have analyzed the toxicity in elderly people, and the results must be treated with caution due to the small sample size of older patient’s subgroups. Diarrhea/colitis and rash seem to be more frequent in elderly, and particular vigilance is required for the risk of dehydration and renal failure (103,104).

Actually, atezolizumab was recently approved by the FDA due to the prolonged PFS in patient with metastatic triple-negative breast cancer, in combination with nab-paclitaxel (105). The use in neoadjuvant setting of Pembrolizumab is currently under investigation in clinical trials (Keynote-756 trial).

The combination of immunotherapy with RT is very interesting, as also RT is able to induce immunological effects (106): mole first described tumor shrinking, distant from other irradiated cancer sites, a phenomenon called “abscopal effect” (107), and Demaria et al. demonstrated that this effect was immune-mediated, through a specific immune response (108). The irradiated tumor cells release a pool of antigens, in addition the RT also induces an increase in MHC-I expression on tumor cells and up-regulation of death receptors (e.g., FAS, NKG2DL) (109). RT can also induce immunogenic cell death (ICD) (109), characterized by the release of “Damage-Associated Molecular Patterns” (DAMPs) acting as an endogenous adjuvant. DAMPs, which include HMGB1 and Calreticulin, act as activation and maturation signal on DCs, increasing the processing and antigenic presentation to cytotoxic T lymphocytes (109). Finally, RT induces an increase in the expression of adhesion molecules on tumor cells and endothelial cells such as VCAM-I and ICAM-I (109), thus inducing an increase of the infiltration of the immune cells into the tumor site. All these mechanisms are believed to underlie the abscopal effect, although this effect is rarely seen, with fewer than 50 documented cases in the literature (110). Preclinical studies, also, showed that RT is able to induce an increase of expression of PD-L1 on tumor cells (111), blocking the induced immune response. This is the preclinical rationale of the combined use of radiotherapy and immunotherapy.

Clinical studies show encouraging results of the use of combined RT and immunotherapy (112-115): RT seems to prolong the survival of advanced NSCLC patients undergone immune modulating treatment (113) or to checkpoint inhibitors (116). The most impressive results were shown in the PACIFIC trial, a phase III study for stage III unresectable NSCLC, whose experimental arm patients received CHT/RT followed by Durvalumab (117).

At the same time, in breast cancer patients, there are no data regarding a concurrent approach.


Age per se should be evaluated together with many other parameters in the decision-making process for elderly patients with breast cancer. Specifically, the overall individual performance status, more than the age, should be considered when treatment options are being evaluated.

Acute and chronic comorbidities, nutritional status, fitness, and disease-specific symptomatology all need to be taken into consideration. All the Clinicians involved in the management of elderly cancer patients should be familiar with geriatric screening test that can be used to identify patients that would benefit from a more intensive geriatric.

On the other hand, the goals of treatment in elderly patients should be always the same as those in younger patients, with an emphasis on the global care of the patients more than the cure of the disease. Finally, studies including elderly people as well as patients with comorbidities need to be considered in future, as the treatment of these subgroups represent the major medical challenge of the next future.




Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


  1. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010;76:S10-9. [Crossref] [PubMed]
  2. Tahir M, Robinson T, Stotter A. How not to neglect the care of elderly breast cancer patients? Breast 2011;20:293-6. [Crossref] [PubMed]
  3. Schairer C, Mink PJ, Carroll L, et al. Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst 2004;96:1311-21. [Crossref] [PubMed]
  4. Bouchardy C, Rapiti E, Blagojevic S, et al. Older female cancer patients: importance, causes, and consequences of undertreatment. J Clin Oncol 2007;25:1858-69. [Crossref] [PubMed]
  5. Dunn C, Wilson A, Sitas F. Older cancer patients in cancer clinical trials are underrepresented. Systematic literature review of almost 5000 meta- and pooled analyses of phase III randomized trials of survival from breast, prostate and lung cancer. Cancer Epidemiol 2017;51:113-7. [Crossref] [PubMed]
  6. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 2005;23:2716-25. [Crossref] [PubMed]
  7. Loprinzi CL, Ravdin PM. Decision-making for patients with resectable breast cancer: individualized decisions for and by patients and their physicians. J Natl Compr Canc Netw 2003;1:189-96. [Crossref] [PubMed]
  8. Tang G, Shak S, Paik S, et al. Comparison of the prognostic and predictive utilities of the 21-gene Recurrence Score assay and Adjuvant! for women with node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. Breast Cancer Res Treat 2011;127:133-42. [Crossref] [PubMed]
  9. Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 2013;31:2783-90. [Crossref] [PubMed]
  10. Mook S, Knauer M, Bueno-de-Mesquita JM, et al. Metastatic potential of T1 breast cancer can be predicted by the 70-gene MammaPrint signature. Ann Surg Oncol 2010;17:1406-13. [Crossref] [PubMed]
  11. Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol 2012;13:e148-60. [Crossref] [PubMed]
  12. Kenis C, Bron D, Libert Y, et al. Relevance of a systematic geriatric screening and assessment in older patients with cancer: results of a prospective multicentric study. Ann Oncol 2013;24:1306-12. [Crossref] [PubMed]
  13. Rodin MB, Mohile SG. A practical approach to geriatric assessment in oncology. J Clin Oncol 2007;25:1936-44. [Crossref] [PubMed]
  14. Overcash JA, Beckstead J, Moody L, et al. The abbreviated comprehensive geriatric assessment (aCGA) for use in the older cancer patient as a prescreen: scoring and interpretation. Crit Rev Oncol Hematol 2006;59:205-10. [Crossref] [PubMed]
  15. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004;351:963-70. [Crossref] [PubMed]
  16. Livi L, Paiar F, Meldolesi E, et al. The management of elderly patients with T1-T2 breast cancer treated with or without radiotherapy. Eur J Surg Oncol 2005;31:473-8. [Crossref] [PubMed]
  17. Livi L, Paiar F, Saieva C, et al. Breast cancer in the elderly: treatment of 1500 patients. Breast J 2006;12:353-9. [Crossref] [PubMed]
  18. Truong PT, Bernstein V, Lesperance M, et al. Radiotherapy omission after breast-conserving surgery is associated with reduced breast cancer-specific survival in elderly women with breast cancer. Am J Surg 2006;191:749-55. [Crossref] [PubMed]
  19. Pötter R, Gnant M, Kwasny W, et al. Lumpectomy plus tamoxifen or anastrozole with or without whole breast irradiation in women with favorable early breast cancer. Int J Radiat Oncol Biol Phys 2007;68:334-40. [Crossref] [PubMed]
  20. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013;31:2382-7. [Crossref] [PubMed]
  21. Kunkler IH, Williams LJ, Jack WJ, et al. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015;16:266-73. [Crossref] [PubMed]
  22. Nagar H, Yan W, Christos P, et al. Older Patients With Early-stage Breast Cancer: Adjuvant Radiation Therapy and Predictive Factors for Cancer-related Death. Am J Clin Oncol 2017;40:300-5. [Crossref] [PubMed]
