Tumor mutational analysis of GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic Oncology Group study

Abstract

Objective Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. Methods Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next–generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9 months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. Results Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01–0.78) and RR (response difference 0.83; 95% CI 0.03–0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20–0.97) but not RR (response difference 0.00, 95% CI −0.34–0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. Conclusions Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.

A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer

“…Mutations in TSC2, although uncommon, have previously been reported in endometrial cancer as well as other tumor types to be associated with clinical response to mTOR inhibition [20, 21]. TSC2 somatic mutations were identified here in 14 (5.8%) patients.…”

Current recommendations and recent progress in endometrial cancer

“…However, no advantage was found from the addition of the mTOR inhibitor temsirolimus to standard carboplatin and paclitaxel chemotherapy, and multiple trials of single‐agent rapamycin‐analog mTOR inhibitors in advanced or recurrent disease have shown only modest activity (<25% response rates even in the setting of chemotherapy‐naive disease), and no association between activity and PTEN or PIK3CA alterations has been observed. One report noted significantly increased PFS and response rates in 3 patients whose tumors had AKT1 mutations …”

Chemotherapy for Endometrial Cancer in Adjuvant and Advanced Disease Settings

“…Several studies have shown no association between tumor PTEN alterations or PI3KCA mutations and clinical benefit from mTOR inhibitors. One report did describe a significant increase in RR and PFS for patients with an activating AKT mutation treated with temsirolimus, suggesting this population, although small, may derive particular benefit from treatment with mTOR inhibitors [94].…”