Table of non-BRCA mutations with clinical characteristics

Survival by mutation type, and mutation data by the source of sequenced DNA

Importance Placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) are rare forms of gestational trophoblastic neoplasia (GTN). These tumors differ from choriocarcinoma as they are monophasic, have slower growth rates, have lower β-hCG concentrations, and are more chemoresistant. Placental site trophoblastic tumor and ETT can be misdiagnosed, leading to inappropriate management. Objective The aim of this study was to review the pathogenesis, presentation, pathologic findings, and treatment for PSTT and ETT. Evidence Acquisition A comprehensive literature review was performed identifying relevant research and review articles. Relevant textbook chapters and guidelines were also reviewed. Results Placental site trophoblastic tumor and ETT can present months to years after any antecedent pregnancy event with abnormal uterine bleeding and an elevated β-hCG. Tumors are typically confined to the uterus and secrete lower levels of β-hCG compared with other GTNs. The International Federation of Gynecology and Obstetrics prognostic scoring system does not correlate well with prognosis. These lesions can be misdiagnosed as smooth muscle tumors, metastatic melanoma, and cervical squamous cell carcinoma. However, they can be distinguished by their unique histologic and immunophenotypic features. Conclusions Surgery is the mainstay of treatment for early-stage PSTT and ETT. For patients with advanced disease or for those with poor prognostic indicators, such as an antecedent pregnancy interval of greater than 48 months, a multimodal treatment paradigm of surgery and chemotherapy using a high-risk GTN platinum-etoposide containing regimen is recommended. Relevance Placental site trophoblastic tumor and ETT should be considered in the differential diagnosis in a reproductive age patient presenting with abnormal uterine bleeding and an elevated β-hCG after any antecedent pregnancy event. Target Audience Obstetricians and gynecologists, family physicians Learning Objectives After participating in this activity, the reader should be better able to identify the presentation and diagnosis of PSTT and ETT; explain how PSTT and ETT differ from the more common forms of GTN; and describe how surgical resection is the primary treatment modality for PSTT and ETT.

Background. Age and ethnicity are among several factors that influence overall survival (OS) in ovarian can-cer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy. Methods. Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three reg-imens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ ethnicity among the study participants. Results. One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 mi-nority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16-1.54). Non-Hispanic Black women had a 54% de-creased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26-0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59-0.90). Conclusions. Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups. (c) 2021 Published by Elsevier Inc.

This review summarizes the current evaluation and management of gestational trophoblastic disease, including evacuation of hydatidiform moles, surveillance after evacuation of hydatidiform mole and the diagnosis and management of gestational trophoblastic neoplasia. Most women with gestational trophoblastic disease can be successfully managed with preservation of reproductive function. It is important to manage molar pregnancies properly to minimize acute complications and to identify gestational trophoblastic neoplasia promptly. Current International Federation of Gynecology and Obstetrics guidelines for making the diagnosis and staging of gestational trophoblastic neoplasia allow uniformity for reporting results of treatment. It is important to individualize treatment based on their risk factors, using less toxic therapy for patients with low-risk disease and aggressive multiagent therapy for patients with high-risk disease. Patients with gestational trophoblastic neoplasia should be managed in consultation with an individual experienced in the complex, multimodality treatment of these patients.

This review summarizes the current evaluation and management of gestational trophoblastic disease, including evacuation of hydatidiform moles, surveillance after evacuation of hydatidiform mole and the diagnosis and management of gestational trophoblastic neoplasia. Most women with gestational trophoblastic disease can be successfully managed with preservation of reproductive function. It is important to manage molar pregnancies properly to minimize acute complications and to identify gestational trophoblastic neoplasia promptly. Current International Federation of Gynecology and Obstetrics guidelines for making the diagnosis and staging of gestational trophoblastic neoplasia allow uniformity for reporting results of treatment. It is important to individualize treatment based on their risk factors, using less toxic therapy for patients with low-risk disease and aggressive multiagent therapy for patients with high-risk disease. Patients with gestational trophoblastic neoplasia should be managed in consultation with an individual experienced in the complex, multimodality treatment of these patients.

