Earlier detection is strongly associated with increased survival for women with ovarian cancer. Unfortunately, current screening strategies, employing serial serum or ultrasound assessments, lack adequate sensitivity and specificity for use in the low-prevalence general population. In contrast, screening for cervical cancer by Pap tests has been routinely performed for over 50 years. Since ovarian cancer cells have been observed in Pap tests, ovarian cancer protein biomarkers may also be present; yet Pap samples have not been rigorously examined for diagnostic proteins. Assessment of cervical effluent, as can be collected in a Pap test, has the potential to differentiate ovarian cancer cases from healthy controls, and thereby demonstrate that intra-abdominal pathology may be detected using this commonly acquired specimen. We hypothesize that proteins shed by ovarian cancer cells can be detected in the SurePath™ liquid-based Pap test fixative using mass spectrometry (MS)-based proteomics, making it possible to distinguish women with ovarian cancer from healthy women. Candidate ovarian cancer biomarkers were successfully identified in liquid-based Pap test samples from 20 cases of high grade serous ovarian cancer, 10 benign ovarian conditions, and 10 healthy control samples, by performing Tandem Mass Tag™ isobaric labeling, 2D liquid chromatography-MS/MS, and bioinformatics integration. Selected reaction monitoring (SRM) MS-based targeted proteomics was then performed using a panel of candidate biomarkers to quantify their abundance in an expanded patient cohort of 90 liquid-based Pap tests. A multi-protein classifier was developed using the SRM-MS data comprised of 6 proteins and achieving an AUC of 0.880 (95

Purpose: The immunosuppressive function of myeloid-derived suppressor cells (MDSCs) has been implicated in the regulation of immune responses against cancer and is associated with poor prognosis. Radiation treatment is known to alter immune cell populations within the tumor; however, whether this results in the recruitment of immunosuppressive MDSC populations is not well understood. Here we evaluate the response of circulating MDSC populations in patients treated per standard-of-care cisplatin chemoradiation therapy (CRT) for locally invasive cervical cancer. Methods and Materials: Newly diagnosed, treatment-naïve patients with locally advanced cervical cancer were enrolled. Blood samples were collected from patients prior to starting CRT (T0), after external beam radiation therapy (T1), and after high-dose-rate brachytherapy (T2). Samples from each time point were processed, and the prevalence of MDSC subsets was determined using flow cytometry. MDSC populations were identified using Live/Dead-CD11b+CD33+HLA-DR- staining. MDSC subsets were further subdivided into granulocytic (g-, CD15+CD14-), monocytic (m-, CD15-CD14+), or early-MDSCs (e-, CD15-CD14-). Results: Most patients in our study were Caucasian nonsmokers with human papillomavirus-associated squamous cell carcinoma of the cervix. We saw a trend for increased MDSC frequency in patients with more advanced-stage disease at the time of initiating treatment. MDSCs increase in response to CRT and peak after brachytherapy (T2). In particular, the g-MDSC subset increases by 6.44 times relative to the baseline. There was no correlation between MDSC expansion and response to therapy. Conclusion: Our study confirms other reports that circulating MDSCs in patients with cervical cancer increase in response to CRT and are associated with more advanced stages. Additionally, we show that MDSC expansion is driven by the g-MDSC subset. We did not see any correlation between MDSC expansion and treatment response, though this may be because of the limited sample size for this study.

OBJECTIVE:To assess the associations between active CMV infection and patient-reported symptoms of cancer-related cognitive impairment (CRCI) and peripheral neuropathy in ovarian cancer survivors. METHODS:We conducted a cross-sectional study among individuals with a diagnosis of ovarian cancer, primary peritoneal cancer, or fallopian tube cancer from academic and community cancer clinics at any time point after completion of front-line chemotherapy. Participants completed a one-time survey and provided a blood sample. Plasma virus DNA levels were measured using digital PCR, with ≥100 copies/mL of plasma considered active infection (CMV+, EBV+ as a control). We measured symptoms of CRCI and peripheral neuropathy using the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function short form 8a and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-NTX) subscale measurements, respectively. Symptoms were compared by active CMV infection status in the full group and among the subgroup receiving active treatment using t-tests and linear regression models. RESULTS:152 participants were included. A total of 59 (38.8 %) participants were CMV+. After adjustment for potential confounding variables, individuals who were CMV+ self-reported significantly more symptoms of peripheral neuropathy that those who were CMV- (p = 0.04). In the subgroup of participants currently receiving chemotherapy, individuals who were CMV+ had significantly lower perceived cognitive functioning compared to individuals who were CMV- (p = 0.03); this was not observed in the full cohort. No associations were observed between outcomes and EBV infection. CONCLUSIONS:Active CMV infection is common in this survivor population and may be associated with more symptoms of CRCI and neuropathy.