  23. Herskovic AC, Wu X, Christos PJ, et al. Omission of Adjuvant Radiotherapy in the Elderly Breast Cancer Patient: Missed Opportunity? Clin Breast Cancer 2018;18:418-31. [Crossref] [PubMed]
  24. Goldberg M, Sutradhar R, Paszat L, et al. Patterns of adjuvant care and outcomes of elderly women with stage I breast cancer after breast-conserving surgery: a population-based analysis. Breast Cancer Res Treat 2019;176:657-67. [Crossref] [PubMed]
  25. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008;371:1098-107. [Crossref] [PubMed]
  26. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008;9:331-41. [Crossref] [PubMed]
  27. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010;362:513-20. [Crossref] [PubMed]
  28. Genebes C, Chand ME, Gal J, et al. Accelerated partial breast irradiation in the elderly: 5-year results of high-dose rate multi-catheter brachytherapy. Radiat Oncol 2014;9:115. [Crossref] [PubMed]
  29. Hannoun-Levi JM, Gourgou-Bourgade S, Belkacemi Y, et al. GERICO-03 phase II trial of accelerated and partial breast irradiation in elderly women: feasibility, reproducibility, and impact on functional status. Brachytherapy 2013;12:285-92. [Crossref] [PubMed]
  30. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014;383:603-13. [Crossref] [PubMed]
  31. Singla R, King S, Albuquerque K, et al. Simultaneous-integrated boost intensity-modulated radiation therapy (SIB-IMRT) in the treatment of early-stage left-sided breast carcinoma. Med Dosim 2006;31:190-6. [Crossref] [PubMed]
  32. Buwenge M, Cammelli S, Ammendolia I, et al. Intensity modulated radiation therapy for breast cancer: current perspectives. Breast Cancer (Dove Med Press) 2017;9:121-6. [Crossref] [PubMed]
  33. Fiorentino A, Mazzola R, Ricchetti F, et al. Intensity modulated radiation therapy with simultaneous integrated boost in early breast cancer irradiation. Report of feasibility and preliminary toxicity. Cancer Radiother 2015;19:289-94. [Crossref] [PubMed]
  34. Jagsi R, Ben-David MA, Moran JM, et al. Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation. Int J Radiat Oncol Biol Phys 2010;76:71-8. [Crossref] [PubMed]
  35. Bourgier C, Acevedo-Henao C, Dunant A, et al. Higher toxicity with 42 Gy in 10 fractions as a total dose for 3D-conformal accelerated partial breast irradiation: results from a dose escalation phase II trial. Radiat Oncol 2012;7:141. [Crossref] [PubMed]
  36. Riou O, Fenoglietto P, Bourgier C, et al. Feasibility of accelerated partial breast irradiation with volumetric-modulated arc therapy in elderly and frail patients. Radiat Oncol 2015;10:209. [Crossref] [PubMed]
  37. Fiorentino A, Gregucci F. Intensity-modulated radiotherapy and hypofractionated volumetric modulated arc therapy for elderly patients with breast cancer: comparison of acute and late toxicities. 2019;124:309-14.
  38. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351:971-7. [Crossref] [PubMed]
  39. Agarwal S, Pappas L, Neumayer L, et al. Effect of breast conservation therapy vs mastectomy on disease-specific survival for early-stage breast cancer. JAMA Surg 2014;149:267-74. [Crossref] [PubMed]
  40. van Maaren MC, de Munck L, de Bock GH, et al. 10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study. Lancet Oncol 2016;17:1158-70. [Crossref] [PubMed]
  41. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-717. [Crossref] [PubMed]
  42. Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007;25:486-92. [Crossref] [PubMed]
  43. Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007;18:1133-44. [Crossref] [PubMed]
  44. Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 2009;361:766-76. [Crossref] [PubMed]
  45. Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131-9. [Crossref] [PubMed]
  46. Mouridsen H, Keshaviah A, Coates AS, et al. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol 2007;25:5715-22. [Crossref] [PubMed]