Objective. To assess quality of life (QOL) in patients who developed lower-extremity lymphedema (LLE) after radical gynecologic cancer surgery on prospective clinical trial GOG 244. Methods. The prospective, national, cooperative group trial GOG-0244 determined the incidence of LLE and risk factors for LLE development, as well as associated impacts on QOL, in newly diagnosed patients undergoing surgery for endometrial, cervical, or vulvar cancer from 6/4/2012-11/17/2014. Patient-reported outcome (PRO) measures of QOL (by the Functional Assessment of Cancer Therapy [FACT)), body image, sexual and vaginal function, limb function, and cancer distress were recorded at baseline (within 14 days before surgery), and at 6, 12, 18, and 24 months after surgery. Assessments of LLE symptoms and disability were completed at the time of lower limb volume measurement. A linear mixed model was applied to examine the association of PROs/QOL with a Gynecologic Cancer Lymphedema Questionnaire (GCLQ) total score incremental change >= 4 (indicative of increased LLE symptoms) from baseline, a formal diagnosis of LLE (per the GCLQ), and limb volume change (LVC) >= 10%. Results. In 768 evaluable patients, those with a GCLQ score change >= 4 from baseline had significantly worse QOL (p < 0.001), body image (p < 0.001), sexual and vaginal function (p < 0.001), limb function (p < 0.001), and cancer distress (p < 0.001). There were no significant differences in sexual activity rates between those with and without LLE symptoms. Conclusions. LLE is significantly detrimental to QOL, daily function, and body image. Clinical intervention trials to prevent and manage this chronic condition after gynecologic cancer surgery are needed. (C) 2020 Elsevier Inc. All rights reserved.

Importance Vulvar intraepithelial neoplasia (VIN) represents an increasingly common, yet challenging diagnosis that shares many common risk factors with cervical intraepithelial neoplasia. However, unlike cervical intraepithelial neoplasia, effective screening and treatment strategies are much less defined for patients with VIN. Objective The objective of this article is to review the underlying risk factors leading to the development of VIN, identify special populations at risk for VIN, and outline acceptable treatment strategies. Evidence Acquisition This literature review was performed primarily using PubMed. Results Vulvar intraepithelial neoplasia can be separated into usual VIN (uVIN) and differentiated VIN (dVIN). The more common uVIN is related to underlying human papillomavirus infection, whereas dVIN occurs in the setting of other vulvar inflammatory conditions such as lichen sclerosis. Differentiated VIN carries a higher risk of progression to invasive malignancy. Extramammary Paget disease is a rare intraepithelial adenocarcinoma unrelated to uVIN and dVIN, although management is similar. Conclusions and Relevance Vulvar intraepithelial neoplasia is a preinvasive neoplasia of the vulva with few robust strategies for surveillance or management. Careful examination with targeted biopsy is warranted for suspicious lesions, and a combination of surgical and medical management can be tailored for individual patient needs. Target Audience Obstetricians and gynecologists, family physicians Learning Objectives After reading this article, the learner should be better able to evaluate the epidemiology and pathophysiology of VIN; assess risk for underlying malignancy, especially when comparing uVIN and dVIN; and compare different options for management of VIN including medical and surgical treatments.