Abstract Screening for ovarian cancer has been hindered by the lack of a clinical assay with sufficient sensitivity and specificity for use in the general population. Since bodily fluids in close proximity to tumors may contain higher concentrations of tumor biomarkers than blood samples, we hypothesized that proteins shed by ovarian cancer tumors could be detected in cervical effluent using the standard Pap test fixative and mass spectrometry (MS)-based proteomic techniques. Briefly, proteins were isolated from SurePathTM liquid-based Pap tests (Becton Dickinson) that were collected from 20 women with high grade serous ovarian cancer (HGSOC) and 10 women with benign ovarian conditions in the gynecologic oncology clinic, as well as 10 healthy women in the women’s clinic. Samples were labeled with tandem mass tags (TMT), fractionated with high pH reversed-phase liquid chromatography (LC), and then analyzed by LC-MS/MS analysis. The resulting spectra were searched against the UniProt human database to obtain quantitative measurements of >3000 proteins. By ANOVA, we found 30 proteins were differentially expressed in the ovarian cancer samples compared to both the benign and healthy samples (non-corrected p-value <0.05). Heavy peptide standards for these 30 proteins (5 candidate sequences per protein) were synthesized (Vivitide) to construct targeted MS assays using selected reaction monitoring (SRM). Peptides from 54 proteins that were previously identified in ovarian cancer tissues from a Clinical Proteomic Tumor Analysis Consortium study conducted at the Pacific Northwest National Laboratory were also included in the SRM assay. Multiplexed SRM analysis was then performed using a panel containing 244 peptides corresponding to 84 candidate biomarker proteins to quantify their abundance in 90 liquid-based Pap tests (40 HGSOC, 30 benign, and 20 healthy). Thirty-seven proteins showed a significant increase in the Pap test samples from women with HGSOC compared to healthy controls. A multi-protein classifier was then developed in which the combination of 6 proteins resulted in an AUC of 0.880 (95% CI: 0.738-0.989). The sensitivity at 90% specificity was 0.800 (95% CI: 0.470-1.00). In conclusion, in this proof of principle study we have demonstrated the translational potential of this approach, pending validation in prospectively collected samples. In the future, incorporating MS-based proteomics into routine Pap testing may allow women to be screened simultaneously for cervical and ovarian cancer. Citation Format: Amy P.N. Skubitz, Kristin L.M. Boylan, Ashley J. Petersen, Joshua R. Hansen, Tao Liu, Yuqian Gao, Yi-Ting Wang, Karin D. Rodland, Melissa A. Geller, Peter A. Argenta, Samantha L. Hoffman, Paul D. Piehowski. Identification of ovarian cancer protein biomarkers in liquid-based Pap tests [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B039.

•Primary angiosarcoma of the ovary historically has no standard treatment due to its rarity, and outcomes have been variable.•Olaparib may represent a viable treatment option for primary angiosarcoma of the ovary with a somatic BRCA mutation.•Next-generation sequencing may play an important component in treatment of very rare cancers to guide new or uncommon therapies.

