Molecular testing for endometrial cancer: An SGO clinical practice statement.

The Cancer Genome Atlas publication first described the genomic landscape of endometrial cancer and characterized these cancers into four molecular subtypes with different prognoses. The Proactive Molecular Classifier for Endometrial Cancer was developed to more easily and inexpensively classify endometrial cancers into four similar molecular subtypes which are termed POLE, mismatch repair deficient, p53 abnormal and no specific molecular profile. Beyond these four subtypes, other molecular biomarkers may influence clinical behavior and response to targeted therapies and include beta-catenin, Her2 amplification, PI3K/mTOR/AKT alterations, L1CAM, hormone receptor expression, tumor mutational burden, and ARID1A. There are numerous clinical trials exploring treatment escalation and de-escalation within the four molecular subtypes as well as matching targeted therapies to specific mutational or biomarker profiles. All endometrial cancers should undergo basic molecular classification that includes assessment of mismatch repair status. POLE and p53 status are prognostic and may become actionable in the future. Clinicians who treat patients with endometrial cancer should understand the role of molecular classification in guiding treatment. The goal of this practice statement is to guide appropriate testing, interpretation, and application of molecular information in endometrial cancer.

Patterns of care and outcomes of risk reducing surgery in women with pathogenic variants in non-BRCA and Lynch syndrome ovarian cancer susceptibility genes.

OBJECTIVES: Guidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. METHODS: Women with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000-9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. RESULTS: 26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. CONCLUSIONS: No occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.

Breast cancer surveillance following ovarian cancer in BRCA mutation carriers.

OBJECTIVES: BRCA 1 or 2 mutation carriers have increased risk of developing breast cancer (BC) and serous epithelial ovarian cancer (EOC). The incidence of BC over time after EOC is unknown. Optimal BC surveillance for BRCA mutation carriers following EOC has not been defined. METHODS: A multi-institutional retrospective chart review was performed. Patients with BRCA -associated EOC diagnosed between 1996 and 2016 were followed for an average of 80 months. Women with previous bilateral mastectomy were excluded; women with prior BC and an intact breast were included. Descriptive statistics, Chi Square, and univariate survival analysis were performed. RESULTS: 184 patients with BRCA -associated EOC were identified. Eighteen (10%) were diagnosed with BC a median of 48 months following EOC. Two (1%) with prior BC developed contralateral BC and 16 (9%) developed primary BC. The majority of BC (55%) was diagnosed 3 years following EOC. The 3-, 5- and 10-year incidence of BC was 5.6%, 9.5% and 33.3%. Annual mammography was performed in 43% and MRI in 34%. Twenty-eight (15%) women underwent risk-reducing mastectomy (RRM). There was no statistically significant difference in BC screening between women with, and without, a prior BC. BC was most commonly detected on mammogram. Three (17%) women had occult BC at the time of RRM. Nine (50%) had DCIS, and 8 (44%) had stage I/II BC. Median 5- and 10-year survival was 68% and 43% and was comparable between groups. CONCLUSIONS: Ten percent of women developed BC after EOC. The incidence of BC following EOC in BRCA carriers increases over time, and surveillance is recommended given their enhanced survival of EOC. Timely genetic testing for women with EOC is imperative to better triage BC screening resources and treatment.

Latest clinical evidence of maintenance therapy in ovarian cancer.

PURPOSE OF REVIEW: To summarize the data supporting the use of maintenance therapy in ovarian cancer treatment. RECENT FINDINGS: Since December 2016, the United States Food and Drug Administration has approved four drugs for six different ovarian cancer maintenance indications based on the results of clinical trials demonstrating efficacy and tolerability. These include antiangiogenesis and poly (adenosine diphosphate-ribose) inhibitors (PARP inhibitors). Four drugs are approved for use in maintenance therapy for recurrent ovarian cancer, including bevacizumab (GOG-0213 and OCEANS), niraparib (NOVA), olaparib (Study 19 and SOLO2) and rucaparib (ARIEL3). Two drugs are approved for use in maintenance therapy in newly diagnosed ovarian cancer, including bevacizumab (GOG-0218) and olaparib (SOLO1). New data were reported at the European Society for Medical Oncology Congress in October 2019 that may lead to the approval of additional strategies in front-line maintenance, including the use of niraparib (PRIMA), veliparib (VELIA) and bevacizumab + olaparib (PAOLA). SUMMARY: The landscape of maintenance treatment options for ovarian cancer has been rapidly expanding and continues to evolve as new data emerge. Currently approved strategies include antiangiogenesis and PARP inhibitor treatments.