BACKGROUND:Sentinel lymph node (SLN) biopsy is increasingly used in endometrial cancer staging; however, success of the technique is variable, and the learning curve needs to be better understood. Success is defined as identification of a SLN specimen containing nodal tissue in bilateral hemi-pelvises.OBJECTIVE:To assess the learning curve of surgeons at an academic institution in performing successful SLN mapping and biopsy during robotic staging for endometrial cancer.METHODS:After institutional review board approval, patients who underwent staging with robotic SLN mapping using indocyanine green at a single academic program between July 2012 and December 2017 were identified. Demographic, pathologic, and surgical data were retrospectively collected from the medical records. Descriptive and comparative statistics were performed. Surgeon rates of successful bilateral SLN mapping and removal of lymphoid-containing SLN specimens were compared. A logistic model was used to analyze the probability of successful SLN mapping and removal of lymph node-containing tissue with increasing number of procedures performed.RESULTS:Three hundred and seventeen patients met the eligibility criteria. Most had early-stage, low-grade endometrial cancer. A total of 194 (61%) patients had successful bilateral mapping. Among seven surgeons, a plateau in rates of successful bilateral mapping was achieved after 40 cases. No linear correlation was seen between the number of surgeries performed and the rate of removal of lymph node-containing tissue among surgeons. Each additional 10 procedures performed was associated with a 5% and an 11% increase in the odds of successful SLN mapping and removal of lymph node-containing tissue, respectively.DISCUSSION:The successful removal of lymph node-containing specimens appears to be a surgeon-specific phenomenon. The plateau of the learning curve for successful bilateral mapping seems to be reached at around 40 cases. These first 40 cases offer a time for auditing of individual rates of SLN mapping and removal to identify surgeons who may benefit from procedure-specific remediation.

Importance Physical activity has many important health benefits. There is also growing evidence that physical activity plays a role in the prevention and prognosis of multiple cancers, including gynecologic malignancies. Despite the many benefits of physical activity, the number of individuals meeting physical activity recommendations remains low. Objective To examine the role that physical activity plays in the prevention, treatment, and prognosis of gynecologic malignancies and to review the feasibility of physical activity interventions among gynecologic cancer survivors. Evidence Acquisition A PubMed search was performed using relevant terms to identify journal articles related to the proposed subject. The websites of multiple national and international organizations were also used to obtain up-to-date guidelines and recommendations. Results Physical activity appears to decrease the risk of ovarian, endometrial, and cervical cancer, with the strongest evidence of this association seen in endometrial cancer. Although the literature is scarce, participation in physical activity is feasible during active treatment for gynecologic cancers and may decrease symptom burden and increase chemotherapy completion rates. Gynecologic cancer survivors are motivated to increase physical activity, and lifestyle intervention programs are feasible and well received among this population. Conclusions and Relevance Health care providers caring for women with gynecologic malignancies must counsel patients regarding the importance of physical activity. This should include a discussion of the health benefits and, specifically, the cancer-related benefits. A personalized approach to physical activity intervention is essential.

•Angiosarcoma is a rare endothelial malignancy associated with radiation exposure.•Very rarely, angiosarcoma has been reported to arise in the uterine cervix.•We report the first case of post-radiation angiosarcoma of the cervix.

Objective: To explore whether patient-reported lymphedema-related symptoms, as measured by the Gynecologic Cancer Lymphedema Questionnaire (GCLQ), are associated with a patient-reported diagnosis of lymphedema of the lower extremity (LLE) and limb volume change (LVC) in patients who have undergone radical surgery, including lymphadenectomy, for endometrial, cervical, or vulvar cancer on Gynecologic Oncology Group (GOG) study 244. Methods: Patients completed the baseline and at least one post-surgery GCLQ and LVC assessment. The 20-item GCLQ measures seven symptom clusters-aching, heaviness, infection-related, numbness, physical functioning, general swelling, and limb swelling. LLE was defined as a patient self-reported LLE diagnosis on the GCLQ. LVC was measured by volume calculations based on circumferential measurements. A linear mixed model was fitted for change in symptom cluster scores and GCLQ total score and adjusted for disease sites and assessment time. Results: Of 987 eligible patients, 894 were evaluable (endometrial, 719; cervical, 136; vulvar, 39). Of these, 14% reported an LLE diagnosis (endometrial, 11%; cervical, 18%; vulvar, 38%). Significantly more patients diagnosed versus not diagnosed with LLE reported >= 4-point increase from baseline on the GCLQ total score (p < 0.001). Changes from baseline were significantly larger on all GCLQ symptom cluster scores in patients with LLE compared to those without LLE. An LVC increment of >10% was significantly associated with reported general swelling (p < 0.001), heaviness (p = 0.005), infection-related symptoms (p = 0.002), and physical function (p = 0.006). Conclusions: Patient-reported symptoms, as measured by the GCLQ discerned those with and without a patient-reported LLE diagnosis and demonstrated predictive value. The GCLQ combined with LVC may enhance our ability to identify LLE. (C) 2019 Elsevier Inc. All rights reserved.

