Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study.

OBJECTIVE: To evaluate patient preference for short (gist) or detailed/extensive decision aids (DA) for genetic testing at ovarian cancer (OC) diagnosis. DESIGN: Cohort study set within recruitment to the Systematic Genetic Testing for Personalised Ovarian Cancer Therapy (SIGNPOST) study (ISRCTN: 16988857). SETTING: North-East London Cancer Network (NELCN) population. POPULATION/SAMPLE: Women with high-grade non-mucinous epithelial OC. METHODS: A more detailed DA was developed using patient and stakeholder input following the principles/methodology of IPDAS (International Patients Decision Aids Standards). Unselected patients attending oncology clinics evaluated both a pre-existing short and a new long DA version and then underwent mainstreaming genetic testing by a cancer clinician. Appropriate inferential descriptive and regression analyses were undertaken. MAIN OUTCOME MEASURES: Satisfaction, readability, understanding, emotional well-being and preference for long/short DA. RESULTS: The mean age of patients was 66 years (interquartile range 11), and 85% were White British ethnicity. Of the participants, 74% found DAs helpful/useful in decision-making. Women reported higher levels of satisfaction (86% versus 58%, p < 0.001), right amount of information provided (76.79% versus49.12%, p < 0.001) and improved understanding (p < 0.001) with the long DA compared with the short DA. There was no statistically significant difference in emotional outcomes (feeling worried/concerned/reassured/upset) between 'short' and 'long' DA; 74% of patients preferred the long DA and 24% the short DA. Patients undergoing treatment (correlation coefficient (coef) = 0.603; 95% CI 0.165-1.041, p = 0.007), those with recurrence (coef = 0.493; 95% CI 0.065-0.92, p = 0.024) and older women (coef = 0.042; 95% CI 0.017-0.066, p = 0.001) preferred the short DA. Ethnicity did not affect outcomes or overall preference for long/short DA. CONCLUSIONS: A longer DA in OC patients has higher satisfaction without increasing emotional distress. Older women and those undergoing treatment/recurrence prefer less extensive information, whereas those in remission preferred a longer DA.

Prognosis Following Surgery for Recurrent Ovarian Cancer and Diagnostic Criteria Predictive of Cytoreduction Success: A Systematic Review and Meta-Analysis.

For women achieving clinical remission after the completion of initial treatment for epithelial ovarian cancer, 80% with advanced-stage disease will develop recurrence. However, the standard treatment of women with recurrent platinum-sensitive diseases remains poorly defined. Secondary (SCS), tertiary (TCS) or quaternary (QCS) cytoreduction surgery for recurrence has been suggested to be associated with increased overall survival (OS). We searched five databases for studies reporting death rate, OS, cytoreduction rates, post-operative morbidity/mortality and diagnostic models predicting complete cytoreduction in a platinum-sensitive disease recurrence setting. Death rates calculated from raw data were pooled based on a random-effects model. Meta-regression/linear regression was performed to explore the role of complete or optimal cytoreduction as a moderator. Pooled death rates were 45%, 51%, 66% for SCS, TCS and QCS, respectively. Median OS for optimal cytoreduction ranged from 16-91, 24-99 and 39-135 months for SCS, TCS and QCS, respectively. Every 10% increase in complete cytoreduction rates at SCS corresponds to a 7% increase in median OS. Complete cytoreduction rates ranged from 9-100%, 35-90% and 33-100% for SCS, TCS and QCS, respectively. Major post-operative thirty-day morbidity was reported to range from 0-47%, 13-33% and 15-29% for SCS, TCS and QCS, respectively. Thirty-day post-operative mortality was 0-6%, 0-3% and 0-2% for SCS, TCS and QCS, respectively. There were two externally validated diagnostic models predicting complete cytoreduction at SCS, but none for TCS and QCS. In conclusion, our data confirm that maximal effort higher order cytoreductive surgery resulting in complete cytoreduction can improve survival.

Impact of minimally invasive surgery on surgical outcomes for obese women with endometrial cancer following robotic surgery introduction; a single centre study.

BACKGROUND: The aim was to assess the surgical outcomes in obese women with endometrial cancer following robotic surgery introduction in a London tertiary gynaecological cancer unit. METHODS: Data was prospectively collected for 281 women undergoing endometrial cancer surgery in 2016, 2018 and 2019 (robotic surgery was introduced in November 2017). RESULTS: The proportion of obese and morbidly obese patients undergoing minimally invasive surgery (MIS) significantly increased following robotic surgery introduction from 43.8% to 69.6% (p < 0.001). Overall robotic surgery operating time was not affected by higher body mass index (r = 0.177, 95% CI -0.068-0.402). There was no difference in the length of stay or in the frequency and severity of complication rates between obese, morbidly obese and non-obese populations undergoing MIS. CONCLUSION: Robotic surgery led to a significant rise in MIS and improved surgical outcomes for obese and morbidly obese women with endometrial cancer within 12 months of its introduction.