Cancer Genetic Counseling and Testing: Perspectives of Epithelial Ovarian Cancer Patients and Gynecologic Oncology Healthcare Providers.

Multi-gene panel testing has expanded the genetic information available to cancer patients. The objective was to assess provider behaviors and attitudes and patient knowledge and attitudes towards genetic counseling and testing. An online survey was distributed to Society of Gynecologic Oncology members and a written questionnaire was administered to patients diagnosed with epithelial ovarian cancer at a tertiary care referral center. Most of the 233 (18% response rate) provider respondents were gynecologic oncologists. Access to a genetic counselor was reported by 87% of providers and 55% deferred all testing to genetic counselors. Of 53 ovarian cancer patient respondents, two-thirds had previously seen a genetic counselor or undergone testing. Patients' attitudes about genetic counseling and/or testing were favorable with respect to themselves (70-81%) and their family members (94%). Less than 25% of patients indicated worrying about health care discrimination, lack of privacy, or high cost. Seventy-seven percent of patients demonstrated a desire to obtain genetic information even if the results were not currently actionable, and 20% of providers stated they test for only those genes with guideline-supported actionable results. Provider practice differences were identified in screening and prevention strategies for patients with deleterious non-BRCA mutations and variants of uncertain significance. The variation in clinical interpretation of results associated with poorly defined cancer risks signals a need for more comprehensive training and guidelines to ensure access to evidence-based care.

Evaluation of venous thrombosis and tissue factor in epithelial ovarian cancer.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) and high grade serous ovarian cancer (HGSOC) are associated with the highest risk of VTE among patients with epithelial ovarian cancer (EOC). Tissue factor (TF) is a transmembrane glycoprotein which can trigger thrombosis. We sought to evaluate if there is an association between VTE and tumor expression of tissue factor (TF), plasma TF, and microvesicle TF (MV TF) activity in this high-risk population. METHODS: We performed a case-control study of OCCC and HGSOC patients with and without VTE. 105 patients who underwent surgery at a tertiary care center between January 1995 and October 2013 were included. Plasma TF was measured with an enzyme-linked immunosorbent assay. A TF-dependent Factor Xa generation assay was used to measure MV TF activity. Immunohistochemical (IHC) analysis was performed to evaluate tumor expression of TF. RESULTS: 35 women with OCCC or HGSOC diagnosed with VTE within 9months of surgery were included in the case group. Those with VTE had a worse OS, p<0.0001, with a greater than three-fold increase in risk of death, HR 3.33 (CI 1.75-6.35). There was no significant difference in median plasma TF level or MV TF activity level between patients with and without VTE. OCCC patients had greater expression of TF in their tumors than patients with HGSOC, p<0.0001. CONCLUSIONS: TFMV activity and plasma TF level were not predictive of VTE in this patient population. Given the extensive expression of TF in OCCC tumors, it is unlikely IHC expression will be useful in risk stratification for VTE in this population.

Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma - A multi-institutional cohort.

OBJECTIVES: To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS: Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS: Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION: Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort.

Occult and subsequent cancer incidence following risk-reducing surgery in BRCA mutation carriers.

