Future directions of radiation therapy in the management of breast cancer

Introduction

Breast cancer management requires a multidisciplinary approach with a combination of surgery, radiation therapy, and systemic therapy. The use of radiation therapy remains a pivotal part of breast cancer treatment for the majority of women affected, where it has been shown to reduce locoregional recurrences and improve survival (1-3). The goal of any therapeutic treatment is to maximize disease control while minimizing treatment related toxicities. Over time, as with surgical techniques and systemic therapies, the therapeutic index of radiation continues to improve. There are now newer, more advanced radiation planning techniques and patient-specific targeted approaches, allowing for fewer toxicities while maintaining the benefit of radiation. With improvements in systemic therapies and greater understanding of the wide array of breast cancers, there are now several different settings where both de-escalation and escalation of radiation therapy may play a role. Clinical trials are pivotal in exploring these variabilities in treatments. Current important ongoing trials include the de-escalation of radiation in favorable patients, the use of shorter radiation treatment regimens, the use of newer or advanced radiation techniques in attempts to minimize toxicities, pre-operative radiation techniques, and using metastasis directed radiation therapy in patients with oligometastatic disease. These trials will help optimize the use of radiation therapy in patients with breast cancer.

Methods

This manuscript describes important ongoing trials using radiation therapy for breast cancer patients. Using clinicaltrials.gov (4) as the source of available and ongoing radiation and breast cancer specific clinical trials, select trials are described below. Most of the trials discussed are large cooperative group trials or other randomized, multi-institutional or important phase I–II trials exploring the safety and efficacy of newer radiation applications or techniques. The majority of discussed trials are actively recruiting at the time of this manuscript preparation, with the exception of a few that are recently closed after meeting accrual.

De-escalation in favorable risk breast cancers

In early-stage breast cancer patients, there is a clear spectrum of disease recurrence risks based on patient and tumor specific characteristics (5-8). Newer genetic profiling techniques including Oncotype Dx and PAM50 have also shown to predict for more favorable outcomes in early-stage breast cancers (9-11). The question remains for many of these patients with favorable disease characteristics if therapy de-escalation, including the omission of radiation, is an acceptable treatment without a greater risk of recurrence. TAILORX was a phase III trial of over 10,000 women with hormone receptor (HR) positive, HER2 negative, node negative breast cancer used the Oncotype DX Breast Recurrence score, a 21-gene expression test, to assess their risk of distant disease recurrence, grouping them into a risk category based on their recurrence score. The trial results were practice changing, demonstrating that the majority of eligible patients (those with low and some intermediate Oncotype DX recurrence scores) can be safely treated with endocrine therapy (ET) alone, and avoid chemotherapy without compromising disease control and survival (12). ASCO guidelines help guide therapeutic decisions using these types of genomic biomarker tests: the Oncotype DX Recurrence Score and a similar 50 gene panel test, PAM-50 (13). Similar to de-escalation of systemic therapy, there have been past trials looking at omission of adjuvant radiation in favorable early-stage breast cancer patients (14-18). As depicted in Table 1, these trials have shown that even with favorable disease characteristics (namely HR positivity, small volume, node negative disease and older age), the addition of radiation to ET provides a statistically significant local disease control benefit, although the clinical significance of this is debatable. Based on these results, omission of radiation is a consideration in select patients—generally older individuals with favorable disease characteristics, who are willing to take at least 5 years of ET and willing to accept a higher risk of local recurrence.

Current ongoing clinical trials aim to take this question a step further utilizing genomic biomarker testing. The IDEA trial is a multi-center registry trial studying omission of radiation in women ages 50–69 with pT1N0 breast cancers, HR positive, HER2 negative with an Oncotype DX recurrence score of ≤18, who will receive a minimum of 5 years of ET (19). This trial recently completed accrual and data are maturing. Similarly, the PRECISION Trial is enrolling patients ages 50–75 with pT1N0 breast cancer, HR positive, HER2 negative, grade 1–2, that are deemed low risk by the genomic marker test, PAM50 (20). In Ontario, the LUMINA trial is enrolling patients age 55+ with pT1N0, grade 1–2 breast cancers, Luminal A (with low Ki-67 of <14%) onto their registry trial treating with ET alone (21). Finally, the EXPERT trial is a randomized, phase III non-inferiority trial assessing women with favorable risk breast cancer based on PAM50, randomized to ET alone vs. adjuvant radiation with ET, with a primary endpoint of 10-year local recurrence (22). All of these studies, summarized in Table 2, A, are aiming to use additional genomic tumor markers to better select for patients who may have low recurrence rates with ET alone, potentially allowing for omission of radiation without compromising disease control. Of note, one must take care in appropriate patient selection and counseling when choosing patients for omission of radiation on or off study, as medication compliance can be an issue. There have been multiple studies demonstrating poor compliance taking daily ET for 5 years in patients who omitted adjuvant breast radiation off trial, with compliance rates of only 40–60% (26,27). Furthermore, shorter courses of radiation now provide more convenient radiation options than in the past. Partly due to compliance issues, there are discussions of a phase III study of adjuvant radiation vs. adjuvant ET in favorable risk breast cancer patients.

