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Purpose: To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus., Methods: A literature search and prospectively defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence., Results: The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs., Recommendations: All women diagnosed with epithelial ovarian cancer should have germline genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic BRCA1/2 variant, somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in BRCA1/2 genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis.

Purpose: No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor., Patients and Methods: Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed., Results: Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy., Conclusion: Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease., (© 2015 by American Society of Clinical Oncology.)

Purpose: To define a gene expression profile of BRCAness that correlates with chemotherapy response and outcome in epithelial ovarian cancer (EOC)., Methods: A publicly available microarray data set including 61 patients with EOC with either sporadic disease or BRCA(1/2) germline mutations was used for development of the BRCAness profile. Correlation with platinum responsiveness was assessed in platinum-sensitive and platinum-resistant tumor biopsy specimens from six patients with BRCA germline mutations. Association with poly-ADP ribose polymerase (PARP) inhibitor responsiveness and with radiation-induced RAD51 foci formation (a surrogate of homologous recombination) was assessed in Capan-1 cell line clones. The BRCAness profile was validated in 70 patients enriched for sporadic disease to assess its association with outcome., Results: The BRCAness profile accurately predicted platinum responsiveness in eight out of 10 patient-derived tumor specimens, and between PARP-inhibitor sensitivity and resistance in four out of four Capan-1 clones. [corrected] When applied to the 70 patients with sporadic disease, patients with the BRCA-like (BL) profile had improved disease-free survival (34 months v 15 months; log-rank P = .013) and overall survival (72 months v 41 months; log-rank P = .006) compared with patients with a non-BRCA-like (NBL) profile, respectively. The BRCAness profile maintained independent prognostic value in multivariate analysis, which controlled for other known clinical prognostic factors., Conclusion: The BRCAness profile correlates with responsiveness to platinum and PARP inhibitors and identifies a subset of sporadic patients with improved outcome. Additional evaluation of this profile as a predictive tool in patients with sporadic EOC is warranted.

Purpose: The prognostic significance of germline BRCA1 and BRCA2 mutations in Jewish patients with pancreatic adenocarcinoma (PAC) is unknown. Our objective was to define the prevalence of BRCA1 and BRCA2 in an unselected group of Jewish patients and to compare the clinical characteristics and overall survival (OS) of patients with resected BRCA mutation-associated PAC to PAC patients without mutations., Patients and Methods: Jewish patients with PAC resected between January 1986 and January 2004 were identified. DNA was extracted from the archived material, anonymized, and genotyped for founder mutations in BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT). Standard two-sided statistical tests were utilized., Results: Of the 187 Jewish patients who underwent resection for PAC, tissue was available for 145 patients. Eight subjects (5.5%) had a BRCA founder mutation (two with BRCA1 [1.3%], six with BRCA2 [4.1%]). The BRCA2 founder mutation was identified in 4.1% of patients with pancreatic adenocarcinoma compared with only 1.1% of cancer-free Washington, DC,-area controls (4.1% v 1.1%; P = .007; odds ratio, 3.85; 95% CI, 2.1 to 10.8). Patients with and without BRCA1 or BRCA2 mutations did not differ in age (mean, 66 v 73 years; P = .6) or other clinicopathologic features. OS was not significantly different (median, 6 v 16 months; P = .35). A previous cancer was reported by 24% (35 of 145) of patients with the most common sites being breast cancer (9 of 35; 74%) and prostate cancer (8 of 35; 23%)., Conclusion: Founder mutations for BRCA1 and BRCA2 were identified in 5.5% of Ashkenazi patients operated on for PAC. BRCA2 mutations were more prevalent than documented by population studies. Consistent with previous reports, BRCA2 mutations are associated with an increased risk of PAC.

Purpose: To compare surgeons' operative assessments of residual disease (RD) to those identified on postoperative computed tomography (CT) scans in patients with advanced ovarian carcinoma reported to have undergone optimal primary cytoreduction., Patients and Methods: All patients at one of two institutions, who were scheduled to have primary surgery for presumed advanced ovarian cancer, were asked to consent to a postoperative CT scan if cytoreduction to < or = 1 cm RD was reported. CT scan findings were graded using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant)., Results: From January 2001 to September 2006, 285 patients were enrolled. A total of 78 patients met eligibility criteria and had postoperative CT scans. In 41 cases (52%), postoperative scan findings correlated with the surgical report of no RD more than 1 cm, and in seven cases (9%), the CT findings were indeterminate. In 10 cases (13%), more than 1 cm RD was noted by the radiologist as probably malignant, and in 20 cases (26%), definitely malignant. In these 30 cases, the radiologically reported median largest residual mass was 1.9 cm (range, 1.1 to 5.1), with RD more than 1 cm reported most commonly in the right upper quadrant (15 patients [50%]) and central abdomen (nine patients [30%])., Conclusion: There was only a 52% correlation between surgeons' assessments and postoperative CT scan evaluations of RD in patients reported to have undergone optimal cytoreduction. Further study is required to determine whether this lack of correlation is due to rapid interval tumor regrowth, RD underestimated by the surgeons, and/or overestimated by the radiologists; and to determine the clinical implications of these discrepancies.