Abstract Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab. Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS). Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57–0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50–0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66–0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59–0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40–0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25–0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations. Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777–83. ©2017 AACR.

STUDY OBJECTIVE:To confirm the safety and feasibility outcomes of robotic radical parametrectomy and pelvic lymphadenectomy and compare the clinicopathological features of women requiring adjuvant treatment with the historical literature.DESIGN:Retrospective cohort study and review of literature (Canadian Task Force classification II-2).SETTING:Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill.PATIENTS:All patients who underwent robotic radical parametrectomy with upper vaginectomy (RRPV), and pelvic lymphadenectomy for occult cervical cancer discovered after an extrafascial hysterectomy at our institution between January 2007 and December 2015.INTERVENTIONS:RRPV and pelvic lymphadenectomy for occult cervical cancer discovered after an extrafascial hysterectomy. We also performed a literature review of the literature on radical parametrectomy after occult cervical carcinoma.MEASUREMENTS AND MAIN RESULTS:Seventeen patients with invasive carcinoma of the cervix discovered after extrafascial hysterectomy underwent RRPV with bilateral pelvic lymphadenectomy. There were 2 intraoperative complications, including 1 bowel injury and 1 bladder injury. One patient required a blood transfusion of 2 units. Three patients underwent adjuvant treatment with chemoradiation with radiation-sensitizing cisplatin. One of these patients had residual carcinoma on the upper vagina, 1 patient had positive parametria and pelvic nodes, and 1 patient had positive pelvic lymph nodes. No patients experienced recurrence, and 1 patient died from unknown causes at 59.4 months after surgery. We analyzed 15 studies reported in the literature and found 238 women who underwent radical parametrectomy; however, no specific preoperative pathological features predicted outcomes, the need for adjuvant treatment, or parametrial involvement.CONCLUSION:RRPV is a feasible and safe treatment option. As reflected in the literature, RRPV can help avoid empiric adjuvant chemoradiation; however, no pathological features predict the need for adjuvant treatment after surgery.

Objective Cervical excision procedures are essential to the care of cervical dysplasia and malignancy. We sought to determine whether learner involvement in cervical excision procedures affects the quality of excision specimen. Materials and Methods A retrospective cohort study of cervical cancer patients diagnosed from July 1, 2000, to July 1, 2015, was performed. We included patients who had (1) a cervical excision procedure, either loop electrosurgical excision procedure or cold knife cone, and (2) pathologic information available. Primary outcome was the margin status of the specimen; secondary outcome was the size of the excision specimen including both width and depth. The exposure of interest was trainee participation, defined as resident physicians under the supervision of either a gynecologist or gynecologic oncologist. Descriptive statistics and general linear models were used for analysis. Results Ninety-four patients were identified. Overall, 58% (n = 54) of procedures were performed with trainee involvement. There was no difference in age, body mass index, or specimen width between trainee-performed and nontrainee-performed excisions. There was no significant difference in the status of margins with or without a trainee [44/57 (77%) and 29/37 (78%), respectively, p = .89]. There was a statistically significant difference in median specimen depth between trainee-performed and nontrainee-performed cases (15.4 mm vs 12 mm, p < .02). When adjusting for age, body mass index, excision type, indication, presence of trainee, and type of supervising physician, only the indication and type of excision were associated with greater depth of excision, (p < .01). Conclusions Trainee involvement in cervical excision procedures does not alter the quality of excision specimen.

