Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer.

BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society.

The role of the fallopian tube in ovarian cancer.

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that "ovarian" HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5-10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes.

Combined methotrexate-dactinomycin: an effective therapy for low-risk gestational trophoblastic neoplasia.

OBJECTIVE: The objective of this study is to examine the outcomes of combined chemotherapy using methotrexate and dactinomycin in the management of women with low-risk gestational trophoblastic neoplasia (GTN). The primary outcome is the total number of cycles of chemotherapy required to achieve a normal level of human chorionic gonadotropin (hCG). The secondary outcome is treatment-related toxicity. METHODS: A retrospective chart review of all patients with GTN treated between 1996-2007 and 1991-2007 was performed at the Alberta Cross Cancer Institute and the British Columbia Cancer Agency, respectively. Patients with low-risk GTN, treated with 0.6 mg/m(2) dactinomycin (days 1 and 2) and methotrexate 100mg/m(2) were included. Toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. The number of cycles to achieve normalization of hCG was determined, and multivariate analyses were performed to identify factors associated with treatment duration. RESULTS: One hundred women were eligible. The average age was 29 years (range 15-46). The median number of cycles to achieve a normal hCG was 3 (range 1-11). Two patients required second-line treatment and one patient chose to proceed with hysterectomy. Ninety-eight percent of patients were primarily cured with this regimen, and 2 were cured with second line treatment. Grade 3 and 4 hematologic toxicities were experienced by 12% and 8% of patients, respectively. Grade 2 and 3 stomatitis or mucositis were noted in 44% and 3% of patients, respectively. CONCLUSIONS: Low-risk GTN is reliably and rapidly cured with combined methotrexate-dactinomycin. Toxicity is modest.