Sensory deficits are a common manifestation of chemotherapy-induced peripheral neuropathy (CIPN), but validated quantification of symptoms requires cumbersome neurologic testing, which is not routinely performed. We sought to validate a novel, easy to use, quantitative tool for assessing sensory neuropathy in patients undergoing platinum and taxane chemotherapy for the treatment of gynecologic cancer. Patients with gynecologic cancer who were undergoing treatment performed tactile sensory testing using the Bumps device before receiving chemotherapy (baseline), after 2–3 cycles (inter-treatment), after six cycles (completion of treatment), and six months after completing chemotherapy. The Bumps testing device comprises 16 squares, each containing five small circles of different colors. One random circle per square contains a bump of varying height ranging from 14 to 2.5 um arranged in non-sequential decreasing height. Thirty-six patients were enrolled in this study. Two patients withdrew prior to initial testing; of the remaining 34 patients, 28 patients had undergone testing more than once. Compared to baseline testing, 14 of 28 patients (50%) experienced a reduction in tactile sensitivity of at least 1.5 um after two cycles of chemotherapy. Eight patients (28.5%) showed no change in sensitivity thresholds. Of the patients who have completed six cycles of chemotherapy, 9 of 14 patients (64%) had a reduction in tactile sensitivity compared to baseline, and 4 patients (28.5%) showed no change. Compared to baseline testing, 7 of 9 (78%) patients had concordant reductions of tactile sensitivity at both inter-treatment and completion-of-treatment testing times. At Completion-of-treatment testing, these seven patients had a median 5.5 um decrease (4.5 to 12.5) in tactile sensitivity compared to a median 1 um decrease (−0.5 (improvement) to 6.5) in the five patients whose inter-treatment testing showed no change or improvement from baseline testing. The Bumps test allows for a rapid, quantitative measure of neuropathy. While some patients recover sensitivity over time, prolonged deficits are common. Our preliminary data suggest that the early reduction of sensation may predict ongoing and more severe sensory deficits. The ability to predict these changes may compel more expeditious changes to treatment regimens (e.g., dose-reductions, alternative chemotherapies). Early treatment changes could help prevent the length and severity of CIPN symptoms.

Tumor hypoxia induces collagen deposition and extensive extracellular matrix remodeling, significantly enhancing the processes of invasion and metastasis. Collagen prolyl-4-hydroxylases (P4HA) play a critical role in collagen post-translational modification. The primary objective of this study is to comprehensively assess the role of P4HA in promoting ovarian cancer growth and facilitating metastasis. Human epithelial ovarian cancer cells were transfected with shRNAs to target P4HA1 and P4HA2. The impact of P4HA knockdown on crucial factors such as collagen I deposition, cell proliferation, and migration were examined in vitro. Additionally, in vivo studies involved the injection of both control and P4HA knockdown cells into athymic mice, enabling the assessment of tumor growth and peritoneal metastasis. The relevance of prolyl hydroxylases to clinical outcomes was then determined by analyzing clinical databases. Quantitative RT-PCR showed upregulation of P4HA1 and P4HA2 mRNA in A2780 cells when exposed to hypoxia. ShRNA-mediated downregulation of P4HA1 and P4HA2 significantly reduced the deposition of collagen I. Knockdown of P4HA expression reduced cell proliferation in vitro and peritoneal seeding in vivo. A2780 cells stably transfected with shP4HA1 and shP4HA2 inhibited tumor growth and metastases in athymic mice. Furthermore, our review of the TCGA dataset revealed that increased P4HA1 and P4HA2 mRNA levels are associated with decreased overall survival in patients with ovarian cancer. The increased expression of collagen P4HA has been linked to ovarian cancer growth and metastasis. This evidence highlights their potential as prognostic biomarkers and promising therapeutic targets.

5041 Background: Optimal carboplatin dosing (CPRx) for patients (pts) with renal dysfunction or low creatinine (Cr) values in the setting of malnutrition and ascites is unknown. Multiple methods have been utilized to estimate Cr clearance (CrCl) but these perform differently in pts with abnormal Cr values. We sought to determine 1) the relationship between adverse events (AE) and baseline CrCl used for CPRx; 2) the effect on CPRx of using Cockcroft-Gault (CG) +/- the NCI/CTEP recommended limits (CGL), Modification of diet in renal disease (MDRD) or Jelliffe Formula (J) renal function estimates. Methods: Retrospective data were drawn from pts treated on GOG 182, a phase III trial of carboplatin doublet vs triplet or sequential doublet combinations in stage III/IV EOC. For patient safety, the protocol was amended to assign the lower limit of Cr at 0.6mg/dl for CPRx. Area under the receiver operating characteristic curve (AUC) was used to describe associations between CrClJ and various AE. Sensitivity and positive predictive values (PPV) described the AE rate in pts with CrClJ <60ml/min. CPRx for each pt was calculated using J, CG, CGL and MDRD. Results: 3830 evaluable pts had a mean age 58.7yrs, mean BMI 26.8kg/m2 and mean baseline CrClJ 81.9ml/min (range 23.4-239). The AUC statistics (range 0.52-0.64) show that the log(CrClJ) was not a good predictor of grade ≥3 AE (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). A cutoff value of CrClJ <60 ml/min would have deemed 15% of pts treated on GOG182 ineligible. The range of PPV for the above AEs in pts with CrClJ <60 ml/min was 1.8-15%. Using CG, CGL, MDRD instead of J for CPRx would have resulted in >10% decrease in CPRx in 21%, 32% and 12% of pts, respectively. Using CG, CGL, MDRD instead of J for CPRx would have resulted in >10% increase in CPRx in 45%, 9.6% and 5.2% of pts, respectively. Conclusions: Our data do not support excluding patients with CrClJ <60ml/min from clinical trials. The new GOG guidelines replacing J with CGL affect CPRx. The clinical significance of this change with regards to toxicity, particularly in pts with abnormally low Cr values, is yet to be determined.

