ECC 2013: PI3KCA-Mutant Tumors Not Likely to Respond to Neoadjuvant HER2 Blockade


Key Points

  • PI3KCA mutations were associated with a lower pathologic complete response rate to dual HER2 blockade, compared to PI3KCA wild-type tumors, in the NeoALTTO trial
  • After treatmenet with lapatinib/trastuzumab, patients lacking the mutation had a pathologic complete response rate of 55.8%, compared to 28.6% among those with the PI3KCA mutation

In patients with early breast cancer receiving anti-HER2 therapy in the NeoALTTO trial, mutations in PIK3CA were associated with lower rates of pathologic complete response, Jose Baselga, MD, reported at the European Cancer Congress 2013 (Abstract 1859) in Amsterdam.

In patients treated with the combination of lapatinib (Tykerb) and trastuzumab (Herceptin), the pathologic complete response rate was 55.8% in those lacking PIK3CA mutations but only 28.6% in those with mutant tumors (P = .02), he reported.

“The lower pathologic complete response rate in PI3KCA-mutant tumors is observed in all treatment arms and irrespective of estrogen receptor status,” said Dr. Baselga, who is Physician-in-Chief at Memorial Sloan-Kettering Cancer Center, New York. “These findings are consistent with experimental data in our laboratories.”

Dr. Baselga explained that PIK3CA mutations are frequent in HER2-positive breast cancer. PIK3CA mutations and low PTEN expression is associated with poor prognosis after trastuzumab therapy, and PTEN loss-of-function mutations or mutations in PIK3CA lead to lapatinib resistance in vitro.

NeoALTTO Details

Dr. Baselga and his team investigated the influence of PI3K pathway mutations (PIK3CA, KRAS, BRAF, AKT1) on sensitivity to trastuzumab, lapatinib, or both agents in combination in patients with early-stage HER2-positive breast cancer enrolled in the phase III NeoALTTO trial. NeoALTTO evaluated neoadjuvant dual HER2 blockade in 449 patients with primary HER2-positive breast cancer.

In NeoALTTO, dual blockade achieved a pathologic complete response rate of 51.3% vs 29.5% for trastuzumab alone (P = .0001). The pathologic complete response rate for lapatinib was 24.7%, which was not significantly different from trastuzumab (P = .34).

PI3KCA Mutations in 23% of Patients

Genotyping was completed on biopsies from 355 patients. The primary efficacy endpoint was pathologic complete response at surgery, defined as the absence of tumor in the breast.

Consistent with previous analyses, according to Dr. Baselga, PIK3CA mutations were found in 23% of patients. Only one patient (0.3%) had a KRAS mutation and none had a BRAF mutation.

The PIK3CA mutation rate was similar among estrogen receptor–negative (22%) and estrogen receptor–positive patients (23%). Per treatment arm, mutations occurred in 23% of patients treated with lapatininb, 19% treated with trastuzumab, and 25% treated with the combination.

PIK3CA Mutations Associated With Lower Pathologic Complete Response

PIK3CA mutations were associated with a lower [pathologic complete response] rate. This relationship was evident across the entire patient cohort, but was most pronounced in the lapatinib/trastuzumab arm,” Dr. Baselga reported.

The rate of pathologic complete response was 34% in PI3KCA wild-type tumors, but dropped to 21% in PI3KCA-mutant tumors (P = .03). In patients treated with the combination, the pathologic complete response rate was 55.8% in those lacking PIK3CA mutations and 28.6% in those with mutant tumors (P = .02). By estrogen receptor status, both positive and negative tumors were less likely to respond in patients with mutations.

To more rigorously determine the association, the investigators conducted a logistic regression model of pathologic complete response, which adjusts for treatment arm and estrogen receptor status. Again, significant differences in pathologic complete response were observed between those with and without the PIK3CA mutation (odds ratio = 0.45, P = .015), he said.

Dr. Baselga said his group has also begun exploring the relationship between PTEN status and achievement of pathologic complete response, and will be reporting these data in the future.  

The study provides further evidence of the role of PIK3CA mutations in resistance to trastuzumab- and lapatinib-based therapies, he said, suggesting that the assessment of PIK3CA status might help identify patients unlikely to derive substantial benefit from these treatments.

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