De-escalation of therapy in node positive patients

Multiple clinical trials have demonstrated a benefit to treating patients with node positive breast cancer with adjuvant radiation, providing superior locoregional control (LRC) and disease-free survival (DFS) (28-31), and in the post-mastectomy setting, a cancer specific survival benefit as well (2). Even in patients with only one to three positive nodes involved, this benefit held true based on a large meta-analysis of over 8,000 post-mastectomy patients, with significant absolute improvements in locoregional recurrence rates (LRR) (by 16.5%), any recurrence (by 11.5%) and a 7.9% reduction in breast cancer specific mortality (71% vs. 80%) (2). A caveat of this meta-analysis is many women had received older, less effective chemotherapy, and outdated radiation techniques so in the modern era, this benefit to radiation may be different. Additional studies are underway to help answer this question of whether de-escalation of radiation is possible in patients with low nodal disease and favorable risk factors.

The UK recently completed and reported early results from the SUPREMO trial assessing whether adjuvant radiation can be safely omitted in patients with one to three involved nodes. This trial recruited women with pT1–2N1, pT3N0, or pT2N0 tumors and lymphovascular invasion or grade 3 disease who had undergone mastectomy, and if node positive, axillary dissection. Women were then randomized to post-mastectomy radiation (PMRT) or no radiation, with the primary endpoint being 10-year overall survival (OS). While their data needs to mature to assess disease specific outcomes, they reported on pre-specified quality of life endpoints at 2 years, demonstrating slightly worse patient reported chest wall symptoms in the PMRT arm compared to no radiation, although the difference was small and unlikely to be of clinical significance. Interestingly, the use of chemotherapy (and not PMRT) was associated with worse arm and shoulder symptoms, suggesting the multifactorial role all therapies have in treatment related toxicities (32). A similar, ongoing phase III non-inferiority trial from the Canadian Cancer Trials Group, MA39, is using the Oncotype Dx recurrence score as part of their enrollment criteria. Patients over 40 with low-risk scores (<18) with 1–3 positive nodes following lumpectomy or mastectomy are randomized to regional nodal radiation vs. omission of regional nodal radiation, with a primary endpoint of breast cancer recurrence free interval (23). These trials will help establish the role of adjuvant nodal radiation in more specific settings of patients with one to three positive nodes.

Another important predictor of LRR is disease response to neoadjuvant chemotherapy, with the biggest predictor of LRR being pathologic response to neoadjuvant chemotherapy, particularly response in the nodes (33). This led the way to the ongoing randomized phase III cooperative group trial, NSABP B-51, enrolling patients with cT1–3, biopsy proven N1 breast cancer who have had a complete pathologic response in the nodes following neoadjuvant chemotherapy. Patients who undergo lumpectomy are randomized to whole breast irradiation +/− regional nodal irradiation. Patients who undergo mastectomy are randomized to no radiation or chest wall and regional nodal irradiation. The goal of the trial is to evaluate if the addition of radiation will significantly reduce the rates of breast cancer recurrence-free interval in these favorable patients, with secondary endpoints including cosmetic outcomes, quality of life differences and molecular predictors of recurrence (24).

De-escalation of nodal treatment aims to minimize an important late toxicity of lymphedema. Both the extent of axillary surgery and the use of nodal radiation contribute to this risk. Thus, another avenue under exploration is de-escalation surgically. ACOSOG Z0011 demonstrated in breast cancer patients who are clinically node negative with 1–2 positive sentinel nodes, omitting further axillary dissection is non-inferior to sentinel lymph node biopsy (SLNB) alone, in terms of 10-year OS and DFS (34). AMAROS was a similar trial randomizing clinically node negative patients with a positive SLNB to either completion axillary dissection vs. axillary nodal radiation, with no difference in axillary recurrence, DFS or OS, but did show a significantly higher rate of lymphedema in the axillary dissection arm (23% vs. 11%) (35). The recently presented 10-year update again demonstrated no difference in OS (36). While these trials demonstrate axillary radiation is appropriate for most clinically node negative, sentinel node positive patients, this question has not yet been assessed in a randomized trial for patients who receive neoadjuvant chemotherapy. There is some non-randomized evidence suggesting it is acceptable to omit axillary dissection in patients with a positive sentinel node who receive adjuvant regional nodal radiation (37). There is an ongoing randomized trial from the Alliance cooperative group trial, A011202 enrolling patients with cT1–3, N1 breast cancer who have a positive sentinel node following neoadjuvant chemotherapy, randomizing them to either completion axillary dissection vs. adjuvant axillary radiation. It will evaluate whether radiation is non-inferior to axillary dissection in terms of breast cancer recurrence free interval (25). For now, the standard is completion axillary dissection for positive sentinel node biopsy following neoadjuvant chemotherapy, with an NCCN category 2b for no further dissection if getting nodal radiation (38). Table 2, B demonstrates the ongoing clinical trials studying de-escalation in the node positive setting.

