PIK3CA Mutation May Reduce Efficacy of Anti-HER2 Treatments

HER2-positive breast cancer patients treated with targeted therapy and chemo were less likely to have a pathologic complete response if they had a PIK3CA mutation.

Newly diagnosed patients with HER2-positive breast cancer with tumors that harbor a PIK3CA mutation are not as likely to have a pathologic complete response (pCR) following HER2-targeted therapy plus neoadjuvant chemotherapy. This was the case regardless of whether patients were treated with single or combination HER2-targeted therapy. pCR rates were lowest for those patients with hormone receptor (HR)-positive, HER2-positive disease who harbored a PIK3CA mutation.

This mutation may be a negative prognostic biomarker for HER2-positive patients. The study was published in the Journal of Clinical Oncology.

According to the authors, this is the largest study to assess the link between PIK3CA mutations and pCR in HER2-positive disease.

Only about one-third of women with HER2-positive breast cancer respond to anti-HER2 therapy-a treatment that has side effects and is costly. Still, all of these patients are ultimately treated with the same regimens because there are currently no assays that test whether a patient is likely to have an improved disease-free or overall survival from the therapy.

Sibylle Loibl, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and colleagues looked for any link between tumors that harbor a PIK3CA mutation and response to anti-HER2 therapy. Analyzing tissue samples from patients who had participated in neoadjuvant clinical trials that tested lapatinib, trastuzumab, or the combination, the team found that those patients whose tumors had a PIK3CA mutation had a significantly lower pCR-19.4% vs 32.8% of patients with a wild-type PIK3CA gene (odds ratio [OR] = 0.49; P = .008).

A positive HR status and PIK3CA mutation status were independently predictive for pCR. Among the 291 patients who had HR-positive disease, the pCR rate was 11.3% for those with a PIK3CA mutation compared with 27.5% for those with PIK3CA wild-type tumors (OR = 0.34; P = .011).

But there was no statistically significant difference in the pCR rate among the 213 patients with HR-negative disease with or without the PIK3CA mutation (30.4% and 40.1%, respectively; OR = 0.65; P = .292).

After a median of 42.3 months of follow-up for 264 patients, disease-free and overall survival were not statistically significantly different between those with mutated or wild-type PIK3CA (hazard ratio [HR] = 1.07; P = .854 for disease-free survival; HR = 0.59; P = .219 for overall survival). There was a trend towards an inferior overall survival among the PIK3CA-mutated patients.

In an adjusted multivariable model, an anti-HER2 treatment appeared to affect only the wild-type PIK3CA cohort.

PIK3CA is the second most frequently mutated gene in breast cancer, found in about 20% of all breast cancers and in about 20% to 25% of HER2-positive breast cancers. These PIK3CA-mutated HER2 tumors have previously been shown to rely on activation of the PI3K pathway and play a role in the resistance to trastuzumab.

Of the 504 patients included in the analysis, 21.4% harbored a PIK3CA mutation in exon 9 or exon 20.

These results are also consistent with data from the Neo ALTTO trial, which showed an association between lower pCR rates and PIK3CA mutations, regardless of HR status and therapy.

“Although they do not have clinical utility, the biologic validity of the data raise the interesting hypothesis that combining a phosphatidylinositol 3-kinase inhibitor with anti-HER2 therapy may be more effective for patients with PIK3CA mutations,” stated N. Lynn Henry, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor, Michigan, and colleagues in an accompanying editorial. Still, they cautioned that PIK3CA-mutated tumors have not been consistently responsive to PI3K inhibitors. Therefore, further prospective studies of the utility of the PIK3CA mutation as a biomarker and drug target are needed.