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Response JNCI J Natl Cancer Inst (2018) 110(5): djx242 doi: 10.1093/jnci/djx242 First published online November 21, 2017 Isabelle Gingras, Hatem A. Azim Jr. Affiliations of authors: Hematology and Oncology department, Hoˆpital du Sacre´-Coeur de Montre´al, Montre´al, Que´bec, Canada (IG); Department of Internal Medicine, American University of Beirut (AUB), Beirut, Lebanon (HAAJr) Correspondence to: Isabelle Gingras, MD, Hoˆ pital du Sacre´-Cœur de Montre´al, Department of hematology and oncology, 5400 Boul. Gouin Ouest, Montre´al, Que´bec, H4J 1C5, Canada (e-mail: isabelle.gingras.md@gmail.com) We thank Belkacemi and colleagues for their interest in our re- and EORTC 22922, even if the nodal burden of their population cent work that evaluated the impact of regional nodal irradia- was lower. tion (RNI) in node-positive human epidermal growth factor The MA20 and EORTC trials were published two years ago; to our knowledge, no international guidelines addressing the use receptor 2 (HER2)–positive breast cancer (BC). They made several of RNI in one to three lymph nodes–positive early BC have been arguments questioning the validity of our findings, and below we provide our response to their comments. published since then. It would be interesting to know how these results have been applied in clinical practice. The panel of Belkacemi and colleagues argued that the results of a recent experts at the 2017 St. Galen conference recommended RNI for meta-analysis showing higher loco-regional recurrence rate patients with pN1 disease and adverse clinical features (age < (LRRR) in HER2-positive BC patients treated with trastuzumab 40 years, estrogen receptor–negative BC, high grade, extensive (1) weaken the rationale of evaluating whether there is a dis- lymphovascular invasion), but recommended weighing risk tinct impact of RNI in this population. This study showed a high against benefit for low-risk patients, as RNI can have significant LRRR in HER2-positive BC, up to 5.6%. However, it was based side effects (6). Interestingly, HER2 was not recognized by this solely on retrospective data and, importantly, more than 25% panel as an adverse prognostic factor to consider in deciding for of HER2-positive patients did not receive trastuzumab. RNI, despite the historical data showing increased LRRR. In Contrastingly, the LRRR observed in prospective randomized tri- agreement with these recommendations, we do not believe in a als in which all patients received trastuzumab such as ALTTO “one size fits all” approach to BC treatment, and we think that and APHINITY is reported to be in the range of 1% to 2% (2,3). an accurate evaluation of the individual patient risk should be We believe that such figures should serve as the reference to considered in treatment decision-making. 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 References prevent both regional and distant DFS (4,5). We would like to re- 1. McGuire A, Lowery AJ, Kell MR, et al. Locoregional recurrence following breast iterate that LRR was low in our study population and most of cancer surgery in the trastuzumab era: A systematic review by subtype. Ann Surg Oncol. In press. the events were distant DFS. Thus, a benefit in distant DFS 2. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and would have been observed by a multivariable analysis for DFS trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2): that was performed in our study. 122–131. We acknowledge that RNI as administered in the ALTTO trial 3. Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzu- mab for early human epidermal growth factor receptor 2–positive breast can- (3) was heterogeneous due to the lack of consensus in this field, cer: Results from the randomized phase III Adjuvant Lapatinib and/or with a low rate of internal mammary node irradiation (IMNI; Trastuzumab Treatment Optimization Trial. J Clin Oncol. 2016;34(10): 14%) compared with the MA20 (5) and EORTC (5) trials. Indeed, 1034–1042. 4. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early- our study cannot completely exclude a benefit of comprehen- stage breast cancer. N Engl J Med. 2015;373(4):307–316. sive RNI including IMNI. Nevertheless, the DFS benefit observed 5. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial in MA20 and EORTC might not be as clinically significant for supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317–327. 6. Curigliano G, Burstein HJ, E PW, et al. De-escalating and escalating treatments patients treated with trastuzumab given the drastic improve- for early-stage breast cancer: The St. Gallen International Expert Consensus ment in their prognosis. The regional relapse rate of our popula- Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. tion was less than 1%, compared with 2.5% and 4.2% in MA20 2017;28(8):1700–1712. Received: October 2, 2017; Accepted: October 12, 2017 © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. Downloaded from https://academic.oup.com/jnci/article-abstract/110/5/541/4645257 by Ed 'DeepDyve' Gillespie user on 20 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

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Oxford University Press
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© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
ISSN
0027-8874
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1460-2105
DOI
10.1093/jnci/djx242
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Abstract