Germline pathogenic loss-of-function (pLOF) variants in DICER1 are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common DICER1 pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of DICER1-related cancers and cascade testing of family members. However, some patients with DICER1-associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense DICER1 RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no DICER1 pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of platinum and taxane chemotherapy leading to decreased quality of life (QOL) in gynecologic cancer patients. There is currently no validated method to quickly quantify the severity of peripheral neuropathy. We sought to determine whether a novel, easy to use, quantitative tool can assess the extent of CIPN in gynecologic oncology patients. Furthermore, we aimed to compare these results with those of the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (NTX) questionnaire. We assessed patients with gynecologic cancer undergoing platinum and taxane-based chemotherapy with two different tests: sensory testing using the "Bumps" device and subjective responses from the NTX questionnaire. The data were collected in a prospective fashion. The Bumps test utilizes a device that contains a series of raised bumps at different heights to quantitatively assess the sensory threshold of patients. These tests were given before receiving chemotherapy (baseline), after 2–3 cycles (intertreatment), after 6 cycles (completion of treatment), and 6 months after completing therapy (recovery). A higher score in the NTX questionnaire indicates worsening neuropathy, as does a decreased threshold of sensation in the Bumps test. We then compared the results of the two tests to see if there was a concordant worsening of neuropathy or improvement of neuropathy at each time point. Of the 36 patients enrolled in the study, 27 have completed the intertreatment testing, 14 patients have performed the completion of treatment testing, and 6 patients have completed the recovery testing. Compared to baseline testing, concordant testing between the Bumps and NTX testing was noted for 11 of 27 (41%) patients at intertreatment testing, 10 of 14 (71%) patients at completion of treatment testing, and 3 of 6 (50%) patients at recovery testing. When comparing the completion of treatment testing to intertreatment testing, concordant testing was noted for 5 of 14 (36%) patients. Lastly, in comparing recovery testing to completion of treatment testing, concordant testing was noted for 2 of 6 (33%) patients. Our study allows us to evaluate whether the results of the Bumps test correlate with the already validated NTX test. This would allow for a quantitative measure of neuropathy in addition to the purely subjective measure provided by the NTX test, which would be valuable in predicting QOL changes in patients with CIPN. Preliminary data suggest that a worse/better NTX score does not predict a concordant change in tactile sensitivity evaluated on the Bumps test. Although we may be able to quantify a sensory deficiency, this study highlights that quantifiable deficits may not accurately gauge the effect of CIPN on perceived QOL. We await analysis of the complete dataset but continue to underscore the importance of managing symptoms on patient-reported deficits in order to optimize QOL.

•Acquired lymphangioma circumscriptum may arise in adulthood as a result of blunt trauma.•Large scale surgical excision may effectively treat recalcitrant lymphangioma circumscriptum.•Patients with large lymphangioma circumscriptum lesions may benefit from earlier surgical intervention.

