The role of postmastectomy radiotherapy in patients with stage II breast cancer

Although the benefits of postmastectomy radiotherapy (PMRT) in patients with locally advanced breast cancer have been established in multiple randomized trials as well as the Early Breast Cancer Trialists' Collaborative Group meta-analysis,1-3 the role of PMRT in patients with early-stage disease remains controversial. This article will discuss which patients with AJCC 7th edition stage II breast cancer may benefit from PMRT. In 2014, an update of the Early Breast Cancer Trialists' Collaborative Group meta-analysis, which included trials predominantly conducted in the 1970s and 1980s, demonstrated a significant reduction in 10-year isolated locoregional recurrence (21.0% vs 4.3%) and 20-year breast cancer-specific mortality (49.4% vs 41.5%) with PMRT for patients with 1 to 3 positive lymph nodes who underwent axillary dissection and received systemic therapy. The proportional reductions in locoregional recurrence and breast cancer-specific mortality did not differ among patients with 2 to 3 positive lymph nodes compared with those with only 1 positive lymph node.3 In contrast, several modern retrospective series have demonstrated lower rates of locoregional disease recurrence in patients with breast cancer with T1-2N1 disease who do not receive PMRT, ranging from 5% to 10%.4-6 This discrepancy may be a result of enhancements in surgical techniques and systemic therapies in the modern era, which can limit the benefits of PMRT within certain subsets of patients. Several series have attempted to identify subgroups of patients at a higher risk of locoregional disease recurrence for whom the benefits of PMRT outweigh the risks associated with treatment. Pathologic features commonly associated with increased rates of disease recurrence include younger age (≤50 years), larger primary tumor size (>3 cm), high-grade disease, the presence of lymphovascular space invasion (LVSI), greater lymph node disease burden (≥25% positive lymph node ratio), presence of extracapsular extension, and hormone-insensitive tumors.4-9 In 2016, the American Society of Clinical Oncology released an update of their joint guidelines regarding the use of PMRT in patients with T1-2N1 breast cancer to reflect the available data. Although the panel unanimously agreed that PMRT does reduce the risk of locoregional failure and breast cancer-related mortality, they recommended a risk-adaptive approach that accounts for additional clinical and pathologic factors to identify patients at higher risk of locoregional disease recurrence for whom the therapeutic ratio favors PMRT. Potential morbidities of treatment, including radiation-induced cardiac disease and deleterious effects on breast reconstruction, should be considered. Multidisciplinary and patient-centered decision making was strongly encouraged.10 The rarity of T3N0 breast cancer has resulted in ongoing controversy regarding its optimal management because there is limited randomized evidence to guide treatment. Based on results from the Danish Breast Cancer Cooperative Group 82b and 82c trials, which demonstrated a survival benefit with the addition of PMRT in patients with high-risk breast cancer, PMRT was commonly recommended for individuals with T3N0 disease. However, these data were limited by a small subset of patients with T3N0 disease (<10% of enrolled patients were lymph node negative), inadequate axillary sampling (the median number of lymph nodes removed was 7), and antiquated systemic therapies. In contrast, a pooled analysis of 5 National Surgical Adjuvant Breast and Bowel Project trials demonstrated an isolated locoregional failure rate of only 7.1% in a subset of 313 lymph node-negative patients after mastectomy with primary tumors measuring ≥5 cm, suggesting that PMRT should not be routinely recommended.11 Multiple additional studies have been conducted using the Surveillance, Epidemiology, and End Results database, with mixed results. The most recent analysis demonstrated improvements in both cancer-specific survival and overall survival with PMRT.12 Several smaller retrospective series have identified pathologic features associated with an increased risk of locoregional disease recurrence, including LVSI and grade 3 histology.13, 14 The European Organization for Research and Treatment of Cancer 22922 trial, which included patients with stages I to III breast cancer with centrally or medially located primary tumors or with externally located tumors and axillary lymph node involvement, randomized patients to breast/chest wall irradiation alone versus breast/chest wall irradiation with regional lymph node irradiation (medial supraclavicular and internal mammary lymph nodes). Approximately 24% of patients underwent a mastectomy. Despite the relatively high rate of pN0 disease (44%), there still was a significant improvement in the 10-year disease-free survival rate (72.1% vs 69.1%; P=.04) and a trend toward improved 10-year overall survival (82.3% vs 80.7%; P=.06) with regional lymph node irradiation.15 This suggests that some patients with lymph node-negative disease with centrally or medially located tumors may benefit from PMRT targeted to both the chest wall and regional lymphatics. In the absence of strong randomized data specifically examining the subset of patients with T3N0 disease, a risk-adaptive approach again is indicated. The role of PMRT after neoadjuvant chemotherapy currently is under active investigation. The available randomized data are derived from a pooled analysis of the National Surgical Adjuvant Breast and Bowel Project B-18 and B-27 trials, which demonstrated locoregional recurrence rates of >10% in patients with residual N1 lymph node disease at the time of mastectomy.16 This was corroborated by additional retrospective series demonstrating locoregional recurrence rates ranging between 10% and 20% without PMRT.17, 18 Although to the best of our knowledge there are no randomized data that demonstrate improved breast cancer mortality rates with PMRT, current American Society of Clinical Oncology guidelines recommend treatment for patients with residual lymph node disease after neoadjuvant chemotherapy given the high reported rates of locoregional failure.10 The SUPREMO (Selective Use of Postoperative Radiotherapy After Mastectomy) trial randomized patients with T1-2N1 disease, T3N0 disease, or T2N0 disease with grade 3 histology or LVSI to PMRT versus no PMRT and was closed to patient accrual in 2013.19 The Tailor RT trial, which is sponsored by the Canadian Cancer Trials Group and will be activated by the Alliance group in the United States, is investigating the role of regional lymph node irradiation after breast conservation or mastectomy in patients with 1 to 3 positive axillary lymph nodes, estrogen receptor-positive tumors, and low-risk Oncotype DX (Genomic Health) recurrence scores (<18).20 Long-term results from both trials may help to clarify which patients benefit from PMRT in the setting of modern surgical and systemic therapies. For patients receiving neoadjuvant chemotherapy, the ongoing Alliance A011202 trial will address the role of axillary lymph node dissection after a positive sentinel lymph node biopsy after chemotherapy. All patients receive radiotherapy to the breast/chest wall and regional lymphatics.21 The decision to recommend PMRT for patients with stage II breast cancer should, in many cases, be individualized, with careful consideration given to clinical and pathologic features that may confer a higher risk of locoregional disease recurrence if PMRT is omitted. A detailed discussion addressing the risks and benefits of treatment with each patient is warranted. No specific funding was disclosed. The authors made no disclosures. Nisha Ohri is an assistant professor of radiation oncology at the Rutgers Cancer Institute of New Jersey. Her clinical and research focus is on breast cancer management and outcomes. Bruce G. Haffty is chief of staff at Rutgers Cancer Institute of New Jersey and professor and chairman of the department of radiation oncology at Rutgers Robert Wood Johnson and New Jersey Medical School. His research interests include molecular and genetic factors in breast cancer and clinical trials in radiation oncology related to breast cancer. Thomas A. Buchholz is a professor of radiation oncology at The University of Texas MD Anderson Cancer Center, where he holds the Hubert L. Stringer Distinguished Chair in Oncology. His academic interest is in clinical outcomes, clinical trials, and translational research in breast cancer radiation oncology.

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