Circulating tumor cells consist of phenotypically distinct subpopulations that originate from the tumor microenvironment. We report a circulating tumor cell dual selection assay that uses discrete microfluidics to select circulating tumor cell subpopulations from a single blood sample; circulating tumor cells expressing the established marker epithelial cell adhesion molecule and a new marker, fibroblast activation protein alpha, were evaluated. Both circulating tumor cell subpopulations were detected in metastatic ovarian, colorectal, prostate, breast, and pancreatic cancer patients and 90% of the isolated circulating tumor cells did not co-express both antigens. Clinical sensitivities of 100% showed substantial improvement compared to epithelial cell adhesion molecule selection alone. Owing to high purity (>80%) of the selected circulating tumor cells, molecular analysis of both circulating tumor cell subpopulations was carried out in bulk, including next generation sequencing, mutation analysis, and gene expression. Results suggested fibroblast activation protein alpha and epithelial cell adhesion molecule circulating tumor cells are distinct subpopulations and the use of these in concert can provide information needed to navigate through cancer disease management challenges.

• Granulocyte-colony stimulating factor (GCSF) secretion by gynecologic tumors is rare. • Elevations in serum GCSF can be seen in the absence of tumor GSCF secretion. • Extreme leukocytosis is associated with autocrine tumor growth and poor prognosis.

Objective Open radical hysterectomy followed by adjuvant radiation for cervical cancer has been associated with significant rates of morbidity. Radical hysterectomy is now often performed robotically. We sought to examine if the robotic platform decreased the morbidity associated with radical hysterectomy followed by adjuvant radiation. Materials/Methods A retrospective cohort of patients with cervical cancer undergoing radical hysterectomy from 1995 to 2013 was evaluated. Complications were assessed using electronic record review and graded. χ 2 tests and Student t tests were used for analysis. Results Overall, 243 patients underwent radical hysterectomy for cervical cancer. Surgical approach was 43% open and 57% robotic. Eighty-three patients (34.2%) required adjuvant radiation. Overall, radical hysterectomy plus adjuvant radiation was associated with increased risk of complication (29%) compared to radical hysterectomy alone (7%) ( P < 0.001). Complications included lymphedema (n = 18), bowel-associated complications (n = 10), and urinary complications (n = 7). There was no difference in time to initiation of radiation between open and robotic surgery (43 vs 47 days; P = 0.33). There was no difference in grade 2/3 complications in patients receiving adjuvant radiation between open and robotic surgery (27.5% vs 27.9%; P = 0.97). Patients undergoing open surgery followed by radiation experienced a trend toward increased adhesion-related complications, such as bowel obstruction and ureteral stricture (10% vs 2.3%; P = 0.19); whereas patients undergoing robotic surgery followed by radiation experienced a trend toward increased lymphedema (19% vs 8%; P = 0.20). Conclusions We found no difference in long-term complications between patients who underwent robotic surgery compared to open radical hysterectomy with adjuvant radiation. There may be fewer adhesion-related complications with robotic surgery. However, as many radiation-related complications occur at later time points, continued follow-up to evaluate for potential differences between the 2 groups is necessary.

Importance The role of lymph node dissection in early-stage endometrial cancer is highly debated, but staging and prognosis are dependent on knowledge of lymph node metastasis.Objective We sought to review the available data on the use of lymph node assessment in presumed early-stage endometrial cancer.Evidence Acquisition A comprehensive literature review was performed using MEDLINE, the Cochrane Collaborative Database, and PubMed.Results There is limited retrospective data that suggest a therapeutic benefit to lymphadenectomy. Prospective randomized trials have not shown a benefit to lymphadenectomy in low-risk patients, but found significant morbidity in patients undergoing lymphadenectomy. Selective lymph node assessment should be used in low-risk endometrial cancer. Sentinel lymph node assessment is emerging as a potential strategy for lymph node assessment.Conclusions and Relevance Selective use of lymphadenectomy in early-stage endometrial cancer can reduce the morbidity associated with lymph node dissection without compromising clinical outcomes. Multiple strategies are available including sentinel lymph nodes and risk factor based lymphadenectomy.Target Audience Gynecologic Oncologists.Learning Objectives After participating in this activity, physicians should be better able to describe the risk factors for lymph node metastasis in endometrial cancer; discuss the modalities of lymph node evaluation available; and describe the incidence of lymphedema after lymphadenectomy.