PIK3CA gene mutations make HER2- and hormone receptor-positive breast cancers treatment-resistant

December 12, 2013

SAN ANTONIO -- Women with breast cancer characterized by high levels of the protein HER2 and hormone receptors gained much less benefit from presurgery treatment with chemotherapy and HER2-targeted therapies if their cancer had one or more mutations in the PIK3CA gene, according to results presented here at the 2013 San Antonio Breast Cancer Symposium, held Dec. 10-14.

Treatment given to shrink or eliminate a tumor before surgery is called neoadjuvant therapy. In some women with breast cancer treated with neoadjuvant therapy, no residual invasive cancer can be detected in breast tissue samples and lymph nodes removed during surgery. Emerging data suggest that these women, who are said to have had a pathologic complete response, have a greater chance of long-term survival compared with women who do not have a pathologic complete response.

"Mutations in the PIK3CA gene are among the most common genetic aberrations in breast cancer," said Sibylle Loibl, M.D., professor at the German Breast Group in Neu-Isenburg, Germany. "We found that very few women with HER2- and hormone receptor-positive breast cancer with a PIK3CA mutation experienced a pathologic complete response after receiving neoadjuvant therapy.

"We need to identify new treatment options for this group of patients and evaluate them in clinical trials," continued Loibl. "We also need to integrate PIK3CA mutation analysis of breast tumors into routine practice so that we can ensure women receive the most appropriate neoadjuvant therapy for their tumor type."

Loibl and colleagues investigated whether the presence of a PIK3CA mutation affected patients enrolled in the GeparSixto (G6) clinical trial in experiencing a pathologic complete response after neoadjuvant therapy. There were 595 participants in the G6 clinical trial, and information on the presence or absence of PIK3CA gene mutations was available for 512,240 with HER2-postive breast cancer and 272 with triple-negative breast cancer.

Participants in the G6 clinical trial received neoadjuvant chemotherapy (paclitaxel and nonpegylated-liposomal doxorubicin) and were randomly assigned the chemotherapy carboplatin or no additional chemotherapy. Patients with HER2-positive disease also received neoadjuvant trastuzumab and lapatinib, two HER2-targeted therapies, while patients with triple-negative disease also received neoadjuvant bevacizumab.

Loibl and colleagues found that patients with HER2-postive breast cancer were more likely to have at least one PIK3CA mutation in their tumor compared with women with triple-negative breast cancer. Overall, the pathologic complete response rate was lower among women with at least one PIK3CA mutation in their tumor compared with women without a PIK3CA mutation, but the effect was only significant among the group of women with HER2- and hormone receptor-positive breast cancer. Among these women, patients with a PIK3CA mutation had a pathologic complete response rate of only 6.5 percent compared with 30.8 percent for those without a PIK3CA mutation.

"To evaluate these findings in a group with only one HER2 treatment, we are currently analyzing data from another clinical trial, the GeparQuinto clinical trial, which is a randomized, phase III clinical trial evaluating two different neoadjuvant therapy regimens with a single anti-HER2 treatment [trastuzumab or lapatinib] for women with HER2-positive breast cancer," said Loibl. "We hope to present these results together with those from the G6 clinical trial in San Antonio."
This study was supported by funds from the European Commission's Seventh RTD Framework Programme grant number 278659 "RESPONSIFY." Loibl declares no conflicts of interest.

This research will be presented at the 2013 San Antonio Breast Cancer Symposium Thursday, Dec. 12, 7:30 a.m. CT, during a press conference hosted by Carlos L. Arteaga, M.D., president-elect of the AACR and associate director for translational/clinical research and director of the Breast Cancer Program at Vanderbilt-Ingram Comprehensive Cancer Center. Press conferences will be held in Room 217D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

Reporters who cannot attend in person can call into the press conferences using the following information: To interview Sibylle Loibl, contact her at sibylle.loibl@germanbreastgroup.de or +49-16-0713-3725. For a photo of Sibylle Loibl, click here. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.

The mission of the 2013 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit http://www.sabcs.org.