  47. Crivellari D, Sun Z, Coates AS, et al. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol 2008;26:1972-9. [Crossref] [PubMed]
  48. Cohen I, Azaria R, Fishman A, et al. Endometrial cancers in postmenopausal breast cancer patients with tamoxifen treatment. Int J Gynecol Pathol 1999;18:304-9. [Crossref] [PubMed]
  49. Goldhirsch A, Wood WC, Coates AS, et al. 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 2011;22:1736-47. [Crossref] [PubMed]
  50. Derks MGM, Bastiaannet E, van de Water W, et al. Impact of age on breast cancer mortality and competing causes of death at 10 years follow-up in the adjuvant TEAM trial. Eur J Cancer 2018;99:1-8. [Crossref] [PubMed]
  51. Derks MGM, Blok EJ, Seynaeve C, et al. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:1211-20. [Crossref] [PubMed]
  52. Bliss JM, Kilburn LS, Coleman RE, et al. Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study. J Clin Oncol 2012;30:709-17. [Crossref] [PubMed]
  53. Regan MM, Price KN, Giobbie-Hurder A, et al. Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer. Breast Cancer Res 2011;13:209. [Crossref] [PubMed]
  54. Li YF, Chang L, Li WH, et al. Radiotherapy concurrent versus sequential with endocrine therapy in breast cancer: A meta-analysis. Breast 2016;27:93-8. [Crossref] [PubMed]
  55. Hind D, Wyld L, Reed MW. Surgery, with or without tamoxifen, vs tamoxifen alone for older women with operable breast cancer: cochrane review. Br J Cancer 2007;96:1025-9. [Crossref] [PubMed]
  56. Fennessy M, Bates T, MacRae K, et al. Late follow-up of a randomized trial of surgery plus tamoxifen versus tamoxifen alone in women aged over 70 years with operable breast cancer. Br J Surg 2004;91:699-704. [Crossref] [PubMed]
  57. Mustacchi G, Ceccherini R, Milani S, et al. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol 2003;14:414-20. [Crossref] [PubMed]
  58. Chesney TR, Yin JX, Rajaee N, et al. Tamoxifen with radiotherapy compared with Tamoxifen alone in elderly women with early-stage breast cancer treated with breast conserving surgery: A systematic review and meta-analysis. Radiother Oncol 2017;123:1-9. [Crossref] [PubMed]
  59. Wickberg Å, Liljegren G, Killander F, et al. Omitting radiotherapy in women >/= 65 years with low-risk early breast cancer after breast-conserving surgery and adjuvant endocrine therapy is safe. Eur J Surg Oncol 2018;44:951-6. [Crossref] [PubMed]
  60. Muss HB, Berry DA, Cirrincione C, et al. Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience. J Clin Oncol 2007;25:3699-704. [Crossref] [PubMed]
  61. Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 1981;304:10-5. [Crossref] [PubMed]
  62. Goldhirsch A, Castiglione M, Gelber RD. Adjuvant chemo-endocrine therapy in postmenopausal women with breast cancer and axillary-node metastases. Lancet 1990;335:1099-100. [Crossref] [PubMed]
  63. Elkin EB, Hurria A, Mitra N, et al. Adjuvant chemotherapy and survival in older women with hormone receptor-negative breast cancer: assessing outcome in a population-based, observational cohort. J Clin Oncol 2006;24:2757-64. [Crossref] [PubMed]
  64. Giordano SH, Duan Z, Kuo YF, et al. Use and outcomes of adjuvant chemotherapy in older women with breast cancer. J Clin Oncol 2006;24:2750-6. [Crossref] [PubMed]
  65. Colleoni M, Price KN, Castiglione-Gertsch M, et al. Mortality during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil. Lancet 1999;354:130-1. [Crossref] [PubMed]
  66. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant Chemotherapy in Older Women with Early-Stage Breast Cancer. N Engl J Med 2009;360:2055-65. [Crossref] [PubMed]
  67. Pinder MC, Duan Z, Goodwin JS, et al. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007;25:3808-15. [Crossref] [PubMed]
  68. Ewer MS, O'Shaughnessy JA. Cardiac toxicity of trastuzumab-related regimens in HER2-overexpressing breast cancer. Clin Breast Cancer 2007;7:600-7. [Crossref] [PubMed]
