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Pathological complete response as a surrogate endpoint
The Breast xxx (2016) 1
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Correspondence
Pathological complete response as a surrogate endpoint
To the Editor,
Conflicts of interest
Fiteni and Bonnetain recently reported that pathological complete response (PCR) after neoadjuvant breast cancer treatment was “not judged to be a valid surrogate for overall survival”(OS) [1]. They also reminded us that the FDA recently endorsed improved PCR as a basis of accelerated drug approval in that setting, based primarily on NSABP trials suggesting that improved PCR in fact does correlate with improved long-term outcome [2,3]. The first FDA approved drug in this context was pertuzumab, based largely on the NeoSphere trial, comparing neoadjuvant chemotherapy with trastuzumab and pertuzumab (C/T/P) to the same therapy without pertuzumab (C/T). The PCR rate was 46% versus 29%, favoring the pertuzumab containing arm. Now, Gianni et al. have reported a 5-year DFS of 84% (C/T/P) compared to 81% (CH), a 15.7% relative improvement in 5-year DFS, apparently validating improved PCR as a surrogate for long-term efficacy [4,5]. Given the findings of Fiteni and Bonnetain, together with the 5year DFS results from the NeoSphere trial, it seems reasonable to conclude that PCR is a valid surrogate for long-term efficacy (eg 5-year DFS or OS), but only in certain settings. Future studies designed with PCR as a primary endpoint should continue to be powered to assess long-term outcome (eg OS or 5-year DFS) as endpoints in order to confirm which breast cancer drugs ultimately should be approved based on PCR. Such studies will not only confirm the value of improved PCR. Of equal or even greater importance, long-term outcome endpoints will provide an estimate of just how much more effective a drug is in reducing recurrence risk, in a particular setting. This will help clinicians provide more precise benefit estimates and enable patients to make more informed decisions.
There are no relevant conflicts of interest related to this correspondence.
References [1] Fiteni F, Bonnetain F. Surrogate end points for overall survival in breast cancer trials: a review. Breast 2016 Oct;29:44e8. http://dx.doi.org/10.1016/ j.breast.2016.06.005. Epub 2016 Jul 9. [2] Pathological complete response in neoadjuvant treatment of high-risk earlystage breast cancer: use as an endpoint to support accelerated approvalucm305501.pdf (Internet). [cite 21 avr 2016]. Disponsible sur: http://www. fda.gov/downloads/frugs/. [3] Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 2008;26(5):778e85. [4] Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2- positive breast cancer (NeoSphere): a randomized, multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13: 25e32. [5] Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;6:791e800. http://dx.doi.org/10.1016/S1470-2045(16)00163-7. Epub 2016 May 11.
Steven Sorscher Wake Forest School of Medicine, Winston-Salem, NC 27157, USA E-mail address: [email protected]. 26 October 2016 Available online xxx
http://dx.doi.org/10.1016/j.breast.2016.11.020 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sorscher SPathological complete response as a surrogate endpoint, The Breast (2016), http://dx.doi.org/ 10.1016/j.breast.2016.11.020
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Correspondence
Pathological complete response as a surrogate endpoint
To the Editor,
Conflicts of interest
Fiteni and Bonnetain recently reported that pathological complete response (PCR) after neoadjuvant breast cancer treatment was “not judged to be a valid surrogate for overall survival”(OS) [1]. They also reminded us that the FDA recently endorsed improved PCR as a basis of accelerated drug approval in that setting, based primarily on NSABP trials suggesting that improved PCR in fact does correlate with improved long-term outcome [2,3]. The first FDA approved drug in this context was pertuzumab, based largely on the NeoSphere trial, comparing neoadjuvant chemotherapy with trastuzumab and pertuzumab (C/T/P) to the same therapy without pertuzumab (C/T). The PCR rate was 46% versus 29%, favoring the pertuzumab containing arm. Now, Gianni et al. have reported a 5-year DFS of 84% (C/T/P) compared to 81% (CH), a 15.7% relative improvement in 5-year DFS, apparently validating improved PCR as a surrogate for long-term efficacy [4,5]. Given the findings of Fiteni and Bonnetain, together with the 5year DFS results from the NeoSphere trial, it seems reasonable to conclude that PCR is a valid surrogate for long-term efficacy (eg 5-year DFS or OS), but only in certain settings. Future studies designed with PCR as a primary endpoint should continue to be powered to assess long-term outcome (eg OS or 5-year DFS) as endpoints in order to confirm which breast cancer drugs ultimately should be approved based on PCR. Such studies will not only confirm the value of improved PCR. Of equal or even greater importance, long-term outcome endpoints will provide an estimate of just how much more effective a drug is in reducing recurrence risk, in a particular setting. This will help clinicians provide more precise benefit estimates and enable patients to make more informed decisions.
There are no relevant conflicts of interest related to this correspondence.
References [1] Fiteni F, Bonnetain F. Surrogate end points for overall survival in breast cancer trials: a review. Breast 2016 Oct;29:44e8. http://dx.doi.org/10.1016/ j.breast.2016.06.005. Epub 2016 Jul 9. [2] Pathological complete response in neoadjuvant treatment of high-risk earlystage breast cancer: use as an endpoint to support accelerated approvalucm305501.pdf (Internet). [cite 21 avr 2016]. Disponsible sur: http://www. fda.gov/downloads/frugs/. [3] Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 2008;26(5):778e85. [4] Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2- positive breast cancer (NeoSphere): a randomized, multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13: 25e32. [5] Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;6:791e800. http://dx.doi.org/10.1016/S1470-2045(16)00163-7. Epub 2016 May 11.
Steven Sorscher Wake Forest School of Medicine, Winston-Salem, NC 27157, USA E-mail address: [email protected]. 26 October 2016 Available online xxx
http://dx.doi.org/10.1016/j.breast.2016.11.020 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sorscher SPathological complete response as a surrogate endpoint, The Breast (2016), http://dx.doi.org/ 10.1016/j.breast.2016.11.020