British Gynaecological Cancer Society Recommendations for Evidence Based, Population Data Derived Quality Performance Indicators for Ovarian Cancer.

Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations.

Patient outcomes following interval and delayed cytoreductive surgery in advanced ovarian cancer: protocol for a multicenter, international, cohort study (Global Gynaecological Oncology Surgical Outcomes Collaborative).

BACKGROUND: The Global Gynecological Oncology Surgical Outcomes Collaborative (GO SOAR) has developed a network of gynecological oncology surgeons, surgical departments, and other interested parties that have the long-term ability to collaborate on outcome studies. Presented is the protocol for the GO SOAR2 study. PRIMARY OBJECTIVES: To compare survival following interval and delayed cytoreductive surgery, between delayed cytoreductive surgery and no surgery (chemotherapy alone); and international variations in access to cytoreductive surgery for women with stage III-IV epithelial ovarian cancer. STUDY HYPOTHESES: There is no difference in survival following interval and delayed cytoreductive surgery; there is poorer survival with no surgery compared with delayed cytoreductive surgery; and there are international disparities in prevalent practice and access to cytoreductive surgery in women with stage III-IV epithelial ovarian cancer. TRIAL DESIGN: International, multicenter, mixed-methods cohort study. Participating centers, will review medical charts/electronic records of patients who had been consecutively diagnosed with stage III-IV ovarian cancer between January 1, 2006 and December 31, 2021. Qualitative interviews will be conducted to identify factors determining international variations in prevalent practice and access to cytoreductive surgery. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria include women with stage III-IV epithelial ovarian cancer, undergoing interval (after 3-4 cycles of chemotherapy) or delayed (≥5 cycles of chemotherapy) cytoreductive surgeries or no cytoreductive surgery (≥5 cycles of chemotherapy alone). PRIMARY ENDPOINTS: Overall survival (defined from date of diagnosis to date of death); progression-free survival (defined from date of diagnosis to date of first recurrence); facilitator/barriers to prevalent practice and access to cytoreductive surgery. SAMPLE SIZE: In order to determine whether there is a difference in survival following interval and delayed cytoreductive surgery and no surgery, data will be abstracted from 1000 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated that recruitment will be completed by 2023, and results published by 2024. TRIAL REGISTRATION: NCT05523804.

Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer.

BACKGROUND: This is an update of the Cochrane Review published in Issue 4, 2015. Cervical cancer is one of the most frequent cause of death from gynaecological cancers worldwide. Many new cervical cancer cases in low-income countries present at an advanced stage. Standard care in Europe and the US for locally advanced cervical cancer (LACC) is chemoradiotherapy. In low-income countries, with limited access to radiotherapy, LACC may be treated with chemotherapy and hysterectomy. It is not certain if this improves survival. It is important to assess the value of hysterectomy with radiotherapy or chemotherapy, or both, as an alternative. OBJECTIVES: To determine whether hysterectomy, in addition to standard treatment with radiotherapy or chemotherapy, or both, in women with LACC (Stage IB2 to III) is safe and effective compared with standard treatment alone. SEARCH METHODS: We searched CENTRAL, MEDLINE via Ovid, Embase via Ovid, LILACS, trial registries and the grey literature up to 3 February 2022. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that compared treatments involving hysterectomy versus radiotherapy or chemotherapy, or both, in women with LACC International Federation of Gynecology and Obstetrics (FIGO) Stages IB2 to III. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We independently assessed study eligibility, extracted data and assessed the risk of bias. Where possible, we synthesised overall (OS) and progression-free (PFS) or disease-free (DFS) survival in a meta-analysis using a random-effects model. Adverse events (AEs) were incompletely reported and we described the results of single trials in narrative form. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: From the searches we identified 968 studies. After deduplication, title and abstract screening, and full-text assessment, we included 11 RCTs (2683 women) of varying methodological quality. This update identified four new RCTs and three ongoing RCTs. The included studies compared: hysterectomy (simple or radical) with radiotherapy or chemoradiotherapy or neoadjuvant chemotherapy (NACT) versus radiotherapy alone or chemoradiotherapy (CCRT) alone or CCRT and brachytherapy. There is also one ongoing study comparing three groups: hysterectomy with CCRT versus hysterectomy with NACT versus CCRT. There were two comparison groups for which we were able to do a meta-analysis. Hysterectomy (radical) with neoadjuvant chemotherapy versus chemoradiotherapy alone Two RCTs with similar design characteristics (620 and 633 participants) found no difference in five-year OS between NACT with hysterectomy versus CCRT. Meta-analysis assessing 1253 participants found no evidence of a difference in risk of death (OS) between women who received NACT plus hysterectomy and those who received CCRT alone (HR 0.94, 95% CI 0.76 to 1.16; moderate-certainty evidence). In both studies, the five-year DFS in the NACT plus surgery group was worse (57%) compared with the CCRT group (65.6%), mostly for Stage IIB. Results of single trials reported no apparent difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between groups (very low-quality evidence). Hysterectomy (simple or radical) with neoadjuvant chemotherapy versus radiotherapy alone Meta-analysis of three trials of NACT with hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received NACT plus hysterectomy had less risk of death (OS) than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93; I2 = 0%; moderate-quality evidence). However, a significant number of participants who received NACT plus hysterectomy also had radiotherapy. There was no difference in the proportion of women with disease progression or recurrence (DFS and PFS) between NACT plus hysterectomy and radiotherapy groups (RR 0.75, 95% CI 0.53 to 1.05; I2 = 20%; moderate-quality evidence). The certainty of the evidence was low or very-low for all other comparisons for all outcomes. None of the trials reported quality of life outcomes. AUTHORS' CONCLUSIONS: From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with LACC who are treated with radiotherapy or CCRT alone. The overall certainty of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The certainty of the evidence for NACT and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate. The same occurred for the comparison involving NACT and hysterectomy compared with CCRT alone. Evidence from other comparisons was generally sparse and of low or very low-certainty. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials assessing medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.