OBJECTIVE: To report the frequency and features of occult carcinomas and the incidence of subsequent cancers following risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers. METHODS: 257 consecutive women with germline BRCA mutations who underwent RRSO between January 1, 2000 and December 31, 2014 were identified in an Institutional Review Board approved study. All patients were asymptomatic with normal physical exams, CA 125 values, and imaging studies preoperatively, and had at least 12months of follow-up post-RRSO. All patients had comprehensive adnexal sectioning performed. Patient demographics and clinico-pathologic characteristics were extracted from medical and pathology records. RESULTS: The cohort included 148 BRCA1, 98 BRCA2, 6 BRCA not otherwise specified (NOS), and 5 BRCA1 and 2 mutation carriers. Occult carcinoma was seen in 14/257 (5.4%) of patients: 9 serous tubal intraepithelial carcinomas (STIC), 3 tubal cancers, 1 ovarian cancer, and 1 endometrial cancer. Three patients (1.2%) with negative pathology at RRSO subsequently developed primary peritoneal serous carcinoma (PPSC), and 2 of 9 patients (22%) with STIC subsequently developed pelvic serous carcinoma. 110 women (43%) were diagnosed with breast cancer prior to RRSO, and 14 of the remaining 147 (9.5%) developed breast cancer following RRSO. Median follow-up of the cohort was 63months. CONCLUSION: In this cohort, 5.4% of asymptomatic BRCA mutation carriers had occult carcinomas at RRSO, 86% of which were tubal in origin. The risk of subsequent PPSC for women with benign adnexa at RRSO is low; however, the risk of pelvic serous carcinoma among women with STIC is significantly higher.

Recurrence and risk of progression to lower genital tract malignancy in women with high grade VAIN.

OBJECTIVE: High-grade vaginal intraepithelial neoplasia (VAIN) II-III has a variable clinical course. Due to the rarity of VAIN, existing data on the efficacy of treatment, risk of recurrence and progression to carcinoma is limited. Our objective was to evaluate predictors of recurrent disease and describe the risk of progression to carcinoma. METHODS: Under an IRB-approved protocol 42 patients with biopsy-proven VAIN II-III from 1995 to 2015 were retrospectively identified. Demographics, treatment, and clinical course were abstracted from medical records. Patients were followed with semi-annual colposcopy and biopsies at physician discretion. Standard statistical analyses were applied. RESULTS: Median patient age was 58years old (range 20-81). Median follow-up time was 45months (range 9-195). Management included excision (31%), laser ablation (33%), topical agents (19%), and observation (10%), with the following rates of recurrence: 38%, 43%, 75%, and 50% (p=0.26). 20 patients (48%) had recurrent or persistent disease during treatment follow-up. No specific primary treatment was significantly more effective in preventing recurrence. Recurrence of VAIN II-III occurred at a median of 17.4months (7-78months) from time of initial diagnosis. Five (12%) patients developed invasive cancer of the lower genital tract. Median time to cancer diagnosis was 64months (30 to 101months). CONCLUSIONS: Patients with VAIN II-III are at high risk of recurrence and progression, suggesting the need for ongoing evaluation with cytology and comprehensive colposcopy by a skilled specialist. There were no clear risk factors or histopathologic criteria which predicted recurrence or progression to cancer.

Leveraging DNA repair deficiency in gynecologic oncology.

PURPOSE OF REVIEW: The review discusses DNA repair deficiencies in ovarian cancer and how this has become the target for poly (ADP-ribose) polymerase (PARP) inhibition as a successful therapeutic strategy. RECENT FINDINGS: Hereditary ovarian cancers arise from germline mutations in BRCA1, BRCA2, or other important genes in the DNA repair process of homologous recombination. Sporadic ovarian cancers can also acquire a phenotype of homologous recombination deficiency through various other mechanisms. Recent studies have found the class of drugs called PARP inhibitors to selectively target ovarian cancers with homologous recombination deficiency. There are eight PARP inhibitors in various phases of clinical development with four being actively studied in phase III trials in ovarian cancer. In December 2014, the first-in-human PARP inhibitor olaparib was approved for ovarian cancer patients with two different clinical indications in Europe and the United States. SUMMARY: Ovarian cancer has become a model for the successful translation of targeted therapy against DNA repair deficiencies in cancer.

Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy.

