Kara Long Roche

Clinicopathologic Features, Molecular Landscape, and Prognostic Implications of Ovarian Low-grade Serous Tumors with Histologic Transformation

Abstract Purpose: The purpose of this study was to characterize the clinicopathologic features, molecular genetic landscape, and clinical behavior of ovarian low-grade serous tumors with histologic transformation (LGS-HT) to indeterminate/high-grade carcinoma. Experimental Design: LGS-HT were retrospectively identified from an institutional cohort of patients with ovarian cancer and underwent central pathology re-review. Data on clinicopathologic characteristics, including age, stage, surgical outcomes, systemic treatments, and overall survival (OS), were collected. IHC profiling and next-generation sequencing were performed. OS comparisons were performed with our institutional cohorts of ovarian low-grade serous carcinoma (n = 109) and high-grade serous carcinoma (n = 1,672). Results: From 4,371 ovarian serous cancers, 40 (0.9%) LGS-HT were identified: 30 with synchronous low-grade and higher-grade tumor components at initial diagnosis and 10 with an ovarian low-grade serous neoplasm that recurred as a higher-grade carcinoma. The most common somatic driver mutations included TP53 (38.5%), KRAS (21.8%), NF1 (15.6%), BRAF (15.6%), and NRAS (12.5%), with coexisting TP53 and RAS/RAF mutations in 18.8% of cases. Alterations in DNA damage response genes (BRCA2, PALB2, CHEK2, ATM, NBN, and RECQL4) were identified in LGS-HT lacking TP53 genetic alterations. Synchronous low-grade and higher-grade tumor components at initial diagnosis were associated with poorer OS (median, 59.7 months) compared with low-grade serous carcinoma (median, 105.4 months; P = 0.026) and were similar to high-grade serous carcinoma (median, 48.8 months; P = 0.61). Severe nuclear atypia and the absence of RAS/RAF-driver mutations were significant adverse prognostic factors. Conclusions: LGS-HT exhibit both low-grade and high-grade morphologic and molecular features, representing an exception to the dualistic classification of ovarian serous neoplasms. The presence of a definitive high-grade carcinoma component in a low-grade serous tumor portends aggressive clinical behavior.

Optimizing Mainstreaming of Genetic Testing in Parallel With Ovarian and Endometrial Cancer Tumor Testing: How Do We Maximize Our Impact?

PURPOSE Although germline genetic testing (GT) is recommended for all patients with ovarian cancer (OC) and some patients with endometrial cancer (EC), uptake remains low with multiple barriers. Our center performs GT in parallel with somatic testing via a targeted sequencing assay (MSK-IMPACT) and initiates testing in oncology clinics (mainstreaming). We sought to optimize our GT processes for OC/EC. METHODS We performed a quality improvement study to evaluate our GT processes within gynecologic surgery/medical oncology clinics. All eligible patients with newly diagnosed OC/EC were identified for GT and tracked in a REDCap database. Clinical data and GT rates were collected by the study team, who reviewed data for qualitative themes. RESULTS From February 2023 to April 2023, we identified 116 patients with newly diagnosed OC (n = 57) and EC (n = 59). Patients were mostly White (62%); English was the preferred language for 90%. GT was performed in 52 (91%) patients with OC (seven external, 45 MSK-IMPACT) and in 44 (75%) patients with EC (three external, 41 MSK-IMPACT). GT results were available within 3 months for 100% and 95% of patients with OC and EC, respectively. Reasons for not undergoing GT included being missed by the clinical team where there was no record that GT was recommended, feeling overwhelmed, financial and privacy concerns, and language barriers. In qualitative review, we found that resources were concentrated in the initial visit with little follow-up to encourage GT at subsequent points of care. CONCLUSION A mainstreaming approach that couples somatic and germline GT resulted in high testing rates in OC/EC; however, barriers were identified. Processes that encourage GT at multiple care points and allow self-directed, multilingual digital consenting should be piloted.