  69. Peto R, Davies C, Godwin J, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012;379:432-44. [Crossref] [PubMed]
  70. von Waldenfels G, Loibl S, Furlanetto J, et al. Outcome after neoadjuvant chemotherapy in elderly breast cancer patients - a pooled analysis of individual patient data from eight prospectively randomized controlled trials. Oncotarget 2018;9:15168-79. [Crossref] [PubMed]
  71. Huang O, Wu D, Zhu L, et al. Concurrent adjuvant radiochemotherapy versus standard chemotherapy followed by radiotherapy in operable breast cancer after breast conserving therapy: A meta-analysis. Journal of Cancer Research and Therapeutics 2016;12:84-9. [Crossref] [PubMed]
  72. Bailur JK, Pawelec G, Hatse S, et al. Immune profiles of elderly breast cancer patients are altered by chemotherapy and relate to clinical frailty. Breast Cancer Research 2017;19:20. [Crossref] [PubMed]
  73. Slamon D, Eiermann W, Robert N, et al. Adjuvant Trastuzumab in HER2-Positive Breast Cancer. New England Journal of Medicine 2011;365:1273-83. [Crossref] [PubMed]
  74. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. New England Journal of Medicine 2005;353:1659-72. [Crossref] [PubMed]
  75. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. New England Journal of Medicine 2005;353:1673-84. [Crossref] [PubMed]
  76. Sawaya H, Sebag IA, Plana JC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 2012;5:596-603. [Crossref] [PubMed]
  77. Serrano JM, Gonzalez I, Del Castillo S, et al. Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors. Oncologist 2015;20:864-72. [Crossref] [PubMed]
  78. Ezaz G, Long JB, Gross CP, et al. Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc 2014;3:e000472. [Crossref] [PubMed]
  79. Leung HWC, Leung JH, Chan ALF. Efficacy and safety of a combination of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis. Expert Opin Drug Saf 2018;17:1-7. [Crossref] [PubMed]
  80. Joensuu H, Fraser J, Wildiers H, et al. Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial. JAMA Oncol 2018;4:1199-206. [Crossref] [PubMed]
  81. Şendur MA, Aksoy S, Yorgun H, et al. Comparison of the long term cardiac effects associated with 9 and 52 weeks of trastuzumab in HER2-positive early breast cancer. Curr Med Res Opin 2015;31:547-56. [Crossref] [PubMed]
  82. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med 2017;377:122-31. [Crossref] [PubMed]
  83. Trovo M, Furlan C, Polesel J, et al. Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial. Radiother Oncol 2018;126:177-80. [Crossref] [PubMed]
  84. Spring L, Bardia A, Modi S. Targeting the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway with selective CDK 4/6 inhibitors in hormone receptor-positive breast cancer: rationale, current status, and future directions. Discov Med 2016;21:65-74. [PubMed]
  85. Turner NC, Slamon DJ, Ro J, et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018;379:1926-36. [Crossref] [PubMed]
  86. Sonke GS, Hart LL, Campone M, et al. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat 2018;167:659-69. [Crossref] [PubMed]
  87. Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat 2017;166:41-54. [Crossref] [PubMed]
  88. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017;35:3638-46. [Crossref] [PubMed]
  89. Battisti NML, De Glas N, Sedrak MS, et al. Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper. Ther Adv Med Oncol 2018;10:1758835918809610. [Crossref] [PubMed]
  90. Hans S, Cottu P, Kirova YM. Preliminary results of the association of Palbociclib and radiotherapy in metastatic breast cancer patients. Radiotherapy and Oncology 2018;126:181. [Crossref] [PubMed]
  91. Meattini I, Desideri I, Scotti V, et al. Ribociclib plus letrozole and concomitant palliative radiotherapy for metastatic breast cancer. Breast 2018;42:1-2. [Crossref] [PubMed]
  92. Ippolito E, Greco C, Silipigni S, et al. Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: Preliminary assessment of toxicity. Breast 2019;46:70-4. [Crossref] [PubMed]