Hypofractionated radiation in post-mastectomy patients

One challenge of adjuvant radiation for breast cancer patients is a logistical one. Typically, radiation is given on weekdays for 4–6 weeks, which can be difficult for patients and caregivers. In recent decades for breast only treatments, radiation hypofractionation (using higher than 2 Gy per fraction treatments given over a shorter number of days) has improved this challenge, allowing for a more convenient, cost-effective treatment course. Multiple trials have established moderately hypofractionated radiation given over 3–4 weeks as the standard for early stage, post-lumpectomy breast cancer patients rather than the historically used standard fractionated radiation course over 6 weeks, with equivalent disease control endpoints, and no increase in acute or late radiation related side effects (39-41). These studies even demonstrated improved acute toxicities, less fatigue, and improved late cosmesis with hypofractionation (39-41). Hypofractionation for post-lumpectomy radiation has even been taken a step further, now with five fraction radiation regimens treating the whole breast (the FAST or FAST-FORWARD regimens), showing equivalent outcomes compared to 4–6-week courses, although this regimen has been slow to adopt in many countries perhaps due to awaiting recently reported 10-year outcomes (42,43). A 3–4-week course of hypofractionated radiation is considered standard for the majority of women requiring whole breast irradiation alone following lumpectomy for invasive or in situ breast cancer (44). Less clear is the role of hypofractionated radiation in the post-mastectomy and node positive setting. Most of the hypofractionation trials were done in women undergoing lumpectomy. There was a recently reported phase III single institution trial from China of 820 women who underwent mastectomy without reconstruction with at least pT3–4 and pN2a breast cancers, randomized to a 5-week standard fractionated radiation course vs. a 3-week hypofractionated radiation course treating the chest wall and regional nodes. The results were favorable with no significant difference in 5-year LRR or late toxicities, as well as fewer acute toxicities in the hypofractionated course (45). It is important to note that this protocol used 6–9 MeV electron beams for chest wall irradiation, rather than more commonly used photons. This has led to concern of the trial’s applicability to all post-mastectomy patients, particularly to women who undergo mastectomy with reconstruction. Although, there are many parts of the world including the UK where hypofractionated radiation is commonly used in the PMRT setting. In the previously mentioned SUPREMO PMRT trial out of the UK, approximately 20% of patients had reconstruction, and the majority of patients in the PMRT arm received hypofractionated radiation—although they do not comment on outcomes of this cohort of reconstructed patients.

There are ongoing trials exploring this question of hypofractionated radiation in post-mastectomy patients with reconstruction (Table 3). The cooperative group Alliance A221505 trial, also known as RT-CHARM is a multi-institutional, phase III, non-inferiority trial enrolling women with stage IIA–IIIA breast cancer who have undergone mastectomy specifically with reconstruction and require PMRT to the chest wall and regional nodes. Various types of reconstruction are allowed. These women are randomized after surgery to standard fractionated PMRT over 5–6 weeks vs. hypofractionated PMRT over 3–4 weeks, with the primary endpoint being non-inferior rates of reconstruction complications (re-operation, Baker 3–4 contracture) with hypofractionation at 24 months post-treatment. Additional endpoints include both disease recurrence rates and toxicities (46). A smaller institutional trial from Dana Farber Cancer Institute, the FABREC trial is also exploring this question of standard vs. hypofractionated PMRT following breast reconstruction, with a primary endpoint of patient reported outcomes at 6 months and secondary oncologic and clinical outcomes including photograph assessment of cosmesis (47). If these trials demonstrate non-inferiority of hypofractionated radiation in reconstructed post-mastectomy patients, it could change the standard radiation course to a more convenient, cost-effective course in the post-mastectomy setting in years to come.

Partial breast irradiation (PBI)

An alternative to adjuvant whole breast radiation for favorable risk patients is PBI, oftentimes done over a shorter time period than the standard 3–4-week course of hypofractionated radiation including Intraoperative Radiation (IORT) done as a single treatment at the time of lumpectomy (48,49). Many PBI options have been shown to be an effective adjuvant radiation treatment for patients with favorable breast cancers, with similar rates of ipsilateral breast tumor recurrence and similar acute and late toxicities, with some exceptions (50-57). Additional ongoing trials are attempting PBI using newer technologies in attempts to shrink radiation volumes even tighter or minimize low radiation dose to surrounding normal structures, with the goal of minimizing toxicity (Table 4). One multi-institutional phase II study is using real-time MRI guidance during radiation treatments, which allows for better visualization of lumpectomy bed targets during treatment and smaller volumes getting treated (58). Proton radiation has dosimetric advantages to photons and in the case of PBI, may limit dose to normal ipsilateral breast tissue and other organs at risk, minimizing risk of late toxicities. There are multiple ongoing phase II trials assessing PBI using protons (59,60).