Almost exactly 20 years after their discovery, the BRCA1 and BRCA2 genes have become the target of the first "personalized" therapy available for patients with ovarian cancer. In December 2014, a poly(ADP-ribose) polymerase (PARP) inhibitor was granted expedited approved by the United States Food and Drug Administration for use in advanced ovarian cancer patients with germline BRCA1/2 mutations who have received three or more prior lines of chemotherapy. This review article will discuss (1) the BRCA1 and BRCA2 genes within the larger context of homologous recombination deficiency; (2) the advances in our understanding of hereditary cancer risk and the dramatic shifts that have occurred in the genetic testing landscape since the landmark 2013 Supreme Court ruling invalidating patents on BRCA1 and BRCA2 genetic testing; and (3) the clinical trials leading to the approval of olaparib, the first in human PARP inhibitor.

Too much, too late: Aggressive measures and the timing of end of life care discussions in women with gynecologic malignancies.

OBJECTIVE: This study describes the patterns of end of life (EOL) discussions and their impact on the use of aggressive measures in women with terminal gynecologic malignancies at a single institution. METHODS: An IRB-approved retrospective chart review identified 136 patients who died of gynecologic cancer between 2010 and 2012 with at least one interaction with their oncologists in the last 6 months of life. Aggressive measures were defined as chemotherapy within the last 14 days of life, emergency department (ED) visits, hospital and intensive care unit (ICU) admissions within the last 30 days of life, and inpatient deaths. The frequency and timing of EOL conversations were recorded. Utilization of hospice care was also described. RESULTS: In the last 30 days of life, 54 (40%) patients were evaluated in the ED, 67 (49%) were admitted into hospital, and 16 (12%) were admitted to the ICU. Thirteen patients (10%) had chemotherapy in the last 14 days of life. Ninety-seven (71%) patients had a documented EOL conversation, eighteen (19%) as outpatients, and 79 (81%) as inpatients. Thirty (22%) patients died in the hospital. At the time of death, 55 (40%) patients were enrolled in outpatient hospice care. The mean amount of time in hospice was 28 days. CONCLUSIONS: End of life care discussions rarely occurred in the outpatient setting or >30 days before death. Inpatient encounters led to discussions about hospice and code status. Evaluation in the ED frequently resulted in escalation of care. Earlier EOL care discussions resulted in less aggressive measures.

Thrombocytosis at secondary cytoreduction for recurrent ovarian cancer predicts suboptimal resection and poor survival.

OBJECTIVES: A growing body of evidence supports a role for thrombocytosis in the promotion of epithelial ovarian cancer biology. However, studies have only linked preoperative platelet count at time of initial cytoreductive surgery to clinical outcome. Here, we sought to determine the impact of elevated platelet count at time of secondary cytoreductive surgery (SCS) for recurrent disease. METHODS: Under an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. We reviewed clinical, laboratory, and pathologic records from this retrospective cohort. The data was analyzed using the chi-squared, Fisher's exact, Cox proportional hazards, and Kaplan-Meier tests. We defined thrombocytosis as a platelet count ≥ 350 × 10(9)/L and optimal resection at SCS as microscopic residual disease. RESULTS: Thirteen of 107 women (12%) with recurrent ovarian cancer had thrombocytosis prior to SCS. Preoperative thrombocytosis at SCS was associated with failure to undergo optimal resection (p=0.0001). Women with preoperative thrombocytosis at time of SCS demonstrated shorter overall survival (33 months) compared to those with normal platelet counts (46 months, p=0.004). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p=0.025) after controlling for age at SCS (p=0.90), disease free interval from primary treatment (0.06), and initial stage of disease (0.66). CONCLUSIONS: Elevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. These data provide further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology.

Ovarian cancer think tank: An overview of the current status of ovarian cancer screening and recommendations for future directions.

Early diagnosis and screening of ovarian cancer remain significant challenges to improving patient outcomes. There is an urgent need to implement both established and modern strategies to address the "early detection" conundrum, especially as new research continues to uncover the complexities of the disease. The discussion provided is the result of a unique research conference focused on reviewing early detection modalities and providing insight into future approaches.

Venous thromboembolism during primary treatment of ovarian clear cell carcinoma is associated with decreased survival.

