PIK3CA Confers Resistance to Trastuzumab/Lapatinib Combo in HER2-Positive Breast Cancer

Pierfranco Conte, MD

Patients with HER2-positive breast cancer who harbor a PIK3CA mutation are less likely to benefit from the combination of trastuzumab plus lapatinib, according to results of a biomarker analysis of the phase II CHER-LOB study published in The Oncologist.

Initial results from the CHER-LOB study, which were published in 2012, showed that the combination added to neoadjuvant chemotherapy was more effective than either single agent alone. Findings from the biomarker analysis coincide with those of the NeoALTTO trial and the combined analysis of the GeparQuattro, GeparQuinto, and GeparSixto studies, where pCR rates after chemotherapy plus single-agent or dual anti-HER2 blockade were lower in PIK3CA-mutated patients compared with PIK3CA wild-type patients.

“We are seeing more and more anti-HER2 treatments becoming available to treat patients with HER2-positive breast cancer,” said study author Pierfranco Conte, MD, a researcher at the Istituto Oncologico Veneto IRCCS in Padova, Italy. “By identifying new markers that help us to predict which patients are more sensitive to which anti-HER2 treatments, we are moving closer to treatment personalization.”

The CHER-LOB study randomized 121 patients to receive neoadjuvant chemotherapy plus either trastuzumab (n = 36), lapatinib (n = 39), or trastuzumab and lapatinib (n = 46). Out of the patients enrolled, 113 had evaluable samples for the biomarker analysis, 110 of which were confirmed by IHC or FISH as HER2 overexpressing.

Pathological complete response (pCR) rates, the study’s primary endpoint, were found to be significantly higher in the combination arm (46.7%) versus either single-agent trastuzumab (25%) or lapatinib (26.3%). In the overall population, pCR rates were found to be similar among both PIK3CA wild-type and PIK3CA-mutated disease (33.7% vs 22.7%, respectively, P = .323).

Within the biomarker analysis, 20% of samples had a mutated PIK3CA gene in exon 20 (n = 16) or 9 (n = 6), while 80% harbored the wild-type form of the gene. Other tissue samples were evaluated for p95-HER2, phosphatase and tensin homolog, Ki67, and apoptosis.

It was found that only 12.5% of patients with PIK3CA-mutated HER2-positive breast cancer responded to the dual anti-HER2 regimen when added to neoadjuvant chemotherapy. The response rate was 48.4% with wild-type PIK3CA. However, these results did not reach statistical significance (P = .06), likely due to the limited sample size, according to the researchers.

Ki67 inhibition was found to be significantly higher in patients following treatment with dual anti-HER2 blockade (P = .0003). The integrated analysis of gene expression and copy number data demonstrated that a 50 genetic signature could effectively be used to predictive lapatinib-induced pCR (93% correct predictions). However, this same signature was not effective for trastuzumab and chemotherapy or the combination, the researchers noted.

Researchers hypothesized that genetic testing for PIK3CA mutations could be a useful tool in predicting response to dual anti-HER2 therapy, though it needs to be studied further. Additionally, markers of PI3 kinase pathway deregulation and p95-HER2 were unconfirmed as biomarkers of different sensitivity to trastuzumab or lapatinib.

“The concept of personalized cancer therapy implies maximal therapeutic benefit with the minimal necessary treatment, leading to a minimum of toxicity,” noted Gabriel Hortobagyi, MD, professor of Medicine, in the Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, and a Breast Cancer Giant of Cancer Care. “This can only be accomplished by the systematic development of effective biomarkers. In the case of anti-HER2 therapy, identifying those patients who need dual targeted therapy and those who get maximum benefit from a single anti-HER2 agent would minimize inconvenience, side effects and costs.”

In the January 2012 NeoALTTO trial, 455 patients with HER2-positive breast cancer were randomly assigned to preoperative therapy with paclitaxel and lapatinib, paclitaxel and trastuzumab, or paclitaxel plus both lapatinib and trastuzumab. Neoadjuvant therapy with dual HER2 inhibition significantly improved the odds of pCR in patients with early disease, though patients who received a single anti-HER2 agent had similar rates of pCR.

The October 2014 combined analysis of the GeparQuattro, GeparQuinto, and GeparSixto studies similarly reported that PIK3CA-mutated patients with HER2-positive breast cancer are less likely to have a pCR with neoadjuvant chemotherapy plus single or dual anti-HER2 treatment.

Guarneri V, Dieci MV, Frassoldati A, et al. Prospective biomarker analysis of the randomized CHER-LOB study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer. The Oncologist [published online August 5, 2015]. doi: 10.1634/theoncologist.2015-0138.