New applications of radiation technology

One newer area under exploration for breast cancer radiation is the use of stereotactic body radiation therapy (SBRT). Compared to standard radiation, SBRT delivers a more precise, higher dose of radiation per treatment, for fewer treatments—typically 5 treatments or less. Stereotactic radiation has historically been used to treat cancers in the brain or lung, but more recently, its use has been rapidly expanding to other disease sites. In breast cancer patients, SBRT is being explored as a potential PBI option both in the post-operative setting and as definitive treatment in inoperable patients. However, there are unique challenges when using SBRT to treat targets in the breast, as it requires strict immobilization for target localization, and usually requires relatively small target volumes—both of which can be issues in breast radiation. In an attempt to address some of these issues, there is a multi-institutional phase II trial using a new radiotherapy system called the GammaPod^TM, a radiation unit made specifically to immobilize and treat targets in the breast. The unit uses a cup where the patient’s breast sits, with a stereotactic frame to immobilize the breast, and employs multiple rotating Cobalt-60 beams to converge on a small focal target. This trial is enrolling women with early-stage breast cancers up to 3 cm in size, who have undergone breast conservation surgery (61). All women are treated with SBRT on the GammaPod^TM, to a dose of 30–40 Gy in a total of 5 fractions, with at least 40 hours between fractions. The primary outcome of the study is quality of life, with a secondary outcome of cosmesis, with a study aim of improving quality of life and cosmesis relative to historical controls, while maintaining similar oncologic outcomes. There is a similar ongoing trial coined RAD 1802, studying the safety of a 30 Gy in 5 fraction SBRT regimen to the lumpectomy bed in favorable risk patients eligible for PBI, but using a conventional linear accelerator (62). This is a pilot study, so primary and secondary outcomes are toxicity related, as well as cosmesis.

While the above studies are in the adjuvant setting, there is also interest using the ablative nature of SBRT in inoperable patients. A recently opened pilot study is investigating the use of SBRT in women with breast cancer who are inoperable (63). Eligible participants will have cT1–4 invasive ductal carcinoma of the breast, deemed either unresectable or the patient is a poor surgical candidate, and who have a life expectancy of >6 months. All patients will undergo SBRT in 5 fractions to a total dose of 40 Gy using a conventional linear accelerator. Their co-primary outcomes are rate of grade 3 adverse events and partial/complete response rates. If successful, results may produce a viable option for definitive treatment of non-operative patients.

Another relatively newer area of technology in radiation is the use of proton therapy. Protons have certain dosimetric distribution advantages compared to commonly used photon radiation. Specifically, protons are able to deliver radiation dose to a target, while sparing dose to structures adjacent, namely posterior to the target. This is of particular interest in breast cancer, where the posteriorly located heart and lungs can be difficult to limit radiation exposure with traditional photon irradiation, particularly when requiring nodal irradiation. Previous studies have shown excess radiation dose to the heart carries risk of significant late cardiac toxicity (64,65). For this reason, protons are currently being investigated as a potential therapeutic option in breast cancer radiation. A multi-center, randomized phase III RADCOMP Consortium Trial is currently comparing traditional photon irradiation to proton irradiation in the adjuvant setting of breast cancer (66). Eligible women can have stage I–III breast cancer of either breast, after lumpectomy or mastectomy and must be proceeding with breast/chest wall radiation and comprehensive nodal radiation therapy. Their primary outcome is to compare major cardiovascular events between the two arms. The results of this trial will help define the role of proton therapy in breast cancer.

The use of intraoperative radiation therapy (IORT) is an established technology in breast cancer as an option for PBI at time of lumpectomy in select patients (56,67). There are current studies investigating new avenues using this technology. The ongoing TARGIT-B trial is a multi-center, randomized phase III trial enrolling women at high risk of local recurrence warranting whole breast irradiation (i.e., different than their initial study, TARGIT-A that used IORT as the sole PBI treatment for favorable breast cancers). Patients in both arms will receive adjuvant whole breast radiation but will be randomized to IORT tumor bed boost vs. a postoperative external beam tumor bed boost (68). The primary outcome is local tumor bed control, with the hypothesis that the IORT boost will be superior compared to traditional external beam boost. Table 5 describes ongoing trials using newer radiation technologies for breast cancer.

Pre-operative radiation

Traditionally, radiation has been delivered following surgery and chemotherapy, when indicated. Recently, there has been growing interest in administering radiation in the preoperative setting, with theoretic advantages of potential downstaging of tumors, more accurate tumor targeting with smaller treatment volumes, and potentially higher rates of pathologic response to neoadjuvant therapy. One hesitation to adopting this treatment paradigm is concern over further delay to surgery, particularly with traditional standard fractionated radiation over 5–6 weeks followed by recovery time, before going to surgical resection. However, now bolstered by the success seen in neoadjuvant chemotherapy and development of more accelerated radiation schedules including SBRT as previously described, interest has been renewed.