Concise Reporting of Benign Endometrial Biopsies is an Acceptable Alternative to Descriptive Reporting.

In the United Kingdom, endometrial biopsy reports traditionally consist of a morphologic description followed by a conclusion. Recently published consensus guidelines for reporting benign endometrial biopsies advocate the use of standardized terminology. In this project we aimed to assess the acceptability and benefits of this simplified "diagnosis only" format for reporting non-neoplastic endometrial biopsies. Two consultants reported consecutive endometrial biopsies using 1 of 3 possible formats: (i) diagnosis only, (ii) diagnosis plus an accompanying comment, and (iii) the traditional descriptive format. Service users were asked to provide feedback on this approach via an anonymized online survey. The reproducibility of this system was assessed on a set of 53 endometrial biopsies among consultants and senior histopathology trainees. Of 370 consecutive benign endometrial biopsies, 245 (66%) were reported as diagnosis only, 101 (27%) as diagnosis plus a brief comment, and 24 (7%) as diagnosis following a morphologic description. Of the 43 survey respondents (28 gynecologists, 11 pathologists, and 4 clinical nurse specialists), 40 (93%) preferred a diagnosis only, with 3 (7%) being against/uncertain about a diagnosis only report. Among 3 histopathology consultants and 4 senior trainees there was majority agreement on the reporting format in 53/53 (100%) and 52/53 (98%) biopsies. In summary, we found that reporting benign specimens within standardized, well-understood diagnostic categories is an acceptable alternative to traditional descriptive reporting, with the latter reserved for the minority of cases that do not fit into specific categories. This revised approach has the potential to improve reporting uniformity and reproducibility.

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51-62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51-71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.

Histopathologic response to neoadjuvant chemotherapy as a prognostic biomarker in tubo-ovarian high-grade serous carcinoma: updated Chemotherapy Response Score (CRS) results.

OBJECTIVE: The Chemotherapy Response Scoring (CRS) system was developed to enable reproducible reporting of histologic tumor response in interval debulking specimens following neoadjuvant chemotherapy in advanced stage tubo-ovarian high-grade serous carcinoma. This prognostic biomarker has been included in ovarian cancer pathology reporting guidelines (International Collaboration on Cancer Reporting, College of American Pathologists) and in the upcoming European Society for Medical Oncology-European Society of Gynaecological Oncology (ESMO-ESGO) guidelines for ovarian cancer management. We present follow-up data on the CRS validation initiatives and suggest research with novel therapeutic agents incorporating this biomarker. METHODS: The cohort on whom CRS was originally developed was analyzed after an extended follow-up of an additional 36 months. The CRS histopathologic scoring system was applied to omental sections obtained at interval surgery from all 80 patients. Progression-free and overall survival were re-calculated. RESULTS: After a median follow-up of 4.3 years the CRS score predicted progression-free survival with an HR of 0.39 (95% CI 0.21 to 0.70), p = 0.002 adjusted for age, stage, and debulking status (median 1.08 vs 2.27 years for CRS1/2 vs CRS3). CRS was also predictive of overall survival with an HR of 0.17 (95% CI 0.07 to 0.44), p = 0.0002 adjusted for age, stage, and debulking status (median 2.55 vs 5.47 years for CRS1/2 vs CRS3). CONCLUSION: CRS3 is a reproducible prognostic biomarker for improved progression-free and overall survival in stage 3C or 4 tubo-ovarian high-grade serous carcinoma after neoadjuvant chemotherapy. The score, obtained at interval debulking surgery, can help facilitate research and biomarker driven first-line treatment of patients with advanced ovarian cancer.