Purpose: Defective DNA mismatch repair is commonly present in sporadic manifestations of gastrointestinal, endometrial, and other cancers. The pathognomonic molecular manifestation of this repair defect is microsatellite instability (MSI). Here, we test the hypothesis that MSI predicts the clinicopathologic features of endometrial carcinoma., Patients and Methods: A retrospective cohort of 473 patients treated for endometrial carcinoma at this institution was identified. All cases were reviewed by a gynecologic pathologist, and clinical information was abstracted from medical records. Using consensus criteria, DNA samples from nontumor and tumor tissue pairs were genotyped for MSI. Associations between MSI status and pathologic and clinical variables were assessed., Results: Ninety-three (20%) of 473 tumors were MSI+. In the MSI+ tumor group compared with the MSI- tumor group, the proportion of advanced compared with early-stage tumors was higher (92% v 81%; P = .01), as was the proportion of tumors of endometrioid compared with nonendometrioid histologic subtype (94% v 23%; P = .001), and the proportion of tumors with myometrial invasion compared with those with none (92% v 78%; P = .01). By multivariate analyses, disease-free survival (hazard ratio, 0.3; 95% CI, 0.2 to 0.7) and disease-specific survival (hazard ratio, 0.3; 95% CI, 0.1 to 0.8) were significantly improved in patients with MSI+ tumors., Conclusion: In endometrial carcinoma, the presence of MSI was independently associated with a more favorable clinical outcome.

Purpose: We investigated whether tumor tissue obtained at diagnosis expresses a specific gene profile that is predictive of findings at second-look surgery in patients with epithelial ovarian cancer (EOC)., Patients and Methods: Tumor tissue obtained at the time of diagnosis was profiled with oligonucleotide microarrays. Class prediction analysis was performed in a training set of 24 patients who had undergone a second-look procedure. The resultant predictive signature was then tested on an independent validation set comprised of 36 patients., Results: A 93-gene signature referred to as the Chemotherapy Response Profile (CRP) was identified through its association with pathologic complete response. When applied to a separate validation set, the CRP distinguished between patients with unfavorable versus favorable overall survival (median 41 months v not yet reached, respectively, log-rank P = .007), with a median follow-up of 52 months. The signature maintained independent prognostic value in multivariate analysis, controlling for other known prognostic factors such as age, stage, grade, and debulking status. There was no genetic overlap between the CRP and our previously described Ovarian Cancer Prognostic Profile (OCPP), which demonstrated similar prognostic value. The combination of the CRP and OCPP yielded better prognostic discrimination then either profile alone. Genes present in the CRP include BAX, a proapoptotic protein previously associated with chemotherapy response in ovarian cancer., Conclusion: Identification of a gene expression profile based on pathologic response in EOC provides independent prognostic information and offers potential insights into the mechanism of drug resistance. Efforts to identify a more tailored profile using selected genes from both the CRP and OCPP are underway.

Purpose: Currently available clinical and molecular prognostic factors provide an imperfect assessment of prognosis for patients with epithelial ovarian cancer (EOC). In this study, we investigated whether tumor transcription profiling could be used as a prognostic tool in this disease., Methods: Tumor tissue from 68 patients was profiled with oligonucleotide microarrays. Samples were randomly split into training and validation sets. A three-step training procedure was used to discover a statistically significant Kaplan-Meier split in the training set. The resultant prognostic signature was then tested on an independent validation set for confirmation., Results: In the training set, a 115-gene signature referred to as the Ovarian Cancer Prognostic Profile (OCPP) was identified. When applied to the validation set, the OCPP distinguished between patients with unfavorable and favorable overall survival (median, 30 months v not yet reached, respectively; log-rank P = .004). The signature maintained independent prognostic value in multivariate analysis, controlling for other known prognostic factors such as age, stage, grade, and debulking status. The hazard ratio for death in the unfavorable OCPP group was 4.8 (P = .021 by Cox proportional hazards analysis)., Conclusion: The OCPP is an independent prognostic determinant of outcome in EOC. The use of gene profiling may ultimately permit identification of EOC patients appropriate for investigational treatment approaches, based on a low likelihood of achieving prolonged survival with standard first-line platinum-based therapy.

Purpose: The aims of this study were to determine the incidence of BRCA mutations among Ashkenazi Jewish patients with fallopian tube carcinoma (FTC) or primary peritoneal carcinoma (PPC), to study the clinicopathologic features of these cancers, and to estimate the risks of these cancers in association with a BRCA mutation., Patients and Methods: A retrospective review at two institutions identified 29 Jewish patients with FTC and 22 Jewish patients with PPC. These patients were genotyped for the three Ashkenazi Jewish BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). Surgical and pathologic information, family history, and survival data were obtained from hospital records. All statistical tests were two sided., Results: Germline BRCA mutations were identified in five of 29 patients with FTC (17%) and nine of 22 patients with PPC (41%). Mutation carriers had a younger mean age at diagnosis than patients without a mutation (60 v 70 years; P =.002). The overall median survival was 148 months for mutation carriers and 41 months for patients without a mutation (P =.04). For BRCA mutation carriers, the lifetime risks of FTC and PPC were 0.6% and 1.3%, respectively., Conclusion: Substantial proportions of Ashkenazi Jewish patients with FTC or PPC are BRCA mutation carriers. Patients with BRCA-associated FTC or PPC are younger at diagnosis and have improved survival compared with patients without a BRCA mutation. Although the lifetime risks of FTC or PPC for patients with BRCA heterozygotes are greater than those for the general population, the absolute risks seem relatively low.