Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer.

Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths.Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing.Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival.Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569-80. ©2017 AACRSee related commentary by Peng and Mills, p. 508.

Prognostic significance of steroid receptor positivity and adjuvant progestogen use in endometrial stromal sarcoma.

BACKGROUND: The prognostic significance of oestrogen and progesterone receptors (ER/PR) in endometrial stromal sarcoma (ESS) has conflicting reports in the literature, and the routine use of adjuvant progestogen is of uncertain efficacy. AIMS: To examine the prognostic significance of ER/PR positivity and of primary adjuvant progestogen use with outcome in ESS. MATERIALS AND METHODS: All women with a diagnosis of ESS in our tertiary institution and associated private practices over the last 23 years were included. Primary variables were ER/PR positivity and adjuvant progestogen use. Other variables included high-grade disease and extrauterine disease. The primary outcome was survival, and the secondary outcome was recurrence-free survival (both overall and at 5 years). Survival was calculated using the Kaplan-Meier method. Univariate analyses were performed with t-test for means and chi-squared test for proportions, and multivariate analysis was used to control for age. RESULTS: 35 women were included. ER/PR positivity was associated with a survival benefit (OR death 0.22, P = 0.02), but primary adjuvant progestogen was not. High-grade disease (OR 13, P = 0.02) and extrauterine disease (OR 8.7, P = 0.04) were associated with decreased survival. No variable significantly affected recurrence-free survival. Eight of ten cases of recurrence treated with progestogen have survived more than 3 years. CONCLUSIONS: ER/PR positivity appears to be useful for prognosis, but routine administration of primary adjuvant progestogen is not supported. There may be a role for progestogen in ER/PR positive tumours with recurrence or incomplete surgical clearance, but further research is required.

Long-term outcomes after progestogen treatment for early endometrial cancer.

BACKGROUND: For select women with early endometrial cancer, particularly nulliparous women, nonsurgical options may be considered. There is increasing experience using progestogens, but little is known about the long-term outcomes and safety of such treatment. AIMS: To present the cancer and pregnancy outcomes of women with greater than five years follow-up after progestogen treatment for early endometrial cancer. METHODS: Ten women who underwent greater than six months of continuous progestogen therapy for early endometrial cancer were included in the study. All were managed by a gynaecological oncologist at a major tertiary centre in Melbourne, Australia. The histology of each subsequent curette was recorded, as was the timing and histology of hysterectomy (if relevant), and the results of any subsequent pregnancies. RESULTS: All ten women showed histological regression of cancer with no cases of recurrence on follow-up curette. Four of ten women have undergone hysterectomy with one case of occult disease persistence in a woman noncompliant with therapy. The mean follow-up time was 89 months (range 62-142 months), there were no deaths and no woman was lost to follow-up. All four women attempting pregnancy were successful. There were eight pregnancies and five live births. CONCLUSIONS: This form of treatment appears to be successful and safe in the long term with good pregnancy outcomes. However, it is not standard and should be supervised in a specialised gynaecological oncology unit.

Ovarian cancer: patterns of care in Victoria during 1993-1995.

OBJECTIVE: To describe the management of and outcomes in patients with newly diagnosed ovarian cancer during 1993, 1994 and 1995 in Victoria. DESIGN AND SETTING: Retrospective cohort study conducted by surveying doctors involved in managing incident ovarian cancer cases identified from the population-based Victorian Cancer Registry. The survey was conducted in 1997 and the cohort was followed up until the end of 1999 to obtain at least four years of follow-up data on all patients. PATIENTS: All women with invasive epithelial ovarian cancer diagnosed during 1993, 1994 and 1995. MAIN OUTCOME MEASURES: Reported management in terms of staging, treatment and survival. RESULTS: Management details were obtained for 84.5% (562/665) of eligible patients. Median age at diagnosis was 66 years (range, 22-98 years). Surgery was the primary therapy in 77.2% of women (434/562). Only one in three women had adequate surgery, which was less likely to be performed by general gynaecologists and general surgeons than gynaecological oncologists (21.3% [35/164] v 13.3% [8/60] v 52% [105/202]). After surgery 78.6% of women (341/434) received chemotherapy, usually with platinum-based regimens. The overall five-year relative survival was 46% for women treated surgically; poor survival was related to increasing age, later tumour stage, presence of ascites, residual disease > 2 cm and poorer histological differentiation of the tumour. CONCLUSIONS: For optimal care a preoperative carcinoma antigen (CA)-125 assay, chest x-ray and pelvic ultrasound should be performed, and early referral to a multi-disciplinary unit for definitive surgery is advised. Every effort should be made to adequately stage or debulk the tumour. Women with high-risk early-stage and advanced disease should be considered for platinum-based chemotherapy.