Objectives: The LAP2 trial demonstrated that short-term outcomes for patients undergoing minimally invasive surgery (MIS) for endometrial cancer are similar to those undergoing laparotomy. However, recent reports in both cervical and uterine cancer suggest that route of surgery had an unanticipated impact on the long-term clinical outcomes of patients, including recurrence and death. Given an increasing use of robotic surgery since LAP2, we undertook to determine if outcomes following robotic surgery are similar to those of laparoscopy during intermediate and long-term follow-up. Methods: We performed a retrospective review of patients from a single, large, academic, urban practice who underwent either laparoscopic or robot-assisted MIS (RA-MIS) for the treatment of stage I endometrial carcinoma and had at least five years of potential followup. Comparisons of recurrence-free (RFS) and overall survival (OS) by route of surgery were conducted using Cox regression models adjusting for stage, grade, use of adjuvant therapy, and age at surgery. Results: We identified 1,138 patients treated in the study window; 482 in the laparoscopy group and 656 in the RA-MIS group. The groups were similar in age, stage, grade, completeness of staging, and adjuvant therapy. There was a steady increase in the use of RA-MIS surgeries during the study window. Traditional risk factors, such as increasing age, stage, and grade, were associated with poorer outcomes. After controlling for these, RA-MIS was associated with poorer RFS (HR: 1.55, 95% CI: 1.12-2.16) and OS (HR: 1.57, 95% CI: 1.06-2.33). Disease-specific death risk was also higher in the RA-MIS group (competing risks analysis; HR: 3.48, 95% CI: 1.79-6.77). Among those who recurred, the median time to the first recurrence was shorter in the RA-MIS group than in the laparoscopy group (16.3 vs 29.3 months, p=0.046). Fifty-three percent of recurrences in the laparoscopy arm and 42% in the RA-MIS group occurred greater than 24 months after surgery, while 18% and 14% occurred after five years. Conclusions: RA-MIS was associated with poorer outcomes, even after adjusting for known risk factors. Our data in this lower-risk population suggest that relevant clinical endpoints may be occurring during intermediate and long-term follow-up windows. These findings support a prospective evaluation of the long-term outcomes of RA-MIS in this setting. Objectives: The LAP2 trial demonstrated that short-term outcomes for patients undergoing minimally invasive surgery (MIS) for endometrial cancer are similar to those undergoing laparotomy. However, recent reports in both cervical and uterine cancer suggest that route of surgery had an unanticipated impact on the long-term clinical outcomes of patients, including recurrence and death. Given an increasing use of robotic surgery since LAP2, we undertook to determine if outcomes following robotic surgery are similar to those of laparoscopy during intermediate and long-term follow-up. Methods: We performed a retrospective review of patients from a single, large, academic, urban practice who underwent either laparoscopic or robot-assisted MIS (RA-MIS) for the treatment of stage I endometrial carcinoma and had at least five years of potential followup. Comparisons of recurrence-free (RFS) and overall survival (OS) by route of surgery were conducted using Cox regression models adjusting for stage, grade, use of adjuvant therapy, and age at surgery. Results: We identified 1,138 patients treated in the study window; 482 in the laparoscopy group and 656 in the RA-MIS group. The groups were similar in age, stage, grade, completeness of staging, and adjuvant therapy. There was a steady increase in the use of RA-MIS surgeries during the study window. Traditional risk factors, such as increasing age, stage, and grade, were associated with poorer outcomes. After controlling for these, RA-MIS was associated with poorer RFS (HR: 1.55, 95% CI: 1.12-2.16) and OS (HR: 1.57, 95% CI: 1.06-2.33). Disease-specific death risk was also higher in the RA-MIS group (competing risks analysis; HR: 3.48, 95% CI: 1.79-6.77). Among those who recurred, the median time to the first recurrence was shorter in the RA-MIS group than in the laparoscopy group (16.3 vs 29.3 months, p=0.046). Fifty-three percent of recurrences in the laparoscopy arm and 42% in the RA-MIS group occurred greater than 24 months after surgery, while 18% and 14% occurred after five years. Conclusions: RA-MIS was associated with poorer outcomes, even after adjusting for known risk factors. Our data in this lower-risk population suggest that relevant clinical endpoints may be occurring during intermediate and long-term follow-up windows. These findings support a prospective evaluation of the long-term outcomes of RA-MIS in this setting.

ObjectiveRecent reports in both cervical and endometrial cancer suggest that minimally invasive surgery (MIS) had an unanticipated negative impact on long-term clinical outcomes, including recurrence and death. Given increasing use of robotic surgery since the LAP2 trial, we sought to compare the intermediate and long-term outcomes between those who underwent robotic surgery or laparoscopy for Stage I endometrial cancer.MethodsWe performed a retrospective review of patients from a single, large, academic, urban practice who underwent either laparoscopic or robot-assisted MIS (RA-MIS) for the treatment of endometrial carcinoma between 2006 and 2016, ensuring at least 5 years of potential follow-up. To adjust for differences in confounding variables between groups, propensity score-based inverse probability of treatment weighting (IPTW) was performed. Overall and recurrence-free survival were compared using Cox proportional hazards regression models adjusting for confounding weights.Results1027 patients were included; 461 received laparoscopy and 566 received RA-MIS. RA-MIS use increased steadily during the study window, which resulted in longer mean surveillance in laparoscopy group (median 8.7 years versus 6.3 years, p < 0.001). RA-MIS was associated poorer recurrence-free (HR: 1.41, 95% CI: 1.12, 1.77) and overall survival (HR: 1.39, 95% CI: 1.06, 1.83). Disease-specific survival was also poorer in the RA-MIS group (HR: 3.51, 95% CI: 2.19, 5.63). Among those who recurred, median time to first recurrence was shorter in the RA-MIS group than the laparoscopy group (16.3 vs. 28.7 months, p = 0.07).ConclusionRA-MIS was associated with poorer long-term patient outcomes. Our data in this lower-risk population indicate relevant clinical endpoints may be occurring during intermediate and long-term follow-up windows. These findings support a prospective evaluation of the long-term outcomes of RA-MIS.

