PIK3CA Mutations Predictive of Resistance to Neoadjuvant Therapy in HER2/HR-Positive Breast Cancers


Key Points

  • Patients with HER2-positive breast cancer were more likely to have PIK3CA mutations than were patients with triple-negative disease.
  • In HER2-positive patients who were hormone receptor–positive, patients with at least one PIK3CA mutation had a significantly lower pathologic complete response rate to neoadjuvant therapy compared to women with wild-type cancer.
  • Patients with PIK3CA-mutant, HER2-positive, and hormone receptor–positive breast cancer were resistant to neoadjuvant chemotherapy and dual anti-HER2 treatment.

Women with HER2-positive, hormone receptor-positive breast cancer with mutations in the PI3K/AKT pathway may respond poorly to neoadjuvant therapy, German researchers reported at the 2013 San Antonio Breast Cancer Symposium (Abstract S4-06).

“We found that very few women with HER2-positive and hormone receptor–positive breast cancer with a PIK3CA mutation experienced a pathologic complete response after neoadjuvant therapy,” said Sibylle Loibl, MD, of the German Breast Group in Neu-Isenburg, Germany.

The PIK3CA mutation is the second most common in breast cancer, observed in about 20% of these tumors, and alterations in this pathway are associated with resistance to anti-HER2 agents. But the data have been discrepant with regard to its prognostic or predictive value, especially in women with HER2-positive tumors, she pointed out.

“We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2-positive and triple-negative primary breast cancer treated with neoadjuvant therapy,” Dr. Loibl said.

G6 Study Details

The study was a prospective analysis of 737 participants of the GeparSixto and GeparQuinto neoadjuvant studies. Patients received either trastuzumab (Herceptin), lapatinib (Tykerb), or both in addition to 18 to 24 weeks of chemotherapy.

Mutational analysis (exons 9 and 20) of tissue samples was available on 360 women with HER2-positive tumors and in 285 women with triple-negative tumors. Within these groups, the PI3KCA mutation was identified in about 20% and 7%, respectively. By hormone receptor status in the HER2-positive patients, mutations were detected in about 21% of both receptor-negative and receptor-positive patients.

PIK3CA Mutation Associated With Less Response

The combined analysis from both studies showed that, in HER2-positive patients, pathologic complete response rates after dual HER2 blockade were significantly lower in the PIK3CA mutant group compared to patients with wild-type tumors (17% vs. 37%). In HER2-positive patients who were hormone receptor–positive and harbored a PIK3CA mutation, the pathologic complete response rate after dual blockade was only 6.3%, Dr. Loibl reported.

“By hormone receptor status, this effect was exclusively confined to the hormone receptor–positive subgroup,” she said. “There was no difference in the hormone receptor–negative group.”

“The difference in pathologic complete response rate between mutant and wild-type patients was largest among patients who received double HER2 blockade,” she added. “The pathologic complete response rates were numerically higher without the mutation, and this seems confined to patients receiving trastuzumab. There was no difference in the lapatinib-treated cohort, who had the same pathologic complete response rate irrespective of mutation status,” she said.

“The results are in concordance with NeoALTTO and Neosphere,” she noted. “Patients with PIK3CA-mutant HER2-positive and hormone receptor–positive breast cancer are resistant to [neoadjuvant] chemotherapy and dual anti-HER2 treatment, and other treatment options are needed to be tested in this group.”

Dr. Loibl and her team are now conducting the randomized phase II neoadjuvant NeoPHOEBE trial of the pan-PI3K inhibitor buparlisib.

The study was funded by the European Commission’s Seventh RTD Framework Programme. Dr. Loibl reported no potential conflicts of interest.

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