Network of PIK3CA mutations may affect response to HER-2–targeted therapies

Issue: January 25, 2016

Mutations in a broad network of PIK3CA-associated genes appeared significantly associated with response to HER-2–targeted therapies, according to analysis of data from the NeoALTTO trial.

PIK3CA appeared to be the only gene that had significant association with response — indicating a lower sensitivity to HER-2–targeted therapies — because it was frequently altered. However, the majority of cases with lower sensitivity to these drugs had mutations in other genes, with each mutation occurring in only few cases.

Lajos Pusztai

“The key findings is that different cancers acquire resistance to trastuzumab [Herceptin, Genentech] through different mutations in different genes,” Lajos Pusztai, MD, DPhil, professor of medicine and chief of breast medical oncology at Yale Cancer Center, said in a press release. “The silver lining is that these genes participate in biological processes that are all connected through the PIK3CA gene.”

Pusztai and colleagues sought to assess whether alterations in nucleic acid variants, genes, pathways, and overall mutational load and clonal heterogeneity affected outcomes of patients who received anti–HER-2 therapies. Researchers evaluated baseline biopsies from 203 patients treated on the NeoALTTO trial — on which patients with early-stage breast cancer received trastuzumab, lapatinib (Tykerb, Novartis) or both concomitant with paclitaxel as preoperative therapy — using whole exome sequencing to examine DNA level alterations in 22,000 genes.

Researchers identified 12 genes that had mutations significantly more frequently than the background mutation rate; however, only PIK3CA mutations demonstrated a link with lower pathological complete response rate (OR = 0.42; P = .019).

Response rate also was not associated with overall mutation load or clonal heterogeneity.

However, researchers identified mutations in 33 biological pathways out of 714 that were significantly linked to response rate in the entire cohort of patients. Twenty-six of these pathways demonstrated an association with residual disease (ie, lesser sensitivity to trastuzumab and lapatinib). All of these pathways shared PIK3CA as a member gene.

“Every single one of the pathways associated with residual disease had protein kinase C in them,” Pusztai said during his presentation. “Much fewer and more diverse pathways were associated with an increased probability of pathological complete response and none of them included protein kinase C.”

Pusztai and colleagues then created a PIK3CA network of 439 genes implicated in these 26 pathways.

Fifty of the 66 patients on the trastuzumab arm harbored at least one of these mutations, and only two of these patients achieved a pathological complete response. Conversely, nine of the 16 patients with wild-type disease achieved a complete response (OR = 0.035; P ˂ .001).

These associations did not persist in the lapatinib arm.

The “regulation of RhoA activity” pathway — which contains 49 genes that primarily activate the RhoA gene — appeared significantly associated with pathological complete response in the entire population (OR = 3.77; P = .0009), in the lapatinib monotherapy arm (complete response rate, 67% vs. 17%; OR = 14.8; P = .008), and the lapatinib plus trastuzumab arm (OR = 3; P = .06). However, the pathway was not significantly associated with response in the trastuzumab monotherapy arm (OR = 1.4).

OS and EFS were also higher among patients with mutations in this pathway.

“A somewhat unexpected finding in this survival analysis was that we also observed very good survival in the trastuzumab-alone arm for patients with Rho-pathway mutation, which suggests that affecting the RhoA activity has a prognostic value in addition to being predictive of sensitivity to lapatinib,” Pusztai said.

“Further, a combined mutation status of the PIK3CA network and the RhoA activity could define a population that seemed to benefit from lapatinib, either alone or with trastuzumab,” Puztai added. “In cancers that did not have mutations in the PIK3CA network — which confers lower sensitivity to trastuzumab, or in the Rho-activation pathways, which conferred sensitivity to lapatinib, lapatinib showed very little efficacy, whereas trastuzumab remained effective.” – by Alexandra Todak

Reference:

Pusztai L, et al. Abstract S5-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.

Disclosure: Pusztai and colleagues report no relevant financial disclosures.