Matthew Ellis, MB, PhD, Professor of Medicine and the Anheuser-Busch Chair in Medical Oncology at Washington University School of Medicine, St. Louis, commented for The ASCO Post on the emerging field of research on drugging PI3K mutations.

Critical Mechanisms

“Multiple somatic lesions in breast cancer cells can activate the PI3 kinase pathway, and developing an understanding of mechanisms whereby these events deregulate signaling is critical for accurate drug targeting. The field is still uncovering new ways where PI3 kinase gets activated,” he noted.

“For example,” Dr. Ellis continued, “in a study from the University of North Carolina, Dr. Perou’s team showed that SOX4 is a novel regulator of PI3K signaling in basal-like breast cancers. It was amplified in approximately 40% of basal-like tumors with high PI3K signaling, which is comparable to the frequency of PIK3CA or PTEN alterations.¹ It’s not clear how SOX4 achieves PI3K pathway activation, but it appears to do so, which means we could potentially target the downstream effect of SOX4 overexpression with PI3K pathway–targeted agents,” he predicted.

“This sort of complexity explains why our initial efforts to link the efficacy of everolimus to the presence of PIK3CA mutations have not yielded clear results, likely because other biologic events and mutations that also determine efficacy have not been taken into account,” he said.

Promising Inhibitors

Targeting of PIK3CA will probably best be achieved with a direct inhibitor, as reported by a number of investigators in San Antonio. BYL-719 and other highly specific PI3K-alpha inhibitors look promising, according to Dr. Ellis. While the BKM120 compound is a broader inhibitor, Dr. Ellis’ group showed that patients who are resistant to endocrine therapy can respond to the combination of fulvestrant and BKM120.

“We are also learning that inhibiting cyclin D/CDK4 activity is important,” he said, and is “clearly targetable” by the LEE-011 CDK4 inhibitor. A triple combination of an endocrine agent, a PI3K inhibitor, and a CDK4 inhibitor could be a potent approach to treatment, he predicted.

In HER2-positive tumors, the associations are similarly complex. In San Antonio, German researchers showed that PI3KCA mutations are associated with poor response to otherwise effective HER2-targeting.² However, since PI3KCA mutations are associated with luminal type biology, “we have to tease all this out because direct cause and effect is not demonstrated in these studies,” Dr. Ellis added.

Other Insights

Insights have also been gained into PI3KCA mutations in the hormone-sensitive environment—affecting not only estrogen receptor–positive tumors, but also androgen receptor–positive tumors that are part of the triple-negative subset of patients. “The molecular apocrine tumors can also be PIK3CA-mutant,” Dr. Ellis noted.

“So it appears that this PIK3CA mutation story is associated with luminal biology and hormone receptor–driven tumors, and it is also associated with androgen receptor expression.” In this setting there is potential for yet another novel strategy: combining an antagonist of the androgen receptor with PIK3CA inhibition. ■

Disclosure: Dr. Ellis reported no potential conflicts of interest.

References

1. Gatza ML, Silva G, Hoadley KA, et al: An integrated genomics approach identifies novel drivers of oncogenic pathway activity in human breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S4-01. Presented December 12, 2013.

2. Loibl S, Denkert C, Schneeweis A, et al: PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer—prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. 2013 San Antonio Breast Cancer Symposium. Abstract S4-06. Presented December 12, 2013.