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Clin Cancer Res. 2015 Jul 1;21(13):2911-5. doi: 10.1158/1078-0432.CCR-14-1760. Epub 2015 Feb 24.

The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer.

Author information

1
University of Pennsylvania, Philadelphia, Pennsylvania.
2
University of Minnesota, Minneapolis, Minnesota.
3
University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Loyola University Medical Center, Maywood, Illinois.
5
Buck Institute for Research on Aging, Novato, California.
6
Mayo Clinic, Rochester, Minnesota.
7
University of California, San Francisco, San Francisco, California.
8
British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
9
Oregon Health and Science University, Portland, Oregon.
10
Inova Fairfax Hospital Cancer Center, Fairfax, Virginia.
11
University of Colorado Denver, Denver, Colorado.
12
University of Alabama at Birmingham, Birmingham, Alabama.
13
University of Texas Southwestern, Dallas, Texas.
14
Georgetown University Medical Center, Washington, DC.
15
Swedish Cancer Institute, Seattle, Washington.
16
University of Washington, Seattle, Washington.
17
Emory University, Atlanta, Georgia.
18
H. Lee Moffitt Cancer Center, Tampa, Florida.
19
University of Chicago, Chicago, Illinois.
20
QuantumLeap Healthcare Collaborative, San Francisco, California.
21
University of California, San Diego, San Diego, California.
22
Gemini Group Ann Arbor, Michigan.
23
George Mason University, Fairfax County, Virginia.
24
University of Southern California, Los Angeles, California.
25
University of Arizona Cancer Center, Tucson, Arizona.
26
University of California, San Francisco, San Francisco, California. Laura.Esserman@ucsfmedctr.org.

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 This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval.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.

PMID:
25712686
PMCID:
PMC4490043
DOI:
10.1158/1078-0432.CCR-14-1760
[Indexed for MEDLINE]
Free PMC Article

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