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Certain mutations in the PI3 kinase pathway seem to influence sensitivity to HER2-targeted therapy, explains Mark D. Pegram, MD. These findings were initially supported by a biomarker analyses from the four-arm NeoSphere trial that examined pertuzumab plus trastuzumab with docetaxel in newly diagnosed patients with HER2-positive early-stage breast cancer.
Overall, this analysis did not show a significant different between PIK3CA
-mutant and wild type, in terms of variation in pathologic complete response (pCR). However, when examining patients with PIK3CA
exon 9 mutations only 2 out of 28 had a pCR, Pegram states. Moreover, 0 out of 4 patients with PIK3CA
exon 7 mutations had a pCR. This information suggests these mutations have a deleterious effect, even for patients receiving pertuzumab, Pegram states.
Interestingly, Pegram notes, a biomarker analyses from the phase III EMILIA trial did not find an association between PIK3CA
mutations and resistance for women with HER2-positive metastatic breast cancer treated with T-DM1. This same analysis found that PIK3CA
mutations negatively impacted the efficacy of lapatinib plus capecitabine. This data seems to suggest that T-DM1 might overcome the deleterious impact of PIK3CA
mutations, Pegram believes.
The overall analysis would suggest that patients with PIK3CA
mutations still benefit from treatment with pertuzumab, notes Joyce A. O’Shaughnessy, MD. This may indicate that pertuzumab impacts the PI3 kinase pathway more than lapatinib, which may have a greater impact on the HER1/ERK pathway.
There are several ongoing clinical trials exploring treatments for HER2-positive breast cancer, including APHINITY, ALTTO, and NeoALTTO, explains Adam M. Brufsky, MD, PhD. The phase III randomized KAITLIN study (BO28407) will compare T-DM1 plus pertuzumab to trastuzumab with pertuzumab plus a taxane as adjuvant therapy following anthracyclines for patients with HER2-positive primary invasive breast cancer.
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Adam M. Brufsky, MD, PhD
Professor of Medicine, University of Pittsburgh
Medical Director of the Women’s Cancer Center at Magee-Womens Hospital of UPMC
and the University of Pittsburgh Cancer Institute
Kimberly L. Blackwell, MD
Professor of Medicine
Assistant Professor in Radiation Oncology
Duke Cancer Institute
Durham, North Carolina
Joyce A. O’Shaughnessy, MD
Co-Director, Breast Cancer Research
Baylor Charles A. Sammons Cancer Center
Texas Oncology, PA/US Oncology,
Mark D. Pegram, MD
Professor of Medicine (Oncology)
Stanford University Medical Center;
Susy Yuan-Huey Hung Professor;
Associate Director of Clinical Research and Director, Breast Cancer Program, Stanford Cancer Institute, Stanford, California
Hope S. Rugo, MD
Professor of Medicine and Director of the Breast Oncology, Clinical Trials, and Education Program, University of California San Francisco Comprehensive Cancer Center,
San Francisco, California
Denise A. Yardley, MD
Senior Investigator, Breast Cancer Research
Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee