Caroline C. Billingsley

Polymerase ɛ (POLE) mutations in endometrial cancer: Clinical outcomes and implications for Lynch syndrome testing

DNA polymerase ɛ (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. POLE‐mutant tumors were described as a molecular subtype with improved progression‐free survival by The Cancer Genome Atlas. In this study, the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations were investigated in patients with endometrioid EC.

Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: An NRG Oncology and Gynecologic Oncology Group study

Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

Predictors of long-acting reversible contraception use among unmarried young adults

OBJECTIVE The objective of the study was to improve the understanding of long-acting reversible contraception (LARC) use patterns among unmarried, young adults at risk of unintended pregnancy. STUDY DESIGN We performed a secondary data analysis of a national survey conducted by Guttmacher Institute of unmarried women and men aged 18-29 years. LARC is defined as an intrauterine device (IUD) or implant. Predictors of LARC use and IUD knowledge among those at risk for unintended pregnancy (n = 1222) were assessed using χ(2) analysis and logistic regression models. RESULTS LARC use was associated with older age, high IUD knowledge, and earlier onset of sexual activity. Respondents with high IUD knowledge were 6 times more likely to be current LARC users (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.4-28.8). Sociodemographic variables did not predict use. Respondents with lower education (OR, 1.76; 95% CI, 1.0-3.0), an external locus of control (OR, 1.6; 95% CI, 1.1-2.3), male sex (OR, 2.8; 95% CI, 1.9-4.1), and foreign language had less knowledge of IUD. CONCLUSION Increasing knowledge of IUD among certain groups may improve LARC use among young, unmarried adults and in turn decrease unintended pregnancy.

Cancer and pregnancy: an overview for obstetricians and gynecologists

A relatively rare occurrence, pregnancy-associated cancer affects approximately 1 in 1000 pregnancies. Optimizing treatment of the cancer and minimizing harm to the fetus are often dependent on the extent of disease, treatment options required, and the impact on the pregnancy as well as the gestational age of pregnancy. When malignancy is diagnosed, the obstetrician-gynecologist plays a key role in the diagnosis, initial evaluation, and coordination of patient care. Furthermore, the obstetrician-gynecologist may be asked to assist in fertility planning for young women with a new diagnosis of cancer and may be responsible for addressing questions about family-planning needs and the safety of future pregnancy. Therefore, the purpose of this article was to provide the obstetrician-gynecologist with a relevant overview of the current literature regarding concurrent pregnancy and cancer diagnoses, management options, including maternal and neonatal outcomes, as well as the future needs of young women diagnosed with cancer who desire fertility preservation.

Does intra-operative radiation at the time of pelvic exenteration improve survival for patients with recurrent, previously irradiated cervical, vaginal, or vulvar cancer?

OBJECTIVE To determine whether intra-operative radiation therapy (IORT) at the time of pelvic exenteration (PE) or laterally extended endopelvic resection (LEER) improves progression-free survival (PFS) in patients with recurrent, previously irradiated gynecologic cancers. METHODS We conducted a single institution retrospective review of patients who had undergone a complete PE for locally recurrent gynecologic cancer. Demographic and clinicopathologic data were collected. RESULTS 32 patients were identified (2000-2012); 21 (66%) cervical cancer, 8 (25%) vaginal, and 3 (9%) vulvar cancer. All patients were previously irradiated. Twenty-one (66%) received IORT. Mean age was 51. Eight patients had a LEER, all with IORT. Median PFS and OS, respectively, for those with PE alone was 33 and 41 vs. 10 and 10 months for PE+IORT compared to 9 and 17 months for LEER+IORT (P=.04). Increasing tumor size negatively impacted PFS (hazard ratio 1.3; 95%CI 1.12-1.52). Margin status was not associated with survival. No patients undergoing LEER+IORT recurred only locally whereas 62% recurred with a distant component (+/- local). Patients with PE alone had mainly local (36%) and few (9%) distant recurrences compared to 31% local and 38% distant (+/- local) recurrences for those with PE+IORT. CONCLUSIONS We failed to demonstrate that IORT changes survival and recurrence outcomes. However, patients with clinical indications for IORT at the time of PE have worse prognosis compared to those who do not require IORT. If the need for IORT is anticipated, the surgeon may consider performing a LEER to decrease local recurrence if cure is the goal or consider palliative treatment options.

Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis.

Objective POLE mutations in high-grade endometrioid endometrial cancer (EEC) have been associated with improved survival. We sought to investigate the prevalence of POLE tumor mutation and its prognostic significance on outcomes and clinical applications in a subanalysis of women with high-grade EEC from a previously described cohort of 544 EEC patients in which POLE mutation status and survival outcomes were assessed. Methods Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 72 tumors. Associations between POLE mutation, demographic and clinicopathologic features, and survival were investigated with Cox proportional hazard models. Results POLE mutations were identified in 7 (9.7%) of 72 grade 3 EECs. No significant differences in the clinicopathologic features between those with POLE mutations and those without were identified. Adjusted for age, a decreased risk of recurrence was suggested in patients with a POLE mutation (adjusted hazard ratio, 0.37; 95% confidence interval, 0.09–1.55), as well as decreased risk of death (adjusted hazard ratio, 0.19; 95% confidence interval, 0.03–1.42). Conclusions POLE mutations in tumors of women with grade 3 EEC are associated with a lower risk of recurrence and death, although not statistically significant because of high variability in these estimates. These findings, consistent with recently published combined analyses, support POLE mutation status as a noteworthy prognostic marker and may favor a change in the treatment of women with grade 3 EECs, particularly in those with early-stage disease, in which omission of adjuvant therapy and decreased surveillance could possibly be appropriate.

