Re: Rethinking neoadjuvant chemotherapy for breast cancer
The opinion piece by Vaidya et al. demonstrates continued confusion about the purpose of neoadjuvant therapy, its efficacy and the tremendous opportunity it presents to change outcomes early in the course of therapy. In fact, the suppositions that neither neoadjuvant therapy nor pathological complete response (pCR) are of benefit to patients runs contrary to the accumulated experience from neoadjuvant studies.
The most recent results are from the I-SPY 2 TRIAL. Based on 8-years of studying neoadjuvant therapy in over 1000 patients, the I-SPY 2 data show a strong and consistent relationship between pCR and 3-year event-free (EFS) and distant recurrence-free survival (DRFS) [1]. In this large prospective trial, pCR offers a clear advantage in long term outcome, with a hazard ratio of 0.2. Importantly, this result was obtained across 10 different agents or combinations, and was similar across subtypes. Patients with 70 gene low risk disease were excluded.
The I-SPY 2 results are consistent with the hazard ratio of 0.24 reported in the Cortazar meta-analysis [2]. However, in relying upon the apparent lack of linear correlation between pCR and EFS across multiple trials to make their case that NAC is ineffectual, the authors of this commentary unfortunately fall prey to confirmation bias. As explained in Berry et al. [3], due to the small treatment differences between trials (which did not use experimental agents), the confidence limits of the regression can neither support nor rule out either a positive or negative correlation. Berry et al. further clarify that the relationship between pCR and EFS is not linear, and demonstrate that results of the NEO-ALTTO and ALTTO trials are entirely consistent with other studies, and with the Cortazar meta-analysis.
It is also important to consider that many neoadjuvant studies (e.g. NeoSphere) referenced by Vaidya et al. included additional systemic adjuvant therapy following surgery, blurring the correlation of pCR and long term outcome. Further, the confirmatory trials often recruit large numbers of patients that have significantly lower risk profiles than neoadjuvant trials, which is another major confounder in interpreting the results. Vaidya and colleagues are mistaken about the benefits of pertuzumab in the APHINITY trial; the addition of pertuzumab to trastuzumab containing adjuvant chemotherapy for patients with HER2-positive early stage breast cancer led to a small and statistically significant improvement in invasive-disease-free survival consistent with the improvement in pCR rates and on this basis was approved by the FDA [4].
Perhaps most surprising is the editorial’s focus on local recurrence. Women with a poor response to local therapy are at highest risk for metastatic recurrence and death from systemic disease, not for local disease. Local recurrence in both I-SPY 2 and I-SPY 1 is uncommon [5]. In fact, in I-SPY 2 EFS and DRFS are essentially the same, further demonstrating that metastatic disease is the critical issue for women with breast cancer at high risk for early recurrence. In this respect, the authors concern about missing a window of opportunity for resection is misplaced. High risk cancers that do not respond to systemic therapy are not cured by earlier resection.
Surgery is not more difficult after neoadjuvant therapy. Patients whose cancers do not respond face the same surgery as they would have at initial presentation. For those with an excellent response, surgical options improve, extent of resection in breast and nodes may be less extensive and the extent of adjuvant radiotherapy can be reduced [6].
It is essential for surgeons, as part of the multidisciplinary team, to understand the extent and site of disease, correlate imaging and the initial exam and ensure that there are clips placed at the site of disease (in the breast and nodes) in the event that there is a complete response to neoadjuvant therapy. Imaging prior to surgery helps to restage and guide the extent of resection, with breast MRI providing the most value in predicting extent of residual disease [7]. In I-SPY 2, we have established a standard for the surgical management of the axilla in the setting of a neoadjuvant trial where pCR is the primary endpoint. Multidisciplinary care including standards for imaging and pathology are essential for characterizing the extent of disease after neoadjuvant therapy. In this setting, extent of residual disease has been shown to be highly predictive of outcome [8,9].
One of the key takeaways from I-SPY 2 is that patient selection matters. Chemotherapy does not provide significant benefit for those with genomically low risk disease [10] and these patients are excluded from I-SPY 2.
We agree that adjuvant and neoadjuvant therapy result in identical long-term outcomes - but neoadjuvant therapy gives us the opportunity to predict long-term outcome using pCR and residual cancer burden as an early endpoint. Understanding response to neoadjuvant therapy has clinical relevance as new systemic agents have shown benefit in extending therapy for HER-2 positive (neratinib) and triple negative (capecitabine) tumors in high risk patients [11,12]. Further, judging response in the neoadjuvant setting provides a platform to accelerate the testing of new agents and find treatments that will make a big impact, e.g. pembrolizumab which when added to standard neoadjuvant chemotherapy nearly tripled the chance of pCR. The neoadjuvant setting is a way for us to discover and individualize the right combinations of agents to help as many patients as possible achieve a complete response, and correspondingly, a better outcome.
