The neoadjuvant model is still the future for drug development in breast cancer

Angela De Michele, Douglas Yee, Donald A. Berry, Kathy S. Albain, Christopher C. Benz, Judy Boughey, Meredith Buxton, Stephen K. Chia, Amy J. Chien, Stephen Y. Chui, Amy Clark, Kirsten Edmiston, Anthony D. Elias, Andres Forero-Torres, Tufia C. Haddad, Barbara Haley, Paul Haluska, Nola M. Hylton, Claudine Isaacs, Henry Kaplan & 22 others Larissa Korde, Brian Leyland-Jones, Minetta C. Liu, Michelle Melisko, Susan E. Minton, Stacy L. Moulder, Rita Nanda, Olufunmilayo I. Olopade, Melissa Paoloni, John W. Park, Barbara A. Parker, Jane Perlmutter, Emanuel F. Petricoin, Hope Rugo, Fraser Symmans, Debasish Tripathy, Laura J. Van't Veer, Rebecca K Viscusi, Anne Wallace, Denise Wolf, Christina Yau, Laura J. Esserman

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.

Original languageEnglish (US)
Pages (from-to)2911-2915
Number of pages5
JournalClinical Cancer Research
Volume21
Issue number13
DOIs
StatePublished - Jul 1 2015

Fingerprint

Breast Neoplasms
Meta-Analysis
Clinical Trials
Pharmaceutical Preparations
Disease-Free Survival
Drug Approval
Drug Combinations
Protein-Tyrosine Kinases
Survival Rate
Biomarkers
Recurrence
Drug Therapy
lapatinib
Therapeutics
Trastuzumab

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

De Michele, A., Yee, D., Berry, D. A., Albain, K. S., Benz, C. C., Boughey, J., ... Esserman, L. J. (2015). The neoadjuvant model is still the future for drug development in breast cancer. Clinical Cancer Research, 21(13), 2911-2915. https://doi.org/10.1158/1078-0432.CCR-14-1760

The neoadjuvant model is still the future for drug development in breast cancer. / De Michele, Angela; Yee, Douglas; Berry, Donald A.; Albain, Kathy S.; Benz, Christopher C.; Boughey, Judy; Buxton, Meredith; Chia, Stephen K.; Chien, Amy J.; Chui, Stephen Y.; Clark, Amy; Edmiston, Kirsten; Elias, Anthony D.; Forero-Torres, Andres; Haddad, Tufia C.; Haley, Barbara; Haluska, Paul; Hylton, Nola M.; Isaacs, Claudine; Kaplan, Henry; Korde, Larissa; Leyland-Jones, Brian; Liu, Minetta C.; Melisko, Michelle; Minton, Susan E.; Moulder, Stacy L.; Nanda, Rita; Olopade, Olufunmilayo I.; Paoloni, Melissa; Park, John W.; Parker, Barbara A.; Perlmutter, Jane; Petricoin, Emanuel F.; Rugo, Hope; Symmans, Fraser; Tripathy, Debasish; Van't Veer, Laura J.; Viscusi, Rebecca K; Wallace, Anne; Wolf, Denise; Yau, Christina; Esserman, Laura J.

In: Clinical Cancer Research, Vol. 21, No. 13, 01.07.2015, p. 2911-2915.