Pre-operative radiation is being investigated at Mayo Clinic, where they have a multi-institutional, single arm phase II trial enrolling women with cT1–2N0 breast cancer (69). Women undergo hypofractionated radiation for a total of 5 fractions to the whole breast, then undergo standard of care surgery 4–16 weeks after radiation. Their primary outcome is rate of pathologic complete response upon resection. Similarly, an ongoing Stanford trial, the NORDIS trial, is a randomized phase II trial examining the role of preoperative accelerated PBI enrolling patients with ductal carcinoma in situ (DCIS) planning to undergo breast conservation surgery, randomizing them to either upfront surgery and adjuvant radiation or neoadjuvant PBI, 30 Gy in five fractions to partial breast, followed by a 12-week delay until surgery (70). The primary outcome and goal of the study is showing the rate of complete pathologic response; they also wish to show if different DCIS subtypes exhibit different sensitivities to preoperative RT.

Other trials are attempting to shorten the preoperative radiation course even further. Using the GammaPod^TM treatment machine described earlier, University of Maryland has an ongoing phase I dose-escalation trial enrolling women with cT1–2N0 breast cancers, delivering preoperative single-fraction SBRT (dose of 21–30 Gy) to the tumor, followed by breast conservation surgery (71). The primary outcomes are related to dose limiting toxicity.

While early in development and exploration of pre-operative radiation, these trials (Table 6) and future ones may pave the way for larger studies and a potential role of pre-operative radiation or definitive radiation in non-operable patients.

Radiation therapy in oligometastatic disease setting

The idea of an oligometastatic state has been around for some time, with the potential for cure or at least long-term DFS following aggressive treatment of all known sites. There are multiple recent trials showing that metastasis directed therapy with surgery or SBRT can provide DFS and OS benefits with low toxicity rates across various cancer types (72-76). The use of SBRT for oligometastases has increased over time (72). The SABR-COMET trial is a Canadian phase II randomized trial of metastasis directed SBRT that recently reported promising long-term results. This trial enrolled patients with a controlled/treated primary malignancy and 1–5 metastases amenable to SBRT and randomized patients to standard of care palliative systemic therapy with or without SBRT to all metastases. Breast cancer patients made up one of the most common malignancies on the study. At 5 years, they demonstrated a remarkable OS benefit in the SBRT arm, with 5-year OS of 17.7% in control arm vs. 42% in SBRT arm. PFS was also improved as expected. Importantly, there were no differences in toxicities or quality of life between the groups (77). There are now many ongoing studies across individual disease sites assessing the role of SBRT in the oligometastatic setting. NRG-BR002 is a phase IIR/III trial of standard of care therapy with or without SBRT and/or surgical ablation for newly oligometastatic breast cancer. Patients with breast cancer involving up to four metastatic sites amenable to SBRT or surgery are eligible. This trial also is open to “de novo” or newly diagnosed metastatic breast cancer patients, so long as the breast primary is controlled prior to registration with surgery +/− radiation. The primary endpoint of this study is 3-year PFS and up to 8-year OS (78). A similar phase III study is being run in France, randomizing patients with “de novo” metastatic breast cancer to standard systemic therapy with or without SBRT, with a primary endpoint of PFS and secondary endpoints of local control and OS (79). Table 7 further describes these studies.