High-Sensitivity Mutation Analysis of Cell-Free DNA for Disease Monitoring in Endometrial Cancer

Abstract Purpose: We sought to determine whether sequencing analysis of circulating cell-free DNA (cfDNA) in patients with prospectively accrued endometrial cancer captures the mutational repertoire of the primary lesion and allows for disease monitoring. Experimental Design: Peripheral blood was prospectively collected from 44 newly diagnosed patients with endometrial cancer over a 24-month period (i.e., baseline, postsurgery, every 6 months after). DNA from the primary endometrial cancers was subjected to targeted next-generation sequencing (NGS) of 468 cancer-related genes, and cfDNA to a high-depth NGS assay of 129 genes with molecular barcoding. Sequencing data were analyzed using validated bioinformatics methods. Results: cfDNA levels correlated with surgical stage in endometrial cancers, with higher levels of cfDNA being present in advanced-stage disease. Mutations in cfDNA at baseline were detected preoperatively in 8 of 36 (22%) patients with sequencing data, all of whom were diagnosed with advanced-stage disease, high tumor volume, and/or aggressive histologic type. Of the 38 somatic mutations identified in the primary tumors also present in the cfDNA assay, 35 (92%) and 38 (100%) were detected at baseline and follow-up, respectively. In 6 patients with recurrent disease, changes in circulating tumor DNA (ctDNA) fraction/variant allele fractions in cfDNA during follow-up closely mirrored disease progression and therapy response, with a lead time over clinically detected recurrence in two cases. The presence of ctDNA at baseline (P < 0.001) or postsurgery (P = 0.014) was significantly associated with reduced progression-free survival. Conclusions: cfDNA sequencing analysis in patients with endometrial cancer at diagnosis has prognostic value, and serial postsurgery cfDNA analysis enables disease and treatment response monitoring. See related commentary by Grant et al., p. 305

Germline Pathogenic Variants and Genetic Counseling by Ancestry in Patients With Epithelial Ovarian Cancer

Mutations in ovarian cancer risk genes are found in women of diverse ancestries, supporting genetic testing for ALL

Characteristics and survival of ovarian cancer patients treated with neoadjuvant chemotherapy but not undergoing interval debulking surgery

Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) confers similar outcomes as primary debulking surgery and chemotherapy. Little is known about patients who receive NACT but do not undergo debulking surgery. Our aim was to characterize these patients. We prospectively identified patients with newly diagnosed stage III/IV ovarian cancer treated with NACT from 7/1/15-12/1/17. Fisher exact and Wilcoxon rank-sum tests were used to compare clinical characteristics by surgical status. The Kaplan-Meier method was used to estimate survival outcomes. Log-rank test and Cox proportional hazards model were applied to assess the relationship of covariates to outcome, and time-dependent covariates were applied to variables collected after diagnosis. Of 224 women who received NACT, 162 (72%) underwent IDS and 62 (28%) did not undergo surgery. The non-surgical group was older (p<0.001), had higher Charlson comorbidity index (CCI; p<0.001), lower albumin levels (p=0.007), lower Karnofsky performance scores (p<0.001), and were more likely to have dose reductions in NACT (p<0.001). Reasons for no surgery included poor response to NACT (39%), death (15%), comorbidities (24%), patient preference (16%), and loss to follow-up (6%). The no surgery group had significantly worse overall survival (OS) than the surgery group (hazard ratio=3.34; 95% confidence interval=1.66-6.72; p<0.001), after adjustment for age, CCI, and dose reductions. A significant proportion of women treated with NACT do not undergo IDS, and these women are older, frailer, and have worse OS. More studies are needed to find optimal therapies to maximize outcomes in this high-risk, elderly population.

