• Major finding: Patients with PIK3CA mutations are more res­ponsive to PI3K/AKT/mTOR inhibitors.

  • Approach: PI3K/AKT/mTOR inhibitors were given to patients with advanced PIK3CA-mutant cancers.

  • Impact: Screening for PIK3CA mutations may guide treatment of breast and gynecologic cancers.

Mutations in the p110α subunit of phosphatidylinositol 3-kinase (PI3K), encoded by PIK3CA, are common in breast and gynecologic malignancies. Preclinical studies have suggested that PIK3CA mutations, which activate the PI3K/AKT/mTOR pathway, respond to treatment with PI3K and mTOR inhibitors. In a prospective clinical trial, Janku and colleagues sequenced PIK3CA in tumor samples from patients with advanced breast, cervical, endometrial, and ovarian cancers that were refractory to standard therapies and referred to the Clinical Center for Targeted Therapy (Phase I Program) at The University of Texas MD Anderson Cancer Center. Of the 140 patients analyzed, 25 (18%) were positive for PIK3CA mutations, and 23 of these patients were then enrolled in a clinical trial that included a PI3K/AKT/mTOR pathway inhibitor. A partial response was observed in 30% of the patients harboring a PIK3CA mutation. In contrast, only 10% of patients with wild-type PIK3CA who were treated on the same protocols and had the same disease types responded to treatment. The authors also tested 81 of these patients for simultaneous mitogen-activated protein kinase pathway mutations, which may mediate resistance to PI3K/AKT/mTOR inhibitors, and found a significant association between the presence of RAS (KRAS or NRAS) or BRAF mutations and PIK3CA mutations. Importantly, 2 of 7 patients with coexisting mutations responded to targeted therapy. Although the overall number of patients included in these studies was small, the findings suggest that PIK3CA mutations are common in patients with advanced breast and gynecologic cancers. Screening for PIK3CA mutations may reveal a subset of patients who are sensitive to treatment regimens that include a PI3K/AKT/mTOR inhibitor.

Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 2012 Jan 23. [Epub ahead of print].

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