Background The purpose of this study was to determine whether the residual fixative from a liquid-based Pap test or a swab of the cervix contained proteins that were also found in the primary tumor of a woman with high grade serous ovarian cancer. This study is the first step in determining the feasibility of using the liquid-based Pap test or a cervical swab for the detection of ovarian cancer protein biomarkers. Methods Proteins were concentrated by acetone precipitation from the cell-free supernatant of the liquid-based Pap test fixative or eluted from the cervical swab. Protein was also extracted from the patient’s tumor tissue. The protein samples were digested into peptides with trypsin, then the peptides were run on 2D-liquid chromatography mass spectrometry (2D-LCMS). The data was searched against a human protein database for the identification of peptides and proteins in each biospecimen. The proteins that were identified were classified for cellular localization and molecular function by bioinformatics integration. Results We identified almost 5000 proteins total in the three matched biospecimens. More than 2000 proteins were expressed in each of the three biospecimens, including several known ovarian cancer biomarkers such as CA125, HE4, and mesothelin. By Scaffold analysis of the protein Gene Ontology categories and functional analysis using PANTHER, the proteins were classified by cellular localization and molecular function, demonstrating that the Pap test fluid and cervical swab proteins are similar to each other, and also to the tumor extract. Conclusions Our results suggest that Pap test fixatives and cervical swabs are a rich source of tumor-specific biomarkers for ovarian cancer, which could be developed as a test for ovarian cancer detection.

Objective. To identify genetic variants associated with chemotherapy-induced peripheral neuropathy (CIPN) symptoms among gynecologic cancer survivors and determine the variants' predictive power in addition to age and clinical factors at time of diagnosis. Methods. Participants of a prospective cohort study on gynecologic cancers provided a DNA saliva sample and reported CIPN symptoms (FACT/GOG-Ntx). Genotyping of 23 single nucleotide polymorphisms (SNPs) previously identified as related to platinum-or taxane-induced neuropathy was performed using iPLEX Gold method. Risk allele carrier frequencies of 19 SNPs that passed quality checks were compared between those with/without high CIPN symptoms using logistic regression, adjusting for age. Receiver operating characteristic (ROC) curves using clinical risk factors (age, diabetes, BMI, Charlson Comorbidity Index, previous cancer diagnosis) with and without the identified SNPs were compared. Results. 107 individuals received platinum or taxane-based chemotherapy and provided sufficient DNA for analysis. Median age was 65.1 years; 39.6% had obesity and 8.4% diabetes; most had ovarian (58.9%) or uterine cancer (29.0%). Two SNPs were significantly associated with high CIPN symptomatology: rs3753753 in GPX7, OR = 2.55 (1.13, 5.72) and rs139887 in SOX10, 2.66 (1.18, 6.00). Including these two SNPs in a model with clinical characteristics led to an improved AUC for CIPN symptomatology (0.65 vs. 0.74, p = 0.04). Conclusions. Genetic and clinical characteristics were predictive of higher CIPN symptomatology in gynecologic cancer survivors, and combining these factors resulted in superior predictive power compared with a model with clinical factors only. Prospective validation and assessment of clinical utility are warranted. (c) 2021 Elsevier Inc. All rights reserved.

PURPOSE Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP. METHODS GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m2 and cisplatin 50 mg/m2 (day 1), followed by paclitaxel 160 mg/m2 (day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m2 and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints. RESULTS From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC ( P = .40). More grade ≥ 3 thrombocytopenia (23% v 12%), vomiting (7% v 4%), diarrhea (6% v 2%), and metabolic (14% v 8%) toxicities were reported with TAP. Neutropenia (52% v 80%) was more common with TC. Small HRQoL differences favored TC. CONCLUSION With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.