Research output: Contribution to journalArticle

De Michele, A, Yee, D, Berry, DA, Albain, KS, Benz, CC, Boughey, J, Buxton, M, Chia, SK, Chien, AJ, Chui, SY, Clark, A, Edmiston, K, Elias, AD, Forero-Torres, A, Haddad, TC, Haley, B, Haluska, P, Hylton, NM, Isaacs, C, Kaplan, H, Korde, L, Leyland-Jones, B, Liu, MC, Melisko, M, Minton, SE, Moulder, SL, Nanda, R, Olopade, OI, Paoloni, M, Park, JW, Parker, BA, Perlmutter, J, Petricoin, EF, Rugo, H, Symmans, F, Tripathy, D, Van't Veer, LJ, Viscusi, RK, Wallace, A, Wolf, D, Yau, C & Esserman, LJ 2015, 'The neoadjuvant model is still the future for drug development in breast cancer', Clinical Cancer Research, vol. 21, no. 13, pp. 2911-2915. https://doi.org/10.1158/1078-0432.CCR-14-1760
De Michele A, Yee D, Berry DA, Albain KS, Benz CC, Boughey J et al. The neoadjuvant model is still the future for drug development in breast cancer. Clinical Cancer Research. 2015 Jul 1;21(13):2911-2915. https://doi.org/10.1158/1078-0432.CCR-14-1760
De Michele, Angela ; Yee, Douglas ; Berry, Donald A. ; Albain, Kathy S. ; Benz, Christopher C. ; Boughey, Judy ; Buxton, Meredith ; Chia, Stephen K. ; Chien, Amy J. ; Chui, Stephen Y. ; Clark, Amy ; Edmiston, Kirsten ; Elias, Anthony D. ; Forero-Torres, Andres ; Haddad, Tufia C. ; Haley, Barbara ; Haluska, Paul ; Hylton, Nola M. ; Isaacs, Claudine ; Kaplan, Henry ; Korde, Larissa ; Leyland-Jones, Brian ; Liu, Minetta C. ; Melisko, Michelle ; Minton, Susan E. ; Moulder, Stacy L. ; Nanda, Rita ; Olopade, Olufunmilayo I. ; Paoloni, Melissa ; Park, John W. ; Parker, Barbara A. ; Perlmutter, Jane ; Petricoin, Emanuel F. ; Rugo, Hope ; Symmans, Fraser ; Tripathy, Debasish ; Van't Veer, Laura J. ; Viscusi, Rebecca K ; Wallace, Anne ; Wolf, Denise ; Yau, Christina ; Esserman, Laura J. / The neoadjuvant model is still the future for drug development in breast cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 13. pp. 2911-2915.
@article{5a25cbe380da4c09b1f7f8b9601aac7c,
title = "The neoadjuvant model is still the future for drug development in breast cancer",
abstract = "The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.",
author = "{De Michele}, Angela and Douglas Yee and Berry, {Donald A.} and Albain, {Kathy S.} and Benz, {Christopher C.} and Judy Boughey and Meredith Buxton and Chia, {Stephen K.} and Chien, {Amy J.} and Chui, {Stephen Y.} and Amy Clark and Kirsten Edmiston and Elias, {Anthony D.} and Andres Forero-Torres and Haddad, {Tufia C.} and Barbara Haley and Paul Haluska and Hylton, {Nola M.} and Claudine Isaacs and Henry Kaplan and Larissa Korde and Brian Leyland-Jones and Liu, {Minetta C.} and Michelle Melisko and Minton, {Susan E.} and Moulder, {Stacy L.} and Rita Nanda and Olopade, {Olufunmilayo I.} and Melissa Paoloni and Park, {John W.} and Parker, {Barbara A.} and Jane Perlmutter and Petricoin, {Emanuel F.} and Hope Rugo and Fraser Symmans and Debasish Tripathy and {Van't Veer}, {Laura J.} and Viscusi, {Rebecca K} and Anne Wallace and Denise Wolf and Christina Yau and Esserman, {Laura J.}",
year = "2015",
month = "7",
day = "1",
doi = "10.1158/1078-0432.CCR-14-1760",
language = "English (US)",
volume = "21",
pages = "2911--2915",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - The neoadjuvant model is still the future for drug development in breast cancer

AU - De Michele, Angela

AU - Yee, Douglas

AU - Berry, Donald A.

AU - Albain, Kathy S.

AU - Benz, Christopher C.

AU - Boughey, Judy

AU - Buxton, Meredith

AU - Chia, Stephen K.

AU - Chien, Amy J.

AU - Chui, Stephen Y.

AU - Clark, Amy

AU - Edmiston, Kirsten

AU - Elias, Anthony D.

AU - Forero-Torres, Andres

AU - Haddad, Tufia C.

AU - Haley, Barbara

AU - Haluska, Paul

AU - Hylton, Nola M.

AU - Isaacs, Claudine

AU - Kaplan, Henry

AU - Korde, Larissa

AU - Leyland-Jones, Brian

AU - Liu, Minetta C.

AU - Melisko, Michelle

AU - Minton, Susan E.

AU - Moulder, Stacy L.

AU - Nanda, Rita

AU - Olopade, Olufunmilayo I.

AU - Paoloni, Melissa

AU - Park, John W.

AU - Parker, Barbara A.

AU - Perlmutter, Jane

AU - Petricoin, Emanuel F.

AU - Rugo, Hope

AU - Symmans, Fraser

AU - Tripathy, Debasish

AU - Van't Veer, Laura J.

AU - Viscusi, Rebecca K

AU - Wallace, Anne

AU - Wolf, Denise

AU - Yau, Christina

AU - Esserman, Laura J.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.

AB - The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.

UR - http://www.scopus.com/inward/record.url?scp=84941678069&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941678069&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-14-1760

DO - 10.1158/1078-0432.CCR-14-1760

M3 - Article

VL - 21

SP - 2911

EP - 2915

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 13

ER -