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.

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 4.9months] 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.

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study.

OBJECTIVES: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma. BACKGROUND: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. METHODS: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. RESULTS: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. CONCLUSIONS: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.

A quality process study of lymph node evaluation in endometrial cancer.

Our objective was to analyze the reported lymph node counts between surgeons, histology prosectors, and pathologists using a cohort of patients enrolled on a national protocol that standardized surgical intent.This is a retrospective review of patients with uterine cancer who underwent a standardized formal staging procedure as dictated by a National Cancer Institute sponsored protocol. Patients were staged using the International Federation of Gynecology and Obstetrics 1988 guidelines. All patients required a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. Lymphadenectomy specimens were separated by the following regions: external iliac, obturator, common iliac, and periaortic. Lymph node counts were analyzed by region, surgeon, histology prosector, and pathologist.There were 78 patients enrolled in the protocol during the study period. Of them, 72 (92%) patients met the inclusion criteria. A total of 2397 lymph nodes were counted, with an average total number of 33 (SD=9) lymph nodes dissected per patient. Surgeons A, B, and C had an average lymph node count of 32, 33, and 35, respectively, with no significant difference in mean node count (P=0.66). Prosectors 1 to 4 dissected an average of 34, 33, 28, and 35 lymph nodes, respectively (P=0.091). There were 2 pathologists with ≥ 10 cases. Their mean lymph node counts were 35 and 30, respectively, with no significant difference in mean node count (P=0.079).This systematic review did not identify a discrepancy in nodal count among surgeons, prosectors, or pathologists at our institution. The methods used may be helpful in structuring interdepartmental reviews for completeness of nodal dissections in cases where surgical intent has been standardized.