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PIK3CA mutation associated with poorer response in HER-2–positive breast cancer
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Presence of a PIK3CA mutation reduced the likelihood that patients with HER-2–positive breast cancer would achieve pathologic complete response after neoadjuvant chemotherapy plus anti-HER–2 treatment, according to study results.
Sibylle Loibl, MD, PhD, professor at the German Breast Group in Neu-Isenburg, Germany, and colleagues evaluated 504 tumor samples from three neoadjuvant studies — GeparQuattro, GeparQuinto and GeparSixto — to assess the association between pathologic complete response (pCR) and PIK3CA genotype in patients with HER-2–positive disease.
All HER-2–positive patients included in the studies received either lapatinib (Tykerb, GlaxoSmithKline), trastuzumab (Herceptin, Genentech) or a combination of the agents, plus anthracycline-taxane chemotherapy.
Researchers identified PIK3CA mutations in 108 of the 504 tumor samples (21.4%).
Overall, pCR rates were lower among patients with PIK3CA mutations than those with PIK3CA wild-type tumors (19.4% vs. 32.8%; OR=0.49; 95% CI, 0.29-0.83). PIK3CA mutations also were associated with lower pCR rates when researchers limited their analysis to patients with HER-2–positive tumors (11.3% vs. 27.5%; OR=0.34; 95% CI, 0.15-0.78) and HER-2–negative tumors (30.4% vs. 40.1%; OR=0.65; 95% CI, 0.32-1.32).
Multivariable analysis showed pCR rates for patients with PIK3CA mutations were 16% among those treated with lapatinib, 24.3% among those treated with trastuzumab, and 17.4% among those treated with both agents (P=.654). In the PIK3CA wild-type group, pCR rates were 18.2% among those treated with lapatinib, 33% among those treated with trastuzumab and 37.1% among those treated with both agents (P=.017).
Researchers observed no statistically significant difference in DFS or OS between those with PIK3CA mutations and those with PIK3CA wild-type tumors.
“The PIK3CA mutation data could be combined with downstream markers such as p4EBP1 using class prediction algorithms to improve characterization of the tumors and select appropriate tumors,” Loibl and colleagues wrote.
The data suggest that future studies designed to evaluate alternative therapies — such as a phosphatidylinositol 3-kinase (PI3K) inhibitor — in PIK3CA-mutatant HER-2–positive breast cancer are warranted, the researchers concluded.
“Although they do not have clinical utility, the biologic validity of the data raise the interesting hypothesis that combining a PI3K inhibitor with anti-HER–2 therapy may be more effective for patients with PIK3CA mutations,” Nora Lynn Henry, MD, PhD, Anne F. Schott, MD, and Daniel F. Hayes, MD, all of University of Michigan Comprehensive Cancer Center, wrote in an accompanying editorial. “However, as of yet, PIK3CA mutations have not been consistently shown to predict for either response to endocrine therapy or response to PI3K pathway inhibitors. Multiple clinical trials of this strategy are already underway, and we hope that the investigators of these trials plan to include mutational analysis as either enrollment criteria or as post hoc correlative studies.”
For more information:
- Henry NL. J Clin Oncol. 2014;doi:10.1200/JCO.2014.57.6132.
- Loibl S. J Clin Oncol. 2014;doi:10.1200/JCO.2014.55.7876.
Disclosure: The researchers report consultant/advisory roles with and honoraria/research funding from Amgen, AstraZeneca, Celgene, Eisai, Genomic Health, GlaxoSmithKline, Novartis, Pfizer, Roche and Teva.
Perspective
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Edith A. Perez, MD
The report of the well-done study by Loibl and colleagues demonstrates that PI3K mutations correlated with pathologic complete response (pCR) but not with DFS. The results of this study further call into question relying on results in the neoadjuvant setting to predict long-term clinical outcomes in patients with early-stage breast cancer. Actually, this study showed that a predictive biomarker for pCR was not a predictive biomarker for DFS, which arguably is the more relevant of the two endpoints.
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