Response

We thank Belkacemi and colleagues for their interest in our recent work that evaluated the impact of regional nodal irradiation (RNI) in node-positive human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC). They made several arguments questioning the validity of our findings, and below we provide our response to their comments. Belkacemi and colleagues argued that the results of a recent meta-analysis showing higher loco-regional recurrence rate (LRRR) in HER2-positive BC patients treated with trastuzumab (1) weaken the rationale of evaluating whether there is a distinct impact of RNI in this population. This study showed a high LRRR in HER2-positive BC, up to 5.6%. However, it was based solely on retrospective data and, importantly, more than 25% of HER2-positive patients did not receive trastuzumab. Contrastingly, the LRRR observed in prospective randomized trials in which all patients received trastuzumab such as ALTTO and APHINITY is reported to be in the range of 1% to 2% (2,3). We believe that such figures should serve as the reference to understand the LRRR in today’s practice. They also express concerns about the primary end point used in our analysis, disease-free survival (DFS), as RNI may prevent both regional and distant DFS (4,5). We would like to reiterate that LRR was low in our study population and most of the events were distant DFS. Thus, a benefit in distant DFS would have been observed by a multivariable analysis for DFS that was performed in our study. We acknowledge that RNI as administered in the ALTTO trial (3) was heterogeneous due to the lack of consensus in this field, with a low rate of internal mammary node irradiation (IMNI; 14%) compared with the MA20 (5) and EORTC (5) trials. Indeed, our study cannot completely exclude a benefit of comprehensive RNI including IMNI. Nevertheless, the DFS benefit observed in MA20 and EORTC might not be as clinically significant for patients treated with trastuzumab given the drastic improvement in their prognosis. The regional relapse rate of our population was less than 1%, compared with 2.5% and 4.2% in MA20 and EORTC 22922, even if the nodal burden of their population was lower. The MA20 and EORTC trials were published two years ago; to our knowledge, no international guidelines addressing the use of RNI in one to three lymph nodes–positive early BC have been published since then. It would be interesting to know how these results have been applied in clinical practice. The panel of experts at the 2017 St. Galen conference recommended RNI for patients with pN1 disease and adverse clinical features (age < 40 years, estrogen receptor–negative BC, high grade, extensive lymphovascular invasion), but recommended weighing risk against benefit for low-risk patients, as RNI can have significant side effects (6). Interestingly, HER2 was not recognized by this panel as an adverse prognostic factor to consider in deciding for RNI, despite the historical data showing increased LRRR. In agreement with these recommendations, we do not believe in a “one size fits all” approach to BC treatment, and we think that an accurate evaluation of the individual patient risk should be considered in treatment decision-making.

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