CT of Ovarian Cancer for Primary Treatment Planning: What the Surgeon Needs to Know—Radiology In Training

A 60-year-old woman presented with intermittent abdominal pain, an elevated serum CA-125 level, and an abnormal CT examination and was ultimately diagnosed with advanced-stage high-grade serous ovarian cancer. Key tumor locations on CT scans that should be highlighted by the radiologist to guide treatment selection are discussed.

Gynecologic Survivorship Tool: Development, Implementation, and Symptom Outcomes

PURPOSE To describe the development and implementation of a new digital health clinical tool (Gynecologic Survivorship Tool [GST]) for symptom management of women surgically treated for gynecologic cancer; to assess its feasibility; and to conduct a retrospective review of the data. MATERIALS AND METHODS The GST was developed on the basis of a comprehensive review of the literature, multidisciplinary expert opinion, and feedback from women with a history of gynecologic cancer. It is composed of 17 questions addressing six main categories—gynecologic health (abnormal bleeding/pain), lymphedema, vaginal/vulvar dryness, sexual health, menopause (hot flushes/sleep difficulties), and bowel/urinary issues. An electronic version using the Memorial Sloan Kettering Cancer Center Engage platform was piloted in two clinics for patients with endometrial or cervical cancer. Health information was generated into clinical summaries and identified concerns for actionable response. Associations of symptom and survey time point were assessed by longitudinal models using generalized estimating equations. RESULTS From January 1, 2019, to February 29, 2020, 3,357 GST assessments were assigned to 1,405 patients, with a 71% completion rate (90% within 5 minutes). Sixty-eight percent were performed at home via a patient portal, 32% at follow-ups using a clinic iPad. The most common symptoms were bowel problems, swelling/fluid, pain during examination, vaginal or vulvar dryness, and vaginal bleeding. Implementation challenges included improving patient compliance and ensuring that reports were reviewed by all clinical teams. We developed screening e-mails detailing patients whose assessments were due, planned training sessions for multidisciplinary teams, and incorporated feedback on methods for reviewing symptoms reports. CONCLUSION The GST demonstrated feasibility, a high completion rate, and minimal time commitment. It was an effective electronic reporting mechanism for patients, enabling the medical team to develop specific strategies for alleviating bothersome symptoms during follow-up.

Multimodal data integration using machine learning improves risk stratification of high-grade serous ovarian cancer

Integration of genomic, histopathology, radiomics and clinical data using machine learning improves risk stratification for 444 patients with high-grade serous ovarian cancer.

Molecular Classification in Relation to Prevention of Endometrial Cancer Recurrence and Lifestyle Factors

Endometrial cancer (EC) is one of the most prevalent cancers in women worldwide with a significantly increasing incidence, especially in developed countries. One of the reasons for the increase in the incidence of this disease is the rising incidence of obesity as the biggest risk factor for the development of this disease. Other important risk factors are hypertension, diabetes mellitus and the general ageing of the population. These risk factors are not only associated with a higher risk of developing the disease, but also, for example, with post-operative complications affecting the quality of life of patients after surgery. The molecular classification of endometrial cancer, which has been introduced into clinical practice in recent years, is currently helping physicians to make treatment decisions for individual patients and predict prognosis. In this project, we would like to focus on the relationship of this molecular classification with genomic mutational signatures detected by whole-exome sequencing and their association with lifestyle risk factors for endometrial cancer (obesity - BMI, hypertension, diabetes mellitus), including the extent of staging lymphadenectomy. Identification and detailed analysis of dominant mutational profiles associated with a specific molecular subtype of EC and their influence on the presence of lifestyle risk factors may have a major impact on both disease development and prevention of disease recurrence. The possible relationship of the mutational profile with the extent of staging lymphadenectomy may help in deciding the extent of this surgical procedure, which subsequently affects the quality of life of patients, especially in patients with high BMI. Given the widespread prevalence of lifestyle risk factors in the developed world, a detailed understanding of the relationship between the genetic profile, its alterations and the prevalence of these risk factors, with potentially major implications for treatment success, is crutial.