JNCI J Natl Cancer Inst (2018) 110(5): djx242 doi: 10.1093/jnci/djx242 First published online November 21, 2017 Isabelle Gingras, Hatem A. Azim Jr. Affiliations of authors: Hematology and Oncology department, Hoˆpital du Sacre´-Coeur de Montre´al, Montre´al, Que´bec, Canada (IG); Department of Internal Medicine, American University of Beirut (AUB), Beirut, Lebanon (HAAJr) Correspondence to: Isabelle Gingras, MD, Hoˆ pital du Sacre´-Cœur de Montre´al, Department of hematology and oncology, 5400 Boul. Gouin Ouest, Montre´al, Que´bec, H4J 1C5, Canada (e-mail: isabelle.gingras.md@gmail.com) We thank Belkacemi and colleagues for their interest in our re- and EORTC 22922, even if the nodal burden of their population cent work that evaluated the impact of regional nodal irradia- was lower. tion (RNI) in node-positive human epidermal growth factor The MA20 and EORTC trials were published two years ago; to our knowledge, no international guidelines addressing the use receptor 2 (HER2)–positive breast cancer (BC). They made several of RNI in one to three lymph nodes–positive early BC have been arguments questioning the validity of our findings, and below we provide our response to their comments. published since then. It would be interesting to know how these results have been applied in clinical practice. The panel of Belkacemi and colleagues argued that the results of a recent experts at the 2017 St. Galen conference recommended RNI for meta-analysis showing higher loco-regional recurrence rate patients with pN1 disease and adverse clinical features (age < (LRRR) in HER2-positive BC patients treated with trastuzumab 40 years, estrogen receptor–negative BC, high grade, extensive (1) weaken the rationale of evaluating whether there is a dis- lymphovascular invasion), but recommended weighing risk tinct impact of RNI in this population. This study showed a high against benefit for low-risk patients, as RNI can have significant LRRR in HER2-positive BC, up to 5.6%. However, it was based side effects (6). Interestingly, HER2 was not recognized by this solely on retrospective data and, importantly, more than 25% panel as an adverse prognostic factor to consider in deciding for of HER2-positive patients did not receive trastuzumab. RNI, despite the historical data showing increased LRRR. In Contrastingly, the LRRR observed in prospective randomized tri- agreement with these recommendations, we do not believe in a als in which all patients received trastuzumab such as ALTTO “one size fits all” approach to BC treatment, and we think that and APHINITY is reported to be in the range of 1% to 2% (2,3). an accurate evaluation of the individual patient risk should be We believe that such figures should serve as the reference to considered in treatment decision-making. 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 References prevent both regional and distant DFS (4,5). We would like to re- 1. McGuire A, Lowery AJ, Kell MR, et al. Locoregional recurrence following breast iterate that LRR was low in our study population and most of cancer surgery in the trastuzumab era: A systematic review by subtype. Ann Surg Oncol. In press. the events were distant DFS. Thus, a benefit in distant DFS 2. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and would have been observed by a multivariable analysis for DFS trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2): that was performed in our study. 122–131. We acknowledge that RNI as administered in the ALTTO trial 3. Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzu- mab for early human epidermal growth factor receptor 2–positive breast can- (3) was heterogeneous due to the lack of consensus in this field, cer: Results from the randomized phase III Adjuvant Lapatinib and/or with a low rate of internal mammary node irradiation (IMNI; Trastuzumab Treatment Optimization Trial. J Clin Oncol. 2016;34(10): 14%) compared with the MA20 (5) and EORTC (5) trials. Indeed, 1034–1042. 4. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early- our study cannot completely exclude a benefit of comprehen- stage breast cancer. N Engl J Med. 2015;373(4):307–316. sive RNI including IMNI. Nevertheless, the DFS benefit observed 5. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial in MA20 and EORTC might not be as clinically significant for supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317–327. 6. Curigliano G, Burstein HJ, E PW, et al. De-escalating and escalating treatments patients treated with trastuzumab given the drastic improve- for early-stage breast cancer: The St. Gallen International Expert Consensus ment in their prognosis. The regional relapse rate of our popula- Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. tion was less than 1%, compared with 2.5% and 4.2% in MA20 2017;28(8):1700–1712. Received: October 2, 2017; Accepted: October 12, 2017 © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. Downloaded from https://academic.oup.com/jnci/article-abstract/110/5/541/4645257 by Ed 'DeepDyve' Gillespie user on 20 June 2018

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JNCI: Journal of the National Cancer Institute – Oxford University Press

Published: Nov 21, 2017

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