PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations

Abstract

Purpose: Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance.

Patients and methods: Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway.

Results: Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response.

Conclusion: PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.

Fig 1.

Waterfall plot of patients with PIK3CA mutations treated with phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin inhibitors. The overall response rate was 30%. Five patients with ovarian cancer and two patients with endometrial cancer had simultaneous PIK3CA and MAPK pathway (KRAS, NRAS, or BRAF) mutations. One patient with breast cancer who was never evaluated for response is not depicted. PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.

Fig 2.

Computed tomography scans of a responding patient (previously treated with cisplatin/gemcitabine, paclitaxel, carboplatin, liposomal doxorubicin, and cetuximab) with endometrial cancer demonstrating response on therapy with temsirolimus, bevacizumab, and liposomal doxorubicin. (A) Pretreatment scans of liver metastasis and pelvic mass. (B) Restaging scans after two cycles (6 weeks) demonstrating response in liver and pelvic mass. (C) Restaging scans after six cycles (18 weeks) demonstrating continuing response in liver and pelvic mass.

Fig 3.

Time to progression (TTP). Seven patients (30%), of whom five had a partial response (blue bars), experienced TTP longer than 6 months. All patients were off therapy at the time of analysis (19 experienced progression, and four withdrew consent).