PIK3CA Mutation Predicts Resistance to HER2-Targeted Therapy

Photo Courtesy © SABCS/Todd Buchanan 2013

Sibylle Loibl, MD

Findings reported at the 2013 San Antonio Breast Cancer Symposium showed thatPIK3CA-mutated tumors in patients with HER2-positive (HER+) breast cancer (BC) are associated with a much lower rate of pathological complete response (pCR). The lowest pCR was observed in HER2+/hormone receptor-positive (HR+),PIK3CA-mutated tumors. These data stemmed from an analysis of patients in the GeparQuinto and GeparSixto trials, who had HER2+ BC and received neoadjuvant therapy, which included anti-HER2 agents.

The purpose of neoadjuvant chemotherapy is to shrink or eliminate a tumor prior to surgery. In some women, neoadjuvant chemotherapy achieves pCR, which is associated with improved long-term survival.

“Mutations in thePIK3CAgene are among the most common genetic aberrations in breast cancer. We found that only 6.3% of women with HER2+ and HR+ breast cancer and aPIK3CAmutation experienced a pathological complete response after receiving neoadjuvant chemotherapy,” said lead author Sibylle Loibl, MD, professor at the German Breast Group in Neu Isenburg, Germany.

According to Loibl, new treatment should be evaluated in clinical trials of women with HER2+, HR+ BC andPIK3CAmutations. “We need to integratePIK3CAmutation analysis of breast tumors into routine practice, so that we can ensure women receive the most appropriate neoadjuvant therapy for their tumor type,” she said.

The aim of the study was to determine the effect ofPIKCAmutations on achieving pCR with neoadjuvant HER2-directed therapy in HER2+ BC.

Investigators first ascertained pCR status: pCR in GeparQuinto was 30.3% in patients receiving epirubicin/cyclophosphamide/docetaxel (ECD) versus 22.7% in those who received lapatinib along with this regimen. In GeparSixto, pCR was 36.3% in those treated with paclitaxel/nonpegylated liposomal doxorubicin/carboplatin (PMCB) versus 33.1% for PMCB plus trastuzumab/lapatinib.

PI3KCA analysis of tumors from the 360 patients enrolled in both trials with HER2+ BC showed that 20.8% hadPIK3CAmutations and 79.2% had wild type (wt) PI3KCA. Overall, detectablePIK3CAmutations were found in 20.8% of patients with HER2+/HR+ BC and in 20.8% of patients with HER2+/HR- BC.

Pathological complete response, according to PIK3CA status and anti-HER2 treatment, was significantly lower in thePIK3CA-mutated cohort compared with the wt cohort in HER2+ tumors (17% vs 37%, respectively, with double HER2 blockade, ie, lapatinib and trastuzumab). Only 6.3% of patients achieved a pCR if they were HER2+/HR+ and harbored aPIK3CAmutation. The difference between mutated and wt patients in pCR rate was largest in patients treated with double HER2 blockade. Similar pCR rates with the different anti-HER2 drugs were seen inPIK3CA-mutated HER2+ tumors.

The phase II NeoPhoebe study will explorePIK3CAinhibition in patients with HER2+ BC. Patients will be randomized to trastuzumab plus placebo versus trastuzumab plus the PIK3CA inhibitor BKM 120, and results will be stratified according toPIK3CAmutations versus wild type PIK3CA.

Loibl S, Denkert C, Schneeweis A, et al. PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer — Prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. The 2013 San Antonio Breast Cancer Symposium, December 10–14, 2013. Publication Number: S4-06.

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