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Pathologic complete response to neoadjuvant therapy predicts extended EFS in breast cancer
The achievement of a pathologic complete response following neoadjuvant therapy appeared associated with prolonged EFS among women with HER-2–positive breast cancer, according to the results of a systematic review and meta-analysis.
This association persisted in randomized controlled trials, results showed.
“In the present era of targeted therapies and rapid progress in cancer biology, what was once regarded to be a single disease is now many diseases, each requiring a potentially different therapeutic strategy,” Donald A. Berry, PhD, founder and statistical scientist at Berry Consultants LLC in Austin, Texas, and colleagues wrote. “Many narrowly focused clinical trials are now required where one trial was once sufficient. Large adjuvant trials are no longer sustainable in breast cancer. … Neoadjuvant systemic therapy holds promise for the early assessment of the effects of targeted systemic agents, as well as of standard therapy.”
Patient-level analyses have shown a link between pathologic complete response after neoadjuvant therapy and improved EFS and OS outcomes, according to study background.
Thus, Berry and colleagues conducted a literature review and meta-analysis to observe the impact of pathologic complete response in neoadjuvant studies of women with HER-2–positive breast cancer.
The researchers accessed Medline, Embase, Central and Northern Light Life Sciences Conference Abstracts in December 2014 to identify cohort studies and randomized controlled trials of neoadjuvant therapy for stage I to stage III HER-2–positive breast cancer, in which pathologic complete response and EFS outcomes were reported.
The initial search generated 2,614 publications, of which 38 met inclusion criteria. The final analysis included data from 36 studies, representing 5,768 patients. Retrospective cohort studies comprised 72% (n = 26) of studies included.
HRs for EFS and OS among patients with vs. without pathologic complete response served as the primary endpoint.
The researchers observed a considerable EFS improvement among patients who achieved pathologic complete response (HR = 0.37; 95% probability interval [PI], 0.32-0.43).
The greatest association occurred among patients with HR-negative disease (HR = 0.29; 95% PI, 0.24-0.36); it appeared less pronounced among patients with HR-positive breast cancer (HR = 0.52; 95% PI, 0.4-0.66).
In 15 studies with available OS data, pathologic complete response appeared associated with prolonged survival (HR = 0.34; 95% PI, 0.26-0.42).
In a weighted linear regression model, the researchers determined that these EFS and OS trends persisted in randomized controlled trials (EFS, R2 = 0.63; OS, R2 = 0.29). Based on absolute treatment improvements in pathologic complete response, predicted HRs for EFS appeared concordant with observed HRs.
“The very large clinical trials of the recent past are not sustainable, and identifying earlier endpoints to estimate longer-term therapeutic benefit will be part of the resolution of this dilemma,” Berry and colleagues wrote. “The importance of improving pathologic complete response rates in the neoadjuvant therapy of breast cancer may allow for more efficient and rational designs for adjuvant and neoadjuvant clinical trials with EFS as a primary endpoint.”
Limitations to this analysis exist, Veerle Bossuyt, MD, assistant professor of pathology at Yale Cancer Center, and Christos Hatzis, PhD, assistant professor of medicine and director of breast medical oncology bioinformatics at Yale Cancer Center, wrote in an accompanying editorial.
“The assumption that experiencing a pathologic complete response has the same effect on survival benefit irrespective of the therapy may not be true for all therapies,” Bossuyt and Hatzis wrote. “The mechanism of action of an experimental drug may be different from that of the baseline drug. Furthermore, the relationship between pathologic complete response gain and survival benefit is a complex one affected by many other factors.”
Bossuyt and Hatzis further offered suggestions for future study of pathologic complete response in this patient population.
“To yield more specific trial design guidelines that account for the baseline prognosis of the study populations, future meta-analyses within specific disease subtypes should indicate stratification by baseline prognosis,” they wrote. “Comparisons across trials can become more meaningful in the future through efforts to standardize pathologic evaluation of response and definitions of endpoints used.” – by Cameron Kelsall
Disclosure: Roche Canada commissioned Berry Consultants LLC to conduct this study. Berry and one other study researcher report an ownership role with Berry Consultants LLC. Other study researchers report employment with Berry Consultants LLC. Please see the full study for a list of all other researchers’ relevant financial disclosures. Bossuyt and Hatzis report no relevant financial disclosures.