OBJECTIVES: To determine the impact of venous thromboembolism (VTE) during primary treatment of ovarian clear cell carcinoma (OCCC) on survival. METHODS: After Institutional Review Board approval, 74 cases of OCCC were retrieved from our pathology files. Clinical and pathological data were obtained by medical record and pathology review. Standard statistical analyses were performed. RESULTS: Among 74 patients with OCCC, VTE was diagnosed in 11 (15%) during primary treatment and 7 (9%) at time of cancer recurrence. 56 (76%) patients never developed VTE. Patients with VTE during OCCC primary treatment had shorter progression-free survival (PFS) and overall survival (OS) than OCCC patients without VTE (median PFS 11 vs. 76 months, p=0.01, median OS 19 vs. 90 months, p=0.001). Patients with VTE during OCCC primary treatment had a 3.9-fold increase in risk of recurrence (p=0.007) and a 6.3-fold increase in risk of death (p<0.001). After controlling for cancer stage, VTE during OCCC primary treatment remained an independent prognostic factor for death (HR=3.6, p=0.005). No patient died of VTE. CONCLUSIONS: VTE during OCCC primary treatment is associated with a significantly higher risk of cancer recurrence and death. This increased risk is not attributable to VTE-related mortality and raises the possibility that a paracrine circuit involving thrombosis might contribute to a more aggressive tumor biology.

Post treatment surveillance of type II endometrial cancer patients.

OBJECTIVE: There are few studies analyzing surveillance for Type II endometrial cancer recurrence. Our objective was to determine the types of post treatment surveillance tests performed in our institution and the efficacy of these tests in detecting recurrence in type II endometrial cancer patients. METHODS: One hundred and thirty six cases of type II endometrial cancers at Cedars-Sinai Medical Center from January of 2000 to August of 2011 were identified and 106 patients met inclusion criteria. Medical charts were reviewed for surveillance methods and number of follow up visits. For patients who underwent a recurrence of disease, the surveillance method utilized for detection was documented. RESULTS: Forty-seven of the 106 (44%) patients developed recurrence with a mean progression free interval of 11 months. All patients had a history and physical at each surveillance visit, 78% had Pap testing, 57% had CA-125 levels drawn, 59% had CT (computed tomography) scans done, 6% had PET (positron emission tomography) scans done for surveillance. In our cohort, recurrence was detected by symptoms in 16, by CA-125 in 11, by physical exam in 7, by CT scan in 12, and by PET scan in one patient. No patients had recurrence detected by vaginal cytology. CONCLUSIONS: Although performed in the majority of patients, Pap testing did not detect any recurrences within this cohort. History and physical exam detected the most recurrences. These findings suggest that educating patients about relevant symptoms and performing thorough follow-up exams may be the most important aspects of detecting type II endometrial cancer recurrence.

Xeroderma pigmentosum complementation group C single-nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression-free survival in advanced ovarian cancer.

BACKGROUND: The nucleotide excision repair (NER) pathway is the principal DNA repair pathway for removing bulky platinum DNA adducts. Suboptimal DNA repair may lead to improved response to platinum agents. The objective of this study was to determine whether single-nucleotide polymorphisms (SNPs) in NER pathway genes could be markers of platinum response in ovarian cancer. METHODS: The authors identified patients with advanced-stage, papillary serous ovarian cancer who underwent primary cytoreductive surgery followed by platinum-based chemotherapy. DNA was isolated from peripheral blood specimens. Twenty-two SNPs within NER genes (xeroderma pigmentosum [XP] complementation group A [XPA], XPB/excision repair cross-complementing rodent repair deficiency, complementation group 3 [ERCC3], XPC, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5, Cockayne syndrome group B protein [CSB]/ERCC8, ERCC1) were genotyped using polymerase chain reaction analysis. RESULTS: In total, 139 patients with stage III and IV papillary serous ovarian cancer were genotyped. The XPC (reference SNP 3731108 [rs3731108]) adenosine-guanine (AG)/AA genotype versus the GG genotype was associated with prolonged a progression-free survival (PFS) of 21.3 months versus 13.4 months (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.42-0.95; P = .03). The XPC (rs1124303) guanosine-thymidine (GT)/GG genotype versus the TT genotype was associated with a prolonged PFS of 22.8 months versus 14.9 months (HR, 0.47; 95% CI, 0.24-0.94; P = .03). The XPC poly(AT) (PAT) (-/+)/(-/-) genotype versus the (+/+) genotype was associated with a prolonged PFS of 17 months versus 11.6 months (HR, 0.56; 95% CI, 0.36-0.89; P = .01). The XPF/ERCC4 (rs12926685) cytidine-thymidine (CT)/CC genotype versus the TT genotype was associated with a prolonged PFS of 16.7 months versus 12.4 months (HR, 0.63; 95% CI, 0.41-0.95; P = .03). On multivariate analysis adjusting for breast cancer (BRCA) gene and cytoreductive surgery status, the XPC SNPs remained significantly associated with prolonged PFS. CONCLUSIONS: The current results indicated that XPC is a key component of the NER pathway that participates in DNA damage repair. SNPs in the XPC gene may represent novel markers of ovarian cancer response to platinum-based chemotherapy.

Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy.

OBJECTIVE: To identify clinical and pathologic predictors of response to progestin treatment in premenopausal women with complex atypical hyperplasia (CAH) and Grade 1 endometrial adenocarcinoma (Grade 1 EA). METHODS: Forty premenopausal patients with Grade 1 EA or CAH who underwent progestin therapy for a minimum of 8 weeks were retrospectively identified. Patient characteristics and histopathologic features of pretreatment and first follow-up endometrial specimens were evaluated as predictors of resolution, defined as absence of hyperplasia or carcinoma. RESULTS: Kaplan-Meier analysis indicated 63% resolution at 18 months of follow-up. Multivariate classification analysis showed that resolution rates were higher in individuals with a low pre-treatment qualitative abnormal architecture score and a BMI <35 (Standardized Resolution Ratio (SRR)=1.48, p=0.03). The diagnosis of benign endometrium or simple hyperplasia on the first follow-up specimen was highly predictive of resolution (SRR=2.25, p=0.002). Resolution rates were lower among subjects with a high pre-treatment qualitative abnormal architecture score (SRR=0.37, p<0.03) and lowest in subjects whose first follow-up specimen showed persistent complexity, atypia, or carcinoma with adjacent stromal decidualization (SRR=0.24, p=0.002). CONCLUSIONS: Clinical and pathologic parameters can predict response to progestin therapy in premenopausal women with CAH and Grade 1 EA. A low likelihood of resolution is predicted by an unfavorable pre-treatment architectural score and lack of pathological response in the first specimen, despite adjacent stromal decidualization.

Cost-effectiveness of hyperthermic intraperitoneal chemotherapy at primary cytoreduction of epithelial ovarian cancer based on residual disease status.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin when used at the time of interval cytoreductive surgery (ICS) after neoadjuvant chemotherapy (NACT) has been shown to provide a survival advantage compared to interval cytoreduction alone for patients with advanced epithelial ovarian cancer in a cost-effective manner. A recent large multi-center retrospective cohort study showed a survival advantage with HIPEC given during primary debulking surgery compared to surgery alone. While there is an ongoing randomized controlled trial examining HIPEC at the time of primary cytoreductive surgery (PCS) before chemotherapy (OVHIPEC-2), there is currently no study of this practice in the United States or cost data to inform incorporation of this practice. To help guide the use of HIPEC in the upfront setting until the results of the OVHIPEC-2 are available in 2026, a decision-analytic cost-effectiveness model of the US healthcare sector was developed for patients undergoing PCS with or without HIPEC. Effectiveness inputs were extracted from a Chinese retrospective cohort study of 425 patients who underwent PCS with HIPEC and 159 patients who underwent PCS alone. We found incremental cost effectiveness ratios (ICER) of $9,789 per life year saved (LYS) for optimal PCS, $18,164/LYS for suboptimal PCS, and $7,854/LYS for all patients. Our findings provide preliminary data to support that HIPEC at the time of primary cytoreductive surgery can be considered cost-effective regardless of residual disease status when using a standard willingness to pay threshold.