Publication Number: S4-06

Presenter: Sibylle Loibl, M.D.

Title: 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

Authors: Sibylle Loibl1, Carsten Denkert2, Andreas Schneeweis3, Stefan Paepke4, Annika Lehmann2, Mahdi Rezai5, Dirk-Michael Zahm6,Peter Sinn3, Fariba Khandan7, Holger Eidtmann8, Karel Dohnal9, Jens Huober10, Sherene Loi11, Berit Pfitzner2, Peter A Fasching12, Fabrice Andre13, Judith Lindner2, Christos Sotiriou14, Sanxing Guo1, Stephan Gade1, Valentina Nekljudova1, Michael Untch15 and Gunter von Minckwitz1,16. 1Germa Breast Group, Neu-Isenburg; 2Charite, Berlin; 3National Center for Tumor Diseases, Heidelberg; 4Klinikum Rechts der Isar der TU, München; 5Luisenkrankenhaus Düsseldorf, Düsseldorf; 6SRH Wald-Klinikum Gera, Gera; 7Agaplesion Markus Krankenhaus, Frankfurt; 8Universitätsklinikum Schleswig-Holstein, Kiel; 9Zentrum für Pathologie & Zytologie, Düsseldorf; 10Universitätsklinikum, Ulm; 11Peter MacCallum Cancer Centre, Melbourne; 12Universitätsklinikum, Erlangen; 13Institut Gustave Roussy, Villejuif; 14Institut Jules Bordet, Brussels; 15Helios Kliniken, Berlin and 16Frauenklinik Frankfurt.

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2+ve and triple negative (TN) primary BC by treated with neoadjuvant therapy.

Methods: We prospectively evaluated PIK3CA mutations in the 512 participants of the neoadjuvant Geparsixto (G6) study (von Minckwitz et al. ASCO 2013) and validated in 225 participants of the GeparQuinto (G5) study (Untch et al. 2012). The G6 study investigates the effect of adding carboplatin to a non-pegylated liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. All HER2+ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. The G5 study showed that trastuzumab added to EC-Doc results in a significantly higher pCR rate than lapatinib.HER2, hormone receptors (HR), and Ki67 were centrally assessed in both studies. PIK3CA was genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy with a tumor cell content of ≥20% using classical Sanger sequencing of exon 9 and 20.

Results: In the G6 study, 595 patients with HER2+ve or TN primary BC have been randomized from 09/2011 to 11/2012. Median age was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2+ve group 62% were HR-positive. Currently, PIK3CA genotype is available from 512 randomized patients - 240 with HER2+ve and 272 with TN disease. Overall, 13.1% were found to have at least one mutation, in HER2+ve: 19.2% and TNBC: 7.7%. PIK3CA mutations were numerically more frequent in the HER2+ve/HR+ve compared to the HER2+ve/HR-ve group: 21.5% vs 15.4% respectively (p=0.245. Overall, pCR rate was significantly lower in the PIK3CA mutant compared to wt group (22.7% vs. 43.6%; p=0.001).This effect was only significant within the HER2+ve group (17.8% vs. 36.8%; p=0.015) compared to TNBC (33.3% vs. 49%; p=0.168). Within the HER2+ve/HR+ subgroup the PIK3CA mutant pts had a pCR rate of only 6.5% compared to 30.8% in the wt group (p=0.005). In contrast there was no difference in pCR (42.9% vs. 46.1%) according to PIK3CA mutation status in the HER2+ve/HR-ve (p=0.825) group. In the G5 study, 225 of 620 HER2+ve pts have biomaterial available for PIK3CA genotyping and central confirmation of HER2 and hormone-receptor status. The analyses are ongoing and the results for the trastuzumab and lapatinib treated cohorts will be presented at the meeting.

Conclusion: Pts with PIK3CA mutant HER2+ve/HR+ve breast cancer are resistant to chemotherapy and dual anti-HER2 treatment. Other treatment options are needed to be tested in this group. The project has been funded within the EU-FP7 project RESPONSIFY No 278659.

American Association for Cancer Research

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