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The increasing use of neoadjuvant chemotherapy for patients with breast cancer with axillary nodal metastases has created debate among multidisciplinary tumor boards centered on the optimal use of locoregional radiotherapy. Clinical decision making regarding the use of postmastectomy and regional nodal radiotherapy has been built on evidence from numerous randomized clinical trials where pathologic staging from upfront surgery was the determinant of receiving treatment after adjuvant chemotherapy. It is generally recommended that patients who have axillary nodal metastases receive radiotherapy to the chest wall and regional nodes after mastectomy or to breast and regional nodes after lumpectomy. Conversely, in patients with negative axillary nodes, radiotherapy is not typically recommended after mastectomy and is confined to the breast alone after lumpectomy. The absence of similar evidence in the setting of neoadjuvant chemotherapy has led to conflicting opinions about the key factors that should drive the clinical decision to administer locoregional radiotherapy. The thoughtful concepts of Marks and Prosnitz endorse the concept that the prechemotherapy-positive axillary nodal metastases are the key factor and caution that reducing radiotherapy based on chemotherapy response places women at risk for worse breast cancer mortality. Conversely, others have supported the idea that pathologic nodal status postchemotherapy is the important factor and argued that for patients who become pathologically node negative after neoadjuvant chemotherapy, radiotherapy may not offer significant benefit. It is clear that the absence of evidence permits the generation of disparate treatment recommendations for the same clinical scenario, placing women at risk for either overor undertreatment. As stated by Marks and Prosnitz, the critical threat of suboptimal locoregional cancer treatment is that it will result in worse breast cancer survival. Significant evidence exists that the addition of locoregional radiotherapy after upfront surgery and adjuvant chemotherapy can improve breast cancer survival in addition to providing large gains in locoregional cancer control. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) 2005 meta-analysis studied the effect of radiotherapy on locoregional recurrence at 5 years and breast cancer mortality at 15 years. This demonstrated that the absolute benefit in reducing breast cancer mortality resulting from radiotherapy was related to the magnitude of locoregional risk in the nonirradiated patients. However, an analysis that divided absolute locoregional recurrence risk reduction after lumpectomy or mastectomy by 5 years into three categories of 10%, 10% to 20%, or 20% demonstrated that for those with 10% absolute reduction in local recurrence resulting from radiotherapy by 5 years, there was no improvement in breast cancer mortality by 15 years. Similarly, the EBCTCG 2011 meta-analysis demonstrated that the reductions gained in 10-year overall breast cancer recurrence rate (local, regional, and distant) by postlumpectomy breast radiotherapy resulted in improvement in 15year breast cancer mortality rate. An analysis that stratified the predicted absolute reduction in 10-year overall breast cancer recurrence risk from radiotherapy into groups of low ( 10%), intermediate (10% to 19%), and large ( 20%) found in the low-risk group an absolute reduction of 6.9% with radiotherapy (18.9% without v 12% with radiotherapy), corresponding to a negligible absolute reduction in 15-year risk of death resulting from breast cancer of 0.1% ( 7.5% to 7.7%). Collectively these analyses support that the survival benefit from radiotherapy after upfront surgery and chemotherapy is related to an individualpatient’sriskofanyrecurrencebasedonclinicalandpathologic features. It is recognized that the extent of response to neoadjuvant chemotherapy is associated with prognosis, with the best relative disease-free survival occurring in those who achieve a complete pathologic response. Therefore, it is logical that if upfront chemotherapy can place a patient in a sufficiently low risk category for locoregional recurrence after surgery, then adding radiotherapy will not significantly reduce the risk of breast cancer mortality. There is supporting evidence that neoadjuvant chemotherapy response is linked to lower rates of subsequent locoregional recurrence risk in the absence of radiotherapy. Mamounas et al analyzed locoregional recurrence rates in approximately 3,000 women enrolled onto two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials evaluating neoadjuvant chemotherapy (NSABP B-18 and NSABP B-27). Both protocols specified that patients treated with lumpectomy were required to receive breast radiotherapy only, and patients treated with mastectomy were not allowed to receive any radiotherapy. The combined analysis of these two trials provides important information on the rates, patterns, and independent predictors of locoregional recurrence after neoadjuvant chemotherapy. The 10-year cumulative incidence of locoregional recurrence was 12.3% for patients who underwent mastectomy (local, 8.9%; regional, 3.4%) JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 32 NUMBER 6 FEBRUARY 2

Locoregional Radiotherapy in Patients With Breast Cancer Responding to Neoadjuvant Chemotherapy: A Paradigm for Treatment Individualization