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Double PIK3CA Mutations and Response Benefit in Breast Cancer


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Patients who have breast cancers with double PIK3CA mutations seem to have a more robust response to PI3Kα inhibitors than those with a single PIK3CA mutation, based on an analysis of the phase III SANDPIPER trial, which tested taselisib plus fulvestrant, according to a presentation during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.1,2


“Patients with multiple-mutant breast cancer achieve greater clinical benefit with PI3Kα inhibition compared with those who have single-mutant tumors.”
— Neil Vasan, MD, PhD

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“Double PIK3CA mutations are a novel and frequent genomic alteration in PIK3CA-mutant cancers,” said lead author Neil Vasan, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York. “This retrospective analysis confirms that patients who have multiple-mutant breast cancer achieve greater clinical benefit with PI3Kα inhibition compared with those who have single-mutant tumors. The findings support the rationale to test PI3Kα inhibitors in multiple PIK3CA-mutant cancers.”

Background

“Oncogene activity is the hallmark of cancer,” Dr. Vasan continued. “PIK3CA is the most frequently mutated oncogene in [breast] cancer, present in approximately 40% of estrogen receptor–positive breast tumors. The vast majority of multiple PIK3CA mutations are double, and they are present early in the course of breast cancer, with similar frequency in primary and metastatic tumors as well as in treatment-refractory tumors.”

The researchers looked at whether the presence of cis PIK3CA mutations—those existing on the same allele—were a predictive biomarker for response to a PI3Kα inhibitor. Using single--molecule real-time sequencing of fresh breast tumor samples, they were able to determine that double PIK3CA mutations are on the same allele. “To our knowledge, this was the first use of -single-molecule real-time sequencing to phase multiple alterations in solid tumors,” Dr. Vasan explained.

Next they showed that double–PIK3CA-mutant cells display increased signaling, cell growth, and tumor growth compared to single mutants. This corresponds to increased sensitivity to PI3Kα inhibitors of double mutants compared to single mutants in cellular models.

Next, they looked retrospectively at a phase III study to determine whether tumors with double PIK3CA mutations were associated with improved response compared with single-mutant tumors.

SANDPIPER Details

The phase III SANDPIPER trial evaluated the efficacy of the -PI3Kα inhibitor taselisib plus fulvestrant vs placebo plus fulvestrant in 631 patients with advanced or metastatic estrogen receptor–positive breast cancer that recurred or progressed during or after aromatase inhibitor therapy. The investigators analyzed 508 patient samples with circulating tumor DNA to identify the presence of a PIK3CA mutation. Of these samples, 339 tested positive for PIK3CA mutations; 19% (n = 66) presented with two or more PIK3CA mutations; and 81% (n = 273) had a single PIK3CA mutation.

“This was the first use of single-molecule real-time sequencing to phase multiple alterations in solid tumors.”
— Neil Vasan, MD, PhD

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Data from a waterfall plot showed that patients with two or more PIK3CA mutations had increased tumor shrinkage with taselisib vs those with a single mutation. Patients with single-mutant tumors in the taselisib arm (n = 193) had a nonsignificantly different overall response rate of 18.1% vs 10.0% in those treated in the placebo arm (n = 80). By contrast, patients with multiple mutations in the taselisib arm (n = 43) achieved an overall response rate of 30.2% vs 8.7% in the placebo arm (n = 23), achieving statistical significance.

KEY POINTS

  • Basic research showed that tumors with double PIK3CA mutations may be more sensitive to PI3Kα inhibition than tumors with single PIK3CA mutations.
  • Analysis of the SANDPIPER trial supports this hypothesis, showing that patients with breast cancer whose tumors have double PIK3CA mutations have improved response rates and progression-free survival compared with those with single PIK3CA mutations.
  • These findings support further study of PI3Kα inhibitors in cancers with multiple PIK3CA mutations.

“This was not the primary endpoint of this trial, but certainly this raises the hypothesis, based on phase III clinical data, that multiple PIK3CA mutations may predict for increased response to PI3Kα inhibitors,” Dr. Vasan said. “In this work, we have identified double mutations as a novel, and relatively frequent, genomic alteration in PIK3CA, which translates into a clinically meaningful number of patients who may derive additional benefit from targeted therapy,” he added. 

DISCLOSURE: Dr. Vasan has served as an advisor or consultant to Novartis, Petra Pharmaceuticals, and Volastra Therapeutics.

REFERENCE

1. Vasan N, Razavi P, Johnson JL, et al: Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. 2020 AACR Virtual Annual Meeting II. Abstract NG16.

2. Razavi P, Dickler MN, Shah PD, et al: Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors. Nature Cancer 1:382-393, 2020.


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