The incorporation of molecular subtypes into the locoregional management of breast cancer has lagged behind its use in systemic therapy. Omission or dose-intensification of RT based on subtypes should be investigated in future trials.
Up until the 1970s, the treatment of breast cancer was dominated by radical mastectomy or modified radical mastectomy of the affected breast. Then, the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial and other studies demonstrated equivalent overall survival (OS) and local control rates with either mastectomy or lumpectomy followed by whole-breast irradiation.[1,2] Additional randomized studies comparing lumpectomy alone with lumpectomy and radiation therapy (RT) clearly demonstrated a threefold reduction in local relapse with the use of RT following surgery.[3-7] Sentinel lymph node (SLN) biopsy gave rise to the next era of breast cancer surgery, allowing surgeons to accurately stage tumor-draining axillary nodes while avoiding morbidities associated with axillary lymph node dissection (ALND). In the 1990s, several studies established that SLN resection in node-negative patients achieves OS and regional control equivalent to ALND but with fewer side effects.
This evolution in breast cancer surgery challenged the need for ALND in SLN-positive patients, with the premise being that only 50% of patients with axillary nodal metastases that were not dissected eventually developed an axillary failure when systemic therapy or RT was not given. The American College of Surgeons Oncology Group Z0011 study sought to resolve this issue by randomizing patients to undergo SLN dissection alone or SLN dissection plus ALND; results showed no statistically significant differences in local recurrence or regional recurrence between the two groups in the presence of whole-breast irradiation. The reason for the low regional relapse rates is likely a combination of factors, including the presence of a favorable-prognosis subset of patients with a low likelihood of a high residual burden of axillary disease and incidental radiation to the residual nodes in level I or II from the tangential breast irradiation, as well as directed radiotherapy to the supraclavicular region.
One trend that has become evident over the last 50 years of locoregional management of early-stage, node-negative breast cancer is that, in general, less comprehensive local therapy consistently results in higher rates of locoregional recurrence. However, under the mantle of “comprehensive local therapy,” one may substitute RT for varying degrees of surgery (and vice versa) and achieve similar rates of locoregional recurrence while preserving a similar rate of OS.
The advisability of regional nodal irradiation for patients with one to three positive lymph nodes has been widely debated, and the recently reported results from the National Cancer Institute of Canada (NCIC) and the European Organisation for Research and Treatment of Cancer (EORTC) provide some clarity on this controversial issue. The EORTC 22922-10925 study randomized patients with an involved axilla and/or medial primary tumor to whole-breast irradiation with or without internal mammary and medial supraclavicular lymph node (IM-MS) irradiation after lumpectomy and ALND. After enrolling over 4,000 women and following up for 10.9 years, the study showed that IM-MS irradiation improved overall, disease-free, and metastasis-free survival without an increase in non–breast cancer-related mortality. Similarly, the NCIC MA.20 study randomized 1,832 women with high-risk node-negative or node-positive breast cancer to whole-breast irradiation with or without regional nodal irradiation (internal mammary, supraclavicular, and high axillary lymph nodes) after lumpectomy and ALND. With a median follow-up of 5 years, the results showed that regional nodal irradiation offered women a statistically significant benefit in terms of locoregional disease–free survival, distant disease–free survival, and OS, with acceptable rates of toxicities. These data support the use of additional comprehensive local therapy in this subset of breast cancer patients to reduce locoregional recurrence (LRR) and improve disease-free survival and OS.
In general, molecular subtypes of breast cancer may be organized into the following categories: luminal A (estrogen receptor [ER]-positive or progesterone receptor [PR]-positive and Ki-67 < 14%), luminal B (ER- or PR-positive and Ki-67 ≥ 14%), luminal human epidermal growth factor receptor 2 (HER2) (ER- or PR-positive and HER2-positive), HER2-enriched (ER-negative, PR-negative, and HER2-positive), and basal-like (ER-, PR-, and HER2-negative; and endothelial growth factor receptor–positive or CK5/6-positive). In comparison with the volume of data on tumor biology and the risk of distant metastases and the potential reduction in OS, the data on its role in local control should still be considered in its infancy.
Several large studies have examined the role of molecular subtypes in LRR in patients managed with breast-conserving surgery (BCS) and RT. Arvold et al reported on a modern series of 1,434 patients with invasive breast cancer treated with BCS and RT. With a median follow-up of 85 months, the 5-year rate of local recurrence was 2.1%; 0.8% for luminal A, 2.3% for luminal B, 1.1% for luminal HER2, 10.8% for HER2-enriched, and 6.7% for triple-negative disease. Voduc et al investigated local and regional relapse rates in 2,985 patients stratified by molecular subtype. With a median follow-up of 12 years, they found that after BCS and RT, patients with luminal A tumors had the most favorable prognosis, with local relapse and regional relapse rates of only 8% and 3%, respectively, at 10 years. The HER2-enriched and basal-like groups exhibited the highest rates of local recurrence (21% and 14%, respectively) and regional relapse (16% and 14%, respectively). After mastectomy, patients with luminal A tumors again had the best prognosis, with rates of local relapse and regional relapse of 8% and 4%, respectively, at 10 years. Finally, Mamounas et al investigated the 10-year risk of LRR in patients with early-stage, node-negative, ER-positive breast cancer treated in the NSABP B-14 and B-20 trials based on the Oncotype DX recurrence score (RS). The RS was available in 355 patients treated with placebo (B-14), in 424 treated with chemotherapy and tamoxifen (B-20), and in 895 treated with tamoxifen alone (B-14 and B-20). In the tamoxifen-only patients, the risk of LRR was 4.3% for patients with low RS (< 18), 7.2% for those with intermediate RS (18 to 30), and 15.8% for those with high RS (> 30). In placebo-treated patients, the risk of LRR was 10.8% for patients with low RS, 20.0% for those with intermediate RS, and 18.4% for those with high RS. In chemotherapy/tamoxifen-treated patients, the risk of LRR was 1.6%, 2.7%, and 7.8% for patients with low, intermediate, and high RS, respectively. The authors concluded that the Oncotype DX RS was a significant predictor of LRR.
These analyses, while showing a consistent trend of higher LRR in HER2-positive and triple-negative patients vs luminal A and B patients in the setting of BCS and RT, should be considered exploratory. The results are not significant enough to drive clinical decision-making at this time. One limitation of these studies is that all patients received BCS and RT, thus preventing the predictive power of molecular subtypes to be determined in patients not treated with RT. We do not know whether we may use molecular subtypes to identify patients at low risk for recurrence without RT, such as the luminal A and luminal B population, in whom the risk of LRR is 1% to 2% after BCS and RT. Fyles et al retrospectively evaluated NCIC data from women aged 50 years or older who were randomized to receive tamoxifen with or without whole-breast RT. Their overall risk of LRR was 13.8% without RT vs 5.3% with RT at 10 years. When examining LRR by molecular subtypes, the investigators reported no reduction in LRR with RT in the luminal A cohort. However, the addition of RT significantly reduced the risk of LRR in the luminal B, triple-negative, basal, and HER2-enriched cohorts. Ideally, in the future, molecular subtypes will be used in large clinical trials in a prospective manner to help identify molecular markers predictive of locoregional outcomes and to identify patients in whom RT may be safely omitted.
Classic locoregional management of breast cancer has been based on anatomic site, stage, and other limited prognostic information. However, we know that breast cancer is a heterogeneous group of tumor subtypes, with each type influencing both locoregional and distant disease control. The incorporation of molecular subtypes into the locoregional management of breast cancer has lagged behind its use in systemic therapy. Omission or dose-intensification of RT based on subtypes should be investigated in future trials.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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