1 Yee D, I-SPY2 Investigators. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 Trial. San Antonio Breast Cancer Symposium, 5-9 Dec 2017.
2 Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384:164–72. doi:10.1016/S0140-6736(13)62422-8
3 Berry D, Hudis C. Neoadjuvant Therapy in Breast Cancer as a Basis for Drug Approval. JAMA Oncology 2015; 1: 875-876 doi:10.1001/jamaoncol.2015.1293
4 von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. The New England Journal of Medicine 2017; 377:122–31. doi:10.1056/nejmoa1703643
5 Cureton EL, Yau C, Alvarado M, et al. Local Recurrence Rates are Low in High-Risk Neoadjuvant Breast Cancer in the I-SPY 1 Trial (CALGB 150007/150012; ACRIN 6657). Annals of Surgical Oncology 2014;21:2889–96. doi:10.1245/s10434-014-3721-7
6 Golshan M, Cirrincione CT, Sikov WM, et al. Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II–III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance). Breast Cancer Research and Treatment 2016;160:297–304. doi:10.1007/s10549-016-4006-6
7 Hylton N, Blume J, Bernreuter W, et al. Locally Advanced Breast Cancer: MR Imaging for Prediction of Response to Neoadjuvant Chemotherapy—Results from ACRIN 6657/I-SPY TRIAL. Radiology 2012; 263:663–72. doi:10.1148/radiol.12110748
8 Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. Journal of Clinical Oncology 2017; 35:1049-1060. doi:10.1200/jco.2015.63.1010
9 Campbell JI, Yau C, Krass P, et al. Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Research and Treatment 2017;165:181–91. doi:10.1007/s10549-017-4303-8
10 Cardoso F, Veer L, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. New England Journal of Medicine 2016 ;375:717–29. doi:10.1056/NEJMoa1602253
11 Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology 2016;17:367–77. doi:10.1016/s1470-2045(15)00551-3
12 Masuda N, Lee S, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. The New England Journal of Medicine 2017;376:2147–59. doi:10.1056/nejmoa1612645
Competing interests:
No competing interests
19 January 2018
Judy Boughey
Surgeon
Anne Wallace, Michael Alvarado, Cheryl Ewing, Rachel Lancaster, Rita Mukhtar, Jasmine Wong, Fraser Symmans, Angie DeMichele, Hope Rugo, Doug Yes, Laura Esserman
Rapid Response:
Re: Rethinking neoadjuvant chemotherapy for breast cancer
The opinion piece by Vaidya et al. demonstrates continued confusion about the purpose of neoadjuvant therapy, its efficacy and the tremendous opportunity it presents to change outcomes early in the course of therapy. In fact, the suppositions that neither neoadjuvant therapy nor pathological complete response (pCR) are of benefit to patients runs contrary to the accumulated experience from neoadjuvant studies.
The most recent results are from the I-SPY 2 TRIAL. Based on 8-years of studying neoadjuvant therapy in over 1000 patients, the I-SPY 2 data show a strong and consistent relationship between pCR and 3-year event-free (EFS) and distant recurrence-free survival (DRFS) [1]. In this large prospective trial, pCR offers a clear advantage in long term outcome, with a hazard ratio of 0.2. Importantly, this result was obtained across 10 different agents or combinations, and was similar across subtypes. Patients with 70 gene low risk disease were excluded.
The I-SPY 2 results are consistent with the hazard ratio of 0.24 reported in the Cortazar meta-analysis [2]. However, in relying upon the apparent lack of linear correlation between pCR and EFS across multiple trials to make their case that NAC is ineffectual, the authors of this commentary unfortunately fall prey to confirmation bias. As explained in Berry et al. [3], due to the small treatment differences between trials (which did not use experimental agents), the confidence limits of the regression can neither support nor rule out either a positive or negative correlation. Berry et al. further clarify that the relationship between pCR and EFS is not linear, and demonstrate that results of the NEO-ALTTO and ALTTO trials are entirely consistent with other studies, and with the Cortazar meta-analysis.
It is also important to consider that many neoadjuvant studies (e.g. NeoSphere) referenced by Vaidya et al. included additional systemic adjuvant therapy following surgery, blurring the correlation of pCR and long term outcome. Further, the confirmatory trials often recruit large numbers of patients that have significantly lower risk profiles than neoadjuvant trials, which is another major confounder in interpreting the results. Vaidya and colleagues are mistaken about the benefits of pertuzumab in the APHINITY trial; the addition of pertuzumab to trastuzumab containing adjuvant chemotherapy for patients with HER2-positive early stage breast cancer led to a small and statistically significant improvement in invasive-disease-free survival consistent with the improvement in pCR rates and on this basis was approved by the FDA [4].
