Hurvitz Discusses PIK3CA Mutations, pCR, CDK4/6 Inhibitors, and Immunotherapies in Breast Cancer

Published: Tuesday, Sep 09, 2014
Sara Hurvitz

Sara Hurvitz, MD

At the 13th Annual Congress on the Future of Breast Cancer, Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center (JCCC), discussed “PIK3CA Mutations in HER2+ Breast Cancer.” In an interview with Oncology & Biotech News (OBTN), Hurvitz, who is director of the Hematology/Oncology Breast Cancer Program and an Associate Professor in the Department of Medicine at UCLA, highlighted the key points of her PIK3CA discussion, and addressed several other key topics in the field of breast cancer.

OBTN: Your discussion covered PIK3CA mutations in HER2-positive breast cancer. Please discuss significant research involving PI3KCA mutations as potential biomarkers for the efficacy of HER2-targeted therapies, including the biomarker analyses from the EMILIA trial.

Hurvitz: A number of studies have looked at whether or not patients with tumors that have a mutation in PIK3CA have a better or worse outcome. Some preclinical data suggests a PIK3CA mutation may make tumors resistant to trastuzumab. There has also been analyses of patients who have never received trastuzumab and those patients who have both HER2 amplification and a PIK3CA mutation seem to do better than those who do not. However, in analyses of patients treated with trastuzumab, those patients who have a PIK3CA mutation seem to do worse. They seem to have a lower chance of pathologic complete response (pCR) and a lower or less favorable progression-free survival. There are several studies that have looked at this. There is the NeoALTTO study, which looked at trastuzumab or lapatinib or the combination of the two in the neoadjuvant setting; there is the GeparQuinto study, which looked at trastuzumab or lapatinib in the neoadjuvant setting; and there is GeparSixto, which looked at trastuzumab and lapatinib in all patients with HER2-positive breast cancer.

These studies consistently showed that those patients whose tumors have a PIK3CA-activating mutation have a lower chance of having a pCR or a worse PFS. Moreover, it appears to be most predictive of pCR in patients treated with both trastuzumab and lapatinib.

Analyses of patients treated with pertuzumab and/or trastuzumab comes from the NeoSphere study. In this study, again, patients with tumors that had an activating mutation of PIK3CA had a lower chance of pCR, whether or not they were treated with trastuzumab, pertuzumab, or both. In the CLEOPATRA study—a metastatic HER2-positive breast cancer trial in which patients were treated with either trastuzumab-based chemo or trastuzumab and pertuzumab—again, patients whose tumors had a PIK3CA mutation had a worse progression-free survival.

These data are in contrast to those data from patients treated with T-DM1. In the EMILIA study—a HER2-positive metastatic breast cancer study in which patients were treated with either lapatinib and capecitabine or T-DM1—those patients treated with lapatinib and capecitabine who had a PIK3CA mutation in their tumor had a worse progression-free survival. But those patients treated with T-DM1 whose tumors had a PIK3CA mutation had the same outcome as those patients treated with T-DM1 whose tumors were wild-type. It was a small subset of patients. There were only about 130 patients treated with T-DM1 included in that analysis. And so whether or not those findings will be confirmed in prospective studies is unclear at this point.

Were you surprised by the results of the ALTTO trial? Specifically there was a lack of benefit with dual HER2 blockade, despite the benefit in pCR in NeoALTTO?

I wasn’t really surprised by ALTTO. First of all, it was not well powdered given the low event rate in the overall study. The majority of patients had hormone receptor–positive breast cancer and approximately 40% of patients were lymph-node negative. With so few events being accrued, it was hard to power it to know whether or not the event-free survival was truly different between the two arms.

Additionally, something that isn’t discussed so much is the fact that dose reduction has to occur in patients treated with lapatinib because of GI toxicity. And [in the plenary presentation of the ALTTO study at the 2014 ASCO Annual Meeting], Dr. Martine Piccart presented a slide toward the end showing the percentage of patients who received at least 85% of the anti-HER2 drugs and showed up to 40% of patients did not receive 85% of the protocol-specified amount of lapatinib. And that may be limiting the impact of dual HER2-targeted therapy.

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