In early breast cancer patients receiving anti-HER2 therapy in the NeoALTTO trial, mutations in PIK3CA were associated with lower rates of pathologic complete response, according to a study reported at the 2013 European Cancer Congress by José Baselga, MD, Physician-in-Chief at Memorial Sloan-Kettering Cancer Center, New York.1
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), Dr. Baselga noted. “The lower [pathologic complete response] rate in PIK3CA-mutant tumors is observed in all treatment arms and irrespective of estrogen receptor status. These findings are consistent with experimental data in our laboratories,” he said.
The study provides further evidence of the role of PIK3CA mutations in resistance to trastuzumab- and lapatinib-based therapies, suggesting that the assessment of PIK3CA status might help identify patients unlikely to derive substantial benefit from these treatments.
PIK3CA mutations are frequent in HER2-positive breast cancer. PIK3CA mutations and low PTEN expression are associated with poor prognosis after trastuzumab therapy, and PTEN loss-of-function mutations and mutations in PIK3CA lead to lapatinib resistance in vitro, Dr. Baselga explained.
The NeoALTTO investigators, therefore, investigated the influence of PI3K pathway mutations (PIK3CA, KRAS, BRAF, AKT1) on sensitivity to trastuzumab, lapatinib, or both agents in combination in early-stage HER2-positive breast cancer patients enrolled in the phase III NeoALTTO trial.
NeoALTTO evaluated neoadjuvant dual HER2 blockade in 449 patients with primary HER2-positive breast cancer. 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).2
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 lapatinib, 19% treated with trastuzumab, and 25% treated with the combination.
Effect of PIK3CA Mutations
“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 said.
The rate of pathologic complete response was 34% in PIK3CA wild-type tumors, but dropped to 21% in PIK3CA-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 used 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).
Dr. Baselga noted that these results are in line with those observed with pertuzumab (Perjeta) and trastuzumab in the NeoSphere and CLEOPATRA trials. He added that 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. ■
Disclosure: Dr. Baselga has served in a consulting or advisory role for Novartis, Roche, and Chugai.
1. Baselga J, Majewski I, Nuciforo PG, et al. 2013 European Cancer Congress. Abstract 1859. Presented September 29, 2013.
2. Baselga J, Bradbury I, Eidtmann H, et al: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): A randomised, open-label, multicentre, phase 3 trial. Lancet 379:633-640, 2012.