Conclusions

It is an exciting time for breast cancer research as newer surgical techniques, radiation techniques and systemic therapies are allowing patients to live longer with lower toxicities than in the past. Clinical trials are key in developing these advances in therapies. There are multiple ongoing breast cancer radiation trials that are attempting to take these advances further. The ultimate goal of any cancer directed therapy is cure with no toxicities. The trials outlined here are all attempting this very goal. For well selected, favorable patients, trials are aiming to de-escalate radiation therapy, and hopefully minimize treatment related toxicities. Other radiation trials are evaluating newer technologies with the goal of delivering safer radiation treatments. And finally, there are promising ongoing trials using escalation of radiation for metastasis directed therapy in the oligometastatic setting, which as breast cancer patients live longer, this may be a very significant role for radiation in the future. It is important for practitioners to educate themselves on these improvements and to enroll patients in ongoing trials whenever possible to help in advancing breast cancer care.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Breast Surgery for the series “Advancements and Opportunities for Breast Irradiation”. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/abs-20-132). The series “Advancements and Opportunities for Breast Irradiation” was commissioned by the editorial office without any funding or sponsorship. WS Jr served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Breast Surgery from August 2019 to July 2023. WS Jr reports personal fees from Carl Zeiss, other from Varian, other from Merck, other from NRG Oncology, outside the submitted work. The authors have no other 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Fisher B, Anderson S, Bryant J, et al. Twenty-Year Follow-up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy plus Irradiation for the Treatment of Invasive Breast Cancer. N Engl J Med 2002;347:1233-41. [Crossref] [PubMed]
2. EBCTCG (Early Breast Cancer Trialists' Collaborative Group). Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014;383:2127-35. Erratum in: Lancet 2014 Nov 22;384(9957):1848. [Crossref] [PubMed]
3. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087-106. [Crossref] [PubMed]
4. National Institute of Health U.S. National Library of Medicine [Internet] ClinicalTrials.gov [accessed on 2020 Sept 25]. Available online: https://clinicaltrials.gov
5. Zhou P, Gautam S, Recht A. Factors affecting outcome for young women with early stage invasive breast cancer treated with breast-conserving therapy. Breast Cancer Res Treat 2007;101:51-7. [Crossref] [PubMed]
6. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403-10. [Crossref] [PubMed]
7. Crowe JP Jr, Gordon NH, Hubay CA, et al. Estrogen receptor determination and long-term survival of patients with carcinoma of the breast. Surg Gynecol Obstet 1991;173:273-8. [PubMed]
8. Smitt MC, Nowels KW, Zdeblick MJ, et al. The importance of the lumpectomy surgical margin status in long-term results of breast conservation. Cancer 1995;76:259-67. [Crossref] [PubMed]
9. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817-26. [Crossref] [PubMed]
10. Curtit E, Mansi L, Maisonnette-Escot Y, et al. Prognostic and predictive indicators in early-stage breast cancer and the role of genomic profiling: Focus on the Oncotype DX(R) Breast Recurrence Score Assay. Eur J Surg Oncol 2017;43:921-30. [Crossref] [PubMed]
11. Ohnstad HO, Borgen E, Falk RS, et al. Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up. Breast Cancer Res 2017;19:120. [Crossref] [PubMed]
12. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2018;379:111-21. [Crossref] [PubMed]
13. Andre F, Ismaila N, Henry L, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women with Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update—Integration of Results from TAILORx. J Clin Oncol 2019;37:1956-64. [Crossref] [PubMed]
14. Fisher ER, Costantino JP, Leon ME, et al. Pathobiology of Small Invasive Breast Cancers Without Metastases (T1a/b, N0, M0). Cancer 2007;110:1929-36. [Crossref] [PubMed]
15. 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]
16. 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]
17. 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]
18. Jayasekera J, Schechter CB, Sparano JA, et al. Effects of Radiotherapy in Early-Stage, Low-Recurrence Risk, Hormone-Sensitive Breast Cancer. J Natl Cancer Inst 2018;110:1370-9. [Crossref] [PubMed]
19. ClinicalTrials.gov [Internet]. Identifier NCT02400190. The IDEA Study (Individualized Decisions for Endocrine Therapy Alone); 2015 March 26 [cited 2020 Aug 28]. Available online: https://clinicaltrials.gov/ct2/show/NCT02400190
20. ClinicalTrials.gov [Internet]. Identifier NCT02653755. The PRECISION Trial (Profiling Early Breast Cancer for Radiotherapy Omission): A Phase II Study of Breast-Conserving Surgery Without Adjuvant Radiotherapy for Favorable-Risk Breast Cancer; 2016 Jan 12 [cited 2020 Aug 28] Available online: https://www.clinicaltrials.gov/ct2/show/NCT02653755
21. ClinicalTrials.gov [Internet]. Identifier: NCT01791829. A Prospective Cohort Study Evaluating Risk of Local Recurrence Following Breast Conserving Surgery and Endocrine Therapy in Low Risk Luminal a Breast Cancer (LUMINA); 2013 Feb 15 [cited 2020 Aug 28]. Available online: https://clinicaltrials.gov/ct2/show/NCT01791829
22. ClinicalTrials.gov [Internet]. Identifier: NCT02889874. EXamining PErsonalised Radiation Therapy for Low-risk Early Breast Cancer (EXPERT); 2016 Sept 7 [cited 2020 Aug 28]. Available online: https://clinicaltrials.gov/ct2/show/NCT02889874