Primary incisional carcinoma (PIC) is a rare, delayed complication of surgery, usually attributed to the malignant transformation of endometriosis.We report a case of incisional carcinoma with nodal metastases in a 55-year-old woman, 18 years after cesarean section. She underwent extirpative surgery, including hysterectomy and bilateral salpingo-oophorectomy, without intraperitoneal disease identifed. Adjuvant treatment included sandwiched platinum-based chemotherapy (carboplatin and paclitaxel) and radiation. She remains disease-free 8 months after completing therapy.We identified 46 additional reported cases. Of these, >90% had undergone an “endometrium-exposing” surgery, most commonly cesarean section; while no cases followed adnexal-only surgery. The median time between antecedent surgery and presentation was 18 years. At presentation, tumors were often large (median 8 cm), and symptomatic with pain (63%) and/or mass (26%). Serum CA125 levels were commonly, albeit slightly, elevated (median 57U/ml (IQR 22–96, Range 6–1690)). Lymph node metastases were common (35%), with most following a vulvar-type spread pattern (inguinal first). Most patients (63%) were treated with chemotherapy +/− radiation. Approximately 50% of patients recurred promptly (median < 6 months), but long-term survival was reported following combined chemotherapy/radiation. Lymph node metastases portended a shorter disease-free interval, with 73% of cases recurring (median 5 months) despite chemotherapy-based treatment.These data suggest that some incisional carcinomas may result from displacement of healthy endometrium followed by delayed malignant transformation. Chemotherapy-only and radiation-only treatments are attended by modest prognosis. Taken together, these data suggest there is both need and potential avenues for improved prevention, detection, and treatment of this condition.

Objective. Physical activity may mitigate the effects of cancer treatment. We sought to evaluate the association between self-reported physical activity, neuropathy symptomatology, and emotional health in gynecologic cancer survivors. Methods. Patients were recruited from an academic gynecologic oncology practice to a prospective cohort study. Participants completed semiannual surveys on quality of life (QOL), neuropathy symptoms, depression, distress, and health behaviors. Abstracted clinical data included cancer type, FIGO stage at diagnosis and treatments received (chemotherapy, surgery, radiation). Physical activity [no: moderate physical activity <150 min/week, yes: >= 150 min/week] and neuropathy symptomatology [high (FACTIGOG-Ntx >= 11; upper quartile); low (<11)] were dichotomized. Linear regression models assessed the associations between physical activity, neuropathy and psychosocial outcomes. Results. A total of 194 participants were included in this analysis. We identified significant interactions between physical activity and neuropathy in the depression (p = 0.0006) and QOL (p = 0.007) models. Greater physical activity and lower neuropathy scores were independently associated with fewer depressive symptoms (p = 0.02 and p <0.0001, respectively) and greater QOL (p 0.005 and p < 0.0001). Low neuropathy scores were associated with lower distress (p < 0.0001). Women with high neuropathy scores had larger beneficial associations between being physically active and depression and QOL In the distress model, interaction between neuropathy and physical activity was suggested (p = 0.05). Conclusions. Physical activity was associated with favorable psychosocial outcomes in gynecologic cancer survivors, most notably among those with worse neuropathy. These data suggest prescriptive exercise should be evaluated as a means of mitigating cancer-associated neuropathies and their effect on emotional health. (C) 2020 Elsevier Inc. All rights reserved.

The majority of patients with high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy; however, most will develop chemotherapy resistance. Gene signatures may change with the development of chemotherapy resistance in this population, which is important as it may lead to tailored therapies. The objective of this study was to compare tumor gene expression profiles in patients before and after treatment with neoadjuvant chemotherapy (NACT). Tumor samples were collected from six patients diagnosed with HGSOC before and after administration of NACT. RNA extraction and whole transcriptome sequencing was performed. Differential gene expression, hierarchical clustering, gene set enrichment analysis, and pathway analysis were examined in all of the samples. Tumor samples clustered based on exposure to chemotherapy as opposed to patient source. Pre-NACT samples were enriched for multiple pathways involving cell cycle growth. Post-NACT samples were enriched for drug transport and peroxisome pathways. Molecular subtypes based on the pre-NACT sample (differentiated, mesenchymal, proliferative and immunoreactive) changed in four patients after administration of NACT. Multiple changes in tumor gene expression profiles after exposure to NACT were identified from this pilot study and warrant further attention as they may indicate early changes in the development of chemotherapy resistance.