  93. Kawamoto T, Shikama N, Sasai K. Severe acute radiation-induced enterocolitis after combined palbociclib and palliative radiotherapy treatment. Radiother Oncol 2019;131:240-1. [Crossref] [PubMed]
  94. Baselga J, Campone M, Piccart M, et al. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer. New England Journal of Medicine 2012;366:520-9. [Crossref] [PubMed]
  95. Pritchard KI, Burris HA 3rd, Ito Y, et al. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2. Clin Breast Cancer 2013;13:421-432.e8. [Crossref] [PubMed]
  96. Cazzaniga M, Verusio C, Ciccarese M, et al. Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study. Oncotarget 2018;9:31877-87. [PubMed]
  97. Manegold PC, Paringer C, Kulka U, et al. Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer. Clin Cancer Res 2008;14:892-900. [Crossref] [PubMed]
  98. Miura Y, Suyama K, Shimomura A, et al. Radiation-induced esophagitis exacerbated by everolimus. Case Rep Oncol 2013;6:320-4. [Crossref] [PubMed]
  99. Ma DJ, Galanis E, Anderson SK, et al. A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro Oncol 2015;17:1261-9. [Crossref] [PubMed]
  100. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019;380:1929-40. [Crossref] [PubMed]
  101. Bernichon E, Vallard A, Wang Q, et al. Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol. Ann Oncol 2017;28:2773-9. [Crossref] [PubMed]
  102. Daste A, Domblides C, Gross-Goupil M, et al. Immune checkpoint inhibitors and elderly people: A review. Eur J Cancer 2017;82:155-66. [Crossref] [PubMed]
  103. Friedman CF, Horvat TZ, Minehart J, et al. Efficacy and safety of checkpoint blockade for treatment of advanced melanoma (mel) in patients (pts) age 80 and older (80+). Journal of Clinical Oncology 2016;34:10009. [Crossref]
  104. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
  105. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 2018;379:2108-21. [Crossref] [PubMed]
  106. Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007;13:54-61. [Crossref] [PubMed]
  107. Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol 1953;26:234-41. [Crossref] [PubMed]
  108. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004;58:862-70. [Crossref] [PubMed]
  109. Levy A, Chargari C, Marabelle A, et al. Can immunostimulatory agents enhance the abscopal effect of radiotherapy? Eur J Cancer 2016;62:36-45. [Crossref] [PubMed]
  110. Abuodeh Y, Venkat P, Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer 2016;40:25-37. [Crossref] [PubMed]
  111. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 2014;74:5458-68. [Crossref] [PubMed]
  112. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013;1:365-72. [Crossref] [PubMed]
  113. Pastina P, Nardone V, Botta C, et al. Radiotherapy prolongs the survival of advanced non-small-cell lung cancer patients undergone to an immune-modulating treatment with dose-fractioned cisplatin and metronomic etoposide and bevacizumab (mPEBev). Oncotarget 2017;8:75904-13. [Crossref] [PubMed]
  114. Tini P, Nardone V, Pastina P, et al. The effects of radiotherapy on the survival of patients with unresectable non-small cell lung cancer. Expert Rev Anticancer Ther 2018;18:593-602. [Crossref] [PubMed]
  115. Nardone V, Pastina P, Giannicola R, et al. How to Increase the Efficacy of Immunotherapy in NSCLC and HNSCC: Role of Radiation Therapy, Chemotherapy, and Other Strategies. Front Immunol 2018;9:2941. [Crossref] [PubMed]
  116. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017;18:895-903. [Crossref] [PubMed]
  117. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
Cite this article as: Nardone V, Falivene S, Giugliano FM, Gaetano M, Giordano P, Muto M, Daniele B, Guida C. The role of radiation therapy and systemic therapies in elderly with breast cancer. Transl Cancer Res 2020;9(Suppl 1):S97-S109. doi: 10.21037/tcr.2019.07.04