23. ClinicalTrials.gov [Internet]. Identifier: NCT03488693. Regional Radiotherapy in Biomarker Low Risk Node Positive Breast Cancer (TAILOR RT). Available online: https://clinicaltrials.gov/ct2/show/NCT03488693
24. ClinicalTrials.gov [Internet] Identifier: NCT01872975. Standard or Comprehensive Radiation Therapy in Treating Patients with Early-Stage Breast Cancer Previously Treated with Chemotherapy and Surgery; 2013 June 7 [cited 2020 Aug 28]. Available online: https://clinicaltrials.gov/ct2/show/NCT01872975
25. ClinicalTrials.gov [Internet]. Identifier NCT01901094. Comparison of Axillary Lymph Node Dissection with Axillary Radiation for Patients with Node-Positive Breast Cancer Treated With Chemotherapy (ALLIANCE A011202). [cited 2020 Aug 20]. Available online: https://clinicaltrials.gov/ct2/show/NCT01901094
26. Wallace AS, Keene KS, Williams CP, et al. Radiation Therapy Utilization in Medicare Beneficiaries with Early-Stage Breast Cancer. Cancer 2018;124:475-81. [Crossref] [PubMed]
27. Joseph K, Zebak S, Alba V, et al. Adjuvant breast radiotherapy, endocrine therapy, or both after breast conserving surgery in older women with low-risk breast cancer: Results from a population-based study. Radiother Oncol 2021;154:93-100. [Crossref] [PubMed]
28. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med 2015;373:307-16. [Crossref] [PubMed]
29. Poortmans PM, Collette S, Kirkovoe C, et al. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med 2015;373:317-27. [Crossref] [PubMed]
30. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 2004;22:4247-54. [Crossref] [PubMed]
31. Nielsen HM, Overgaard M, Grau C, et al. Study of Failure Pattern Among High-Risk Breast Cancer Patients with or Without Postmastectomy Radiotherapy in Addition to Adjuvant Systemic Therapy: Long-Term Results from the Danish Breast Cancer Cooperative Group DBCG 82 b and c Randomized Studies. J Clin Oncol 2006;24:2268-75. [Crossref] [PubMed]
32. Velikova G, Williams LJ, Willis S, et al. Quality of life after postmastectomy radiotherapy in patients with intermediate-risk breast cancer (SUPREMO): 2-year follow-up results of a randomised, controlled trial. Lancet Oncol 2018;19:1516-29. [Crossref] [PubMed]
33. Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of Locoregional Recurrence After Neoadjuvant Chemotherapy: Results from Combined Analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol 2012;30:3960-6. [Crossref] [PubMed]
34. Giuliano AE, Ballman KV, McCall L, et al. Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women with Invasive Breast Cancer and Sentinel Node Metastasis The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA 2017;318:918-26. [Crossref] [PubMed]
35. Donker M, Tienhoven GV, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 2014;15:1303-10. [Crossref] [PubMed]
36. Rutgers EJ, Donker M, Poncet C, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: 10 year follow up results of the EORTC AMAROS trial (EORTC 10981/22023). Cancer Res 2019;79:abstr GS4-01.
37. Pilewskie M, Morrow M. Axillary Nodal Management Following Neoadjuvant Chemotherapy. JAMA Oncol 2017;3:549-55. [Crossref] [PubMed]
38. NCCN Clinical Practice Guidelines in Oncology–Breast Cancer. NCCN.org [internet] [cited 2020 Aug 24] Available online: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
39. 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]
40. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10‐year follow-up results of two randomised controlled trials. Lancet Oncol 2013;14:1086-94. [Crossref] [PubMed]
41. Shaitelman SF, Lei X, Thompson A, et al. Three-Year Outcomes With Hypofractionated Versus Conventionally Fractionated Whole-Breast Irradiation: Results of a Randomized, Noninferiority Clinical Trial. J Clin Oncol 2018;36:JCO1800317. [Crossref] [PubMed]
42. Brunt AM, Haviland JS, Sydenham M, et al. Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer. J Clin Oncol 2020;38:3261-72. [Crossref] [PubMed]
43. Murray Brunt A, Haviland JS, Wheatley DA, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non- inferiority, randomised, phase 3 trial. Lancet 2020;395:1613-26. [Crossref] [PubMed]
44. Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Pract Radiat Oncol 2018;8:145-52. [Crossref] [PubMed]
45. Wang SL, Fang H, Song YW, et al. Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2019;20:352-60. [Crossref] [PubMed]
46. ClinicalTrials.gov [Internet]. Identifier: NCT03414970. Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients with Stage IIa-IIIa Breast Cancer; 2018 Jan 30 [cited 2020 Sept 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT03414970
47. ClinicalTrials.gov [Internet]. Identifier: NCT03422003. Study of Radiation Fractionation on Patient Outcomes After Breast REConstruction (FABREC) for Invasive Breast Carcinoma; 2018 Feb 5 [cited 2020 Sept 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT03422003
48. Correa C, Harris EE, Leonardi MC, et al. Accelerated partial breast irradiation: Executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol 2017;7:73-9. [Crossref] [PubMed]
49. Polgár C, Van Limbergen E, Potter R, et al. Patient selection for accelerated partial breast irradiation (APBI) after breast-conserving surgery: Recommendations of the Group e Europeen de Curietherapie -European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol 2010;94:264-73. [Crossref] [PubMed]
50. Whelan TJ, Julian JA, Berrang TS, et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial. Lancet 2019;394:2165-72. [Crossref] [PubMed]
51. Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet 2019;394:2155-64. [Crossref] [PubMed]
52. Coles CE, Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017;390:1048-60. [Crossref] [PubMed]
53. Meattini I, Marrazzo L, Saieva C, et al. Accelerated Partial-Breast Irradiation Compared With Whole-Breast Irradiation for Early Breast Cancer: Long-Term Results of the Randomized Phase III APBI-IMRT-Florence Trial. J Clin Oncol 2020;38:4175-83. [Crossref] [PubMed]
54. Strnad V, Ott OJ, Hildebrandt PG, et al. 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet 2016;387:229-38. [Crossref] [PubMed]
55. Kennedy WR, Thomas MA, Stanley JA, et al. Single-Institution Phase 1/2 Prospective Clinical Trial of Single-Fraction, High-Gradient Adjuvant Partial-Breast Irradiation for Hormone Sensitive Stage 0-I Breast Cancer. Int J Radiat Oncol Biol Phys 2020;107:344-52. [Crossref] [PubMed]
56. Vaidya JS, Bulsara M, Baum M, et al. Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial. BMJ 2020;370:m2836. [Crossref] [PubMed]
57. Silverstein MJ, Fastner G, Matula S, et al. Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 2--TARGIT. Ann Surg Oncol 2014;21:3793-9. [Crossref] [PubMed]
58. ClinicalTrials.gov [Internet]. Identifier: NCT04368702. CONFIRM: Magnetic Resonance Guided Radiation Therapy (CONFIRM); 2020 Apr 3 [cited 2020 Sept 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT04115254
59. ClinicalTrials.gov [Internet]. Identifier: NCT01766297. Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer; 2013 Jan 11 [cited 2020 Sept 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT01766297
60. ClinicalTrials.gov [Internet]. Identifier: NCT03940248. Proton Accelerated Partial Breast Irradiation (APBI); 2019 May 7 [cited 2020 Sept 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT03940248
61. ClinicalTrials.gov [Internet]. Identifier NCT03581136. Phase II multi-center trial evaluating 5 fraction stereotactic partial breast irradiation using Gammapod; 2018 July 10 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT03581136
62. ClinicalTrials.gov [Internet]. Identifier NCT03643861. RAD 1802: Pilot trial of LINAC based stereotactic body radiotherapy for early stage breast cancer patients eligible for post-operative accelerated partial breast irradiation (APBI); 2018 Aug 23 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT03643861
63. ClinicalTrials.gov [Internet]. Identifier NCT04532177. Stereotactic body radiation therapy (SBRT) for invasive breast cancer patients not undergoing definitive surgery (SBRT BREAST); 2020 Aug 31 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT04532177
64. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol 2017;35:1171-8. [Crossref] [PubMed]
65. Darby SC, Ewertz M, McGale P, et al. Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer. N Engl J Med 2013;368:987-98. [Crossref] [PubMed]
66. ClinicalTrials.gov [Internet]. Identifier NCT02603341. Pragmatic randomized trial of proton vs. photon therapy for patients with non-metastatic breast cancer: A radiotherapy comparative effectiveness (RADCOMP) consortium trial; 2015 Nov 11 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT02603341
67. 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. Erratum in: Lancet 2014 Feb 15;383(9917):602. [Crossref] [PubMed]
68. ClinicalTrials.gov [Internet]. Identifier NCT01792726. A comparison of intra-operative radiotherapy boost with external beam radiotherapy boost in early breast cancer. (TARGIT-B); 2013 Feb 15 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT01792726?term=iort&recrs=a&cond=Breast+Cancer&draw=3&rank=12
69. ClinicalTrials.gov [Internet]. Identifier NCT03624478. Hypofractionated radiation therapy in treating participants with breast cancer before surgery; 2018 Aug 10 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT03624478
70. ClinicalTrials.gov [Internet]. Identifier NCT03909282. Phase II surgical excision vs neoadjuvant radiotherapy + delayed surgical excision of ductal carcinoma (NORDIS); 2019 Apr 10 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT03909282
71. ClinicalTrials.gov [Internet]. Identifier NCT04234386. GammaPod dose escalation radiation for early stage breast cancer; 2020 Jan 21 [cited 2020 Sep 15]. Available online: https://clinicaltrials.gov/ct2/show/NCT04234386
72. Lewis SL, Porceddu S, Nakamura N, et al. Definitive Stereotactic Body Radiotherapy (SBRT) for Extracranial Oligometastases: An International Survey of >1000 Radiation Oncologists. Am J Clin Oncol 2017;40:418-22. [Crossref] [PubMed]
73. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2018;4:e173501. [Crossref] [PubMed]
74. Ruers T, Van Coevorden F, Punt CJ, et al. Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial. J Natl Cancer Inst 2017;109:djx015. [Crossref] [PubMed]
75. Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol 2019;37:1558-65. [Crossref] [PubMed]
76. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open- label trial. Lancet 2019;393:2051-8. [Crossref] [PubMed]
77. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 2020;38:2830-8. [Crossref] [PubMed]
78. ClinicalTrials.gov [Internet]. Identifier: NCT02364557. Standard of Care Therapy with or Without Stereotactic Radiosurgery and/or Surgery in Treating Patients With Limited Metastatic Breast Cancer (NRG BR002); 2015 Feb 18 [cited 2020 Sept 25]. Available online: https://clinicaltrials.gov/ct2/show/NCT02364557
79. ClinicalTrials.gov [Internet]. Identifier: NCT02089100. Trial of Superiority of Stereotactic Body Radiation Therapy in Patients with Breast Cancer (STEREO-SEIN); 2014 March 17 [cited 2020 Sept 25]. Available online: https://clinicaltrials.gov/ct2/show/NCT02089100