Perhaps most surprising is the editorial’s focus on local recurrence. Women with a poor response to local therapy are at highest risk for metastatic recurrence and death from systemic disease, not for local disease. Local recurrence in both I-SPY 2 and I-SPY 1 is uncommon [5]. In fact, in I-SPY 2 EFS and DRFS are essentially the same, further demonstrating that metastatic disease is the critical issue for women with breast cancer at high risk for early recurrence. In this respect, the authors concern about missing a window of opportunity for resection is misplaced. High risk cancers that do not respond to systemic therapy are not cured by earlier resection.
Surgery is not more difficult after neoadjuvant therapy. Patients whose cancers do not respond face the same surgery as they would have at initial presentation. For those with an excellent response, surgical options improve, extent of resection in breast and nodes may be less extensive and the extent of adjuvant radiotherapy can be reduced [6].
It is essential for surgeons, as part of the multidisciplinary team, to understand the extent and site of disease, correlate imaging and the initial exam and ensure that there are clips placed at the site of disease (in the breast and nodes) in the event that there is a complete response to neoadjuvant therapy. Imaging prior to surgery helps to restage and guide the extent of resection, with breast MRI providing the most value in predicting extent of residual disease [7]. In I-SPY 2, we have established a standard for the surgical management of the axilla in the setting of a neoadjuvant trial where pCR is the primary endpoint. Multidisciplinary care including standards for imaging and pathology are essential for characterizing the extent of disease after neoadjuvant therapy. In this setting, extent of residual disease has been shown to be highly predictive of outcome [8,9].
One of the key takeaways from I-SPY 2 is that patient selection matters. Chemotherapy does not provide significant benefit for those with genomically low risk disease [10] and these patients are excluded from I-SPY 2.
We agree that adjuvant and neoadjuvant therapy result in identical long-term outcomes - but neoadjuvant therapy gives us the opportunity to predict long-term outcome using pCR and residual cancer burden as an early endpoint. Understanding response to neoadjuvant therapy has clinical relevance as new systemic agents have shown benefit in extending therapy for HER-2 positive (neratinib) and triple negative (capecitabine) tumors in high risk patients [11,12]. Further, judging response in the neoadjuvant setting provides a platform to accelerate the testing of new agents and find treatments that will make a big impact, e.g. pembrolizumab which when added to standard neoadjuvant chemotherapy nearly tripled the chance of pCR. The neoadjuvant setting is a way for us to discover and individualize the right combinations of agents to help as many patients as possible achieve a complete response, and correspondingly, a better outcome.
1 Yee D, I-SPY2 Investigators. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 Trial. San Antonio Breast Cancer Symposium, 5-9 Dec 2017.
2 Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384:164–72. doi:10.1016/S0140-6736(13)62422-8
3 Berry D, Hudis C. Neoadjuvant Therapy in Breast Cancer as a Basis for Drug Approval. JAMA Oncology 2015; 1: 875-876 doi:10.1001/jamaoncol.2015.1293
4 von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. The New England Journal of Medicine 2017; 377:122–31. doi:10.1056/nejmoa1703643
5 Cureton EL, Yau C, Alvarado M, et al. Local Recurrence Rates are Low in High-Risk Neoadjuvant Breast Cancer in the I-SPY 1 Trial (CALGB 150007/150012; ACRIN 6657). Annals of Surgical Oncology 2014;21:2889–96. doi:10.1245/s10434-014-3721-7
6 Golshan M, Cirrincione CT, Sikov WM, et al. Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II–III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance). Breast Cancer Research and Treatment 2016;160:297–304. doi:10.1007/s10549-016-4006-6
7 Hylton N, Blume J, Bernreuter W, et al. Locally Advanced Breast Cancer: MR Imaging for Prediction of Response to Neoadjuvant Chemotherapy—Results from ACRIN 6657/I-SPY TRIAL. Radiology 2012; 263:663–72. doi:10.1148/radiol.12110748
8 Symmans WF, Wei C, Gould R, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. Journal of Clinical Oncology 2017; 35:1049-1060. doi:10.1200/jco.2015.63.1010
9 Campbell JI, Yau C, Krass P, et al. Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Research and Treatment 2017;165:181–91. doi:10.1007/s10549-017-4303-8
10 Cardoso F, Veer L, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. New England Journal of Medicine 2016 ;375:717–29. doi:10.1056/NEJMoa1602253
11 Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology 2016;17:367–77. doi:10.1016/s1470-2045(15)00551-3
12 Masuda N, Lee S, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. The New England Journal of Medicine 2017;376:2147–59. doi:10.1056/nejmoa1612645
Competing interests: No competing interests