PIK3CA Mutations May Predict Resistance in HER2-Positive Breast Cancer

PIK3CA Mutations May Predict Resistance in HER2-Positive Breast Cancer

August 11, 2015

Breast cancer patients with PIK3CA gene mutations may not benefit from dual anti-HER2 inhibition, according to a new study in The Oncologist.

Breast cancer patients with PIK3CA gene mutations may not benefit from dual anti-HER2 inhibition, according to a new study in The Oncologist.1 The purpose of the study was to help identify ways to predict sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers.

A phase II study, CHER-LOB, showed that the combination of kinase inhibior lapatinib (Tykerb) and monclonal antibody trastuzumab (Herceptin) plus chemotherapy increases the pathologic complete remission (pCR) rate in patients with HER2-positive breast cancer compared with chemotherapy plus either trastuzumab or lapatinib.

The study included 121 patients with HER2-positive breast cancer. Of these patients, some were randomly assigned to receive neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Of 113 tumor samples available for centralized HER2 evaluation, 110 were confirmed as HER2 overexpressing.

The results showed that pCR was documented in 33% of patients. The distribution of pCR was as follows:

  • Arm A: 25% (90% CI: 13.1%-36.9%) in patients randomly assigned to chemotherapy plus trastuzumab.
  • Arm B: 26.3% (90%CI: 14.5%-38.1%) in patients randomly assigned to chemotherapy plus lapatinib.
  • Arm C: 46.7% (90% CI: 34.4%-58.9%) in patients randomly assigned to chemotherapy plus trastuzumab and lapatinib.

The pCR rate was higher in patient samples that lacked hormone receptors. The expression of p95-HER2 was not able to predict a different probability of achieving pCR by exposure to trastuzumab or lapatinib or both. Expression of p95-HER2 had already been identified as a marker of resistance to trastuzumab not affecting the efficacy of lapatinib.

Another goal of the study was to identify a gene signature that can identify sensitivity to lapatinib. A 50- gene signature was identified as a predictor of pCR in the chemotherapy plus lapatinib arm, but was unable to predict pCR in that arm.

The researchers concluded that indeed PIK3CA mutations are a practical predictive marker of resistance to dual anti-HER2 treatment that should be further studied in breast cancer. This is important because as more HER2-positive breast cancer treatments become readily available, it will be crucial to be able to identify which patients with the most aggressive subtypes of breast cancer will benefit most from specific treatment options.

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