Breast cancer patients with newly diagnosed human epidermal growth factor receptor 2–positive tumors with a PIK3CA mutation are less likely to achieve a pathologic complete response after neoadjuvant anthracycline-taxane–based chemotherapy with anti-HER2 treatment, results from a German study demonstrated.
"This effect remains, even if a dual anti-HER2 treatment is given and rates of pCR [pathologic complete response] are lowest in the HR-positive/HER2-positive tumors harboring the PIK3CA mutation," German Breast Group researchers led by Dr. Sibylle Loibl wrote in a study published online Sept. 8 in the Journal of Clinical Oncology. "The PIK3CA mutation data could be combined with downstream markers such as p4EBP1 using class prediction algorithms to improve characterization of the tumors and select appropriate tumors. Our data suggest that investigation of alternative therapies (such as a PI3K inhibitor) in PIK3CA-mutant HER2-positive breast cancers is warranted."
Although mutations of the PIK3CA gene are found in about 20% of all breast cancers, the frequency of such mutations is not equally distributed among the different biologic subtypes. Dr. Loibl and her associates set out to investigate the association between PIK3CA genotype and pCR rates in HER2-positive breast cancer treated with either dual or single anti-HER2 treatments in addition to neoadjuvant chemotherapy. They evaluated 504 tumor samples from participants in the GeparQuattro, GeparQuinto, and GeparSixto studies, in which all HER2-positive patients received either trastuzumab or lapatinib or the combination plus anthracycline-taxane chemotherapy (J. Clin. Oncol. 2014 Sept. 8 [Epub doi:10.1200/JCO.2014.55.7876]). PIK3CA mutations were evaluated in tumor material from formalin-fixed, paraffin-embedded tissue core biopsies taken before therapy with a tumor content of at least 20% determined by using classical Sanger sequencing of hot-spot mutations in exon 9 and exon 20.
Of the 504 patients, 291 had hormone receptor (HR)–positive tumors and 213 had HR-negative tumors. During a median follow-up period of 42 months, the researchers observed no statistically significant differences in disease-free survival or in overall survival between patients with or without a PIK3CA mutation (hazard ratios of 1.07 and 0.59, respectively). More than one in five of the patients (21.4%) harbored a PIK3CA mutation, and detection of a PIK3CA mutation was associated with a significantly lower pCR (19.4%, compared with 32.8% among those in the PIK3CA wild-type group [odds ratio, 0.49; P = .008]), Dr. Loibl, professor at the University of Frankfurt, Germany, and her associates reported.
Among the 291 HR-positive tumors, the pCR rate was 11.3% in patients with a PIK3CA mutation, compared with 27.5% in the PIK3CA wild-type group (OR, 0.34; P = .011). Among the 213 HR-negative tumors, the pCR rate was 30.4% in patients with a PIK3CA mutation, compared with 40.1% in those without the mutation (OR, 0.65; P = .223).
Multivariate analysis adjusted for age, tumor stage, nodal status, histologic type, tumor grade, study, and anti-HER2 treatment revealed that, in patients with a PIK3CA mutation, the pCR rates with lapatinib, trastuzumab, and the combination were 16%, 24.3%, and 17.4%, respectively (P = .654), while those rates in the wild-type group were with 18.2%, 33.8%, and 37.1% (P = .017).
"In this study, it seemed that HER2-positive patients with PIK3CA mutations derived long-term benefit from adjuvant trastuzumab, indicating sensitivity rather than resistance to anti-HER2 treatment, although numbers of patients were small," the researchers wrote.
"In the metastatic setting, data sets are small, conflicting, and without clear treatment effects. Indeed, the lower pCR rate in the HR-positive/HER2-positive PIK3CA mutant cohort could reflect lower chemosensitivity or resistance to anti-HER2 therapy. HR-positive/HER2-positive patients historically had a lower pCR rate with chemotherapy alone. In our data set, patients with PIK3CA mutations had similar pCR rates across all anti-HER2 treatment arms. In past studies, this pCR rate was as low as that of HER2-positive patients receiving chemotherapy without trastuzumab. However, because trastuzumab is now the standard of care, we cannot make any comments based on our data regarding the impact of PIK3CA genotype on patients who did not receive anti-HER2 therapy," they said.
The study was supported by a grant from the RESPONSIFY Consortium. Members of the research team disclosed numerous financial relationships with industry.
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