Evaluation of the Hematologic Safety of Same Day Versus Standard Administration (24- to 72-Hour Delay) of Pegfilgrastim in Gynecology Oncology Patients Undergoing Cytotoxic Chemotherapy.

Objective We assessed the safety and efficacy of administration of pegfilgrastim on the same day compared with standard administration 24 to 72 hours after chemotherapy in patients with gynecologic malignancies. Methods A retrospective review was conducted on patients undergoing pegfilgrastim to mitigate the myelosuppressive consequences of chemotherapy. The primary outcome was incidence of grade 3 to 4 neutropenia following pegfilgrastim for same-day administration (D1) versus standard administration (D2+). Secondary outcomes included dose delay, regimen change, hospitalization due to neutropenia, and incidence of febrile neutropenia. Results Four hundred twenty-one patients with 2071 administrations of pegfilgrastim were included. Five hundred six administrations of pegfilgrastim were given on D1 compared with 1565 administrations on D2+. The most common malignancy was ovarian cancer (79.1%), followed by endometrial (14.5%). Comparing the D1 and D2+ cohorts, noninferiority was not established for the incidence of grade 3 to 4 neutropenia (2.6% vs 1.8%, adjusted relative risk [aRR], 1.6; 90% confidence interval [CI], 0.87–3.2) or dose modification (6.5% vs 4.9%; aRR, 1.3; 90% CI, 0.9–1.8). However, the rate of treatment delays (7.3% vs 9.4%; aRR, 0.8; 90% CI, 0.6–1.1) in the D1 and D2+ groups suggested that delays in the D1 group were not more common than in the D2+ group. Conclusions The incidence of hematologic toxicities and dose modification in patients receiving same-day pegfilgrastim were not as low as in those undergoing standard administration. However, treatment delays were found to be no more frequent in those receiving same-day pegfilgrastim versus standard administration. Same-day administration of pegfilgrastim is a reasonable option.

Survival outcomes of obese patients in type II endometrial cancer: Defining the prognostic impact of increasing BMI

OBJECTIVE To investigate the role of obesity as a risk factor for type II endometrial cancer (EC), as well as the prognostic significance of increasing body mass index (BMI) on survival. METHODS A single institution retrospective analysis of 154 type II EC cases from 1987 to 2010 was conducted. Patients were categorized into cohorts by BMI (normal (<25), overweight (25-29.9), obese class I (30-34.9), and obese class II-III (≥35)). Descriptive, regression and ANOVA analyses were performed. Kaplan-Meier curves were compared with log rank tests. RESULTS The BMI distribution was 22.8% normal BMI; 24% overweight; 17.5% class I; and 35.7% class II-III. The median follow up was 41 months. The median progression-free survival (PFS) was 45.4, 36.0, 35.3 and 42.0 months and overall survival (OS) was 54.7, 44.7, 44.8 and 49.7 months, among the respective groups. There was no association between BMI and PFS (p=0.71), OS (p=0.72), or time to recurrence (p=0.71). There were no differences among the increasing BMI groups compared to normal weight women for the risk of death. CONCLUSIONS Our analysis did not reveal any differences in outcomes by BMI group. Our data reveals that obesity is highly prevalent in type II ECs, though obesity has not historically been described as a risk factor. While BMI as a single variable may not be prognostic for survival outcomes, the role of obesity as a risk factor for type II EC should be further investigated, given the increasing prevalence of obesity in type II ECs.

Options for repair of rectus abdominis myocutaneous perineal/vaginal flap prolapse: A case series

Highlights • The VRAM flap is commonly used for perineal and vaginal reconstruction at the time of pelvic exenteration.• Prolapse of the VRAM flap may be under reported.• We have shown successful repair of VRAM flap prolapse via an obliterative technique and sacral suspension.

A case of parametrial lymph node involvement in stage IA2 squamous cell carcinoma of the cervix treated with radical hysterectomy and a review of the literature: a case report.

Cervical cancer classified as stage IA2 and IB1 according to the International Federation of Gynecology and Obstetrics has historically been treated with radical hysterectomy and bilateral lymph node dissection, but recent recommendations suggest more conservative treatment modalities. We report a woman with stage IA2 cervical cancer at low risk for parametrial spread including no lymphovascular space invasion, clear conization margins, and tumor size less than 2 cm, who underwent radical hysterectomy and was found to have a single positive metastatic parametrial lymph node. This case report is an important reminder that parametrial involvement occurs in low-risk early-stage cervical cancers.