Copy number signatures and mutational processes in ovarian carcinoma.

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.

Persistence of fimbrial tissue on the ovarian surface after salpingectomy.

BACKGROUND: Salpingectomy is recommended as a risk-reducing strategy for epithelial tubo-ovarian cancer. The gold standard procedure is complete tubal excision. OBJECTIVE: The purpose of this study was to assess the presence of residual fimbrial/tubal tissue on ovarian surfaces after salpingectomy. STUDY DESIGN: Prospective analysis of patients who underwent salpingo-oophorectomy with or without hysterectomy for benign indications, early cervical cancer, or low-risk endometrial cancer at a UK National Health Service Trust. Salpingectomy with or without hysterectomy was performed initially, followed by oophorectomy within the same operation. Separately retrieved tubes and ovaries were sectioned serially and examined completely histologically. The main outcome measure was histologically identified fimbrial/ tubal tissue on ovarian surface. Chi-square/Fisher's exact tests were used to evaluate categoric variables. RESULTS: Twenty-five consecutive cases (mean age, 54.8 ± 5.0 years) that comprised 41 adnexae (unilateral, 9; bilateral, 16) were analyzed. Seventeen (68.0%), 5 (20.0%), and 3 (12.0%) procedures were performed by consultant gynecologists, subspecialty/specialist trainees, and consultant gynecologic oncologists, respectively. Twelve of 25 procedures (48.0%) were laparoscopic, and 13 of 25 procedures (52.0%) involved laparotomy. Four of 25 patients (16.0%; 95% confidence interval, 4.5-36.1%) or 4 of 41 adnexae (9.8%; 95% confidence interval, 2.7-23.1%) showed residual microscopic fimbrial tissue on the ovarian surface. Tubes/ovaries were free of adhesions in 23 cases. Two cases had dense adnexal adhesions, but neither had residual fimbrial tissue on the ovary. Residual fimbrial tissue was not associated significantly with surgical route or experience (consultant, 3/20 [15%]; trainee, 1/5 [20%]; P=1.0). CONCLUSION: Residual fimbrial tissue remains on the ovary after salpingectomy in a significant proportion of cases and could impact the level of risk-reduction that is obtained.

A Case of Stage 4B Seromucinous Ovarian Borderline Tumor With Endometriosis and Review of the Literature.

Ovarian mucinous borderline tumors are traditionally divided into 2 morphologic groups: endocervical type, also known as seromucinous, and intestinal type. We present a case of stage 4B seromucinous ovarian borderline tumor with endometriosis and review the literature. At the time of writing, this is believed to be the first case of a seromucinous borderline tumor reported at such an advanced stage.

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma.

PURPOSE: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response. EXPERIMENTAL DESIGN: We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response. RESULTS: There was evidence of T-cell activation in omental biopsies after NACT: CD4(+) T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8(+) T-cell and CD45RO(+) memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3(+) T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. CONCLUSIONS: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025-36. ©2016 AACR.

Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma.

PURPOSE: To develop and validate a histopathologic scoring system for measuring response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIC to IV tubo-ovarian high-grade serous carcinoma. PATIENTS AND METHODS: A six-tier histopathologic scoring system was proposed and applied to a test cohort (TC) of 62 patients treated with neoadjuvant chemotherapy and interval debulking surgery. Adnexal and omental sections were independently scored by three pathologists. On the basis of TC results, a three-tier chemotherapy response score (CRS) system was developed and applied to an independent validation cohort of 71 patients. RESULTS: The initial system showed moderate interobserver reproducibility and prognostic stratification of TC patients when applied to the omentum but not to the adnexa. Condensed to a three-tier score, the system was highly reproducible (kappa, 0.75). When adjusted for age, stage, and debulking status, the score predicted progression-free survival (PFS; score 2 v 3; median PFS, 11.3 v 32.1 months; adjusted hazard ratio, 6.13; 95% CI, 2.13 to 17.68; P < .001). The three-tier CRS system applied to omental samples from the validation cohort showed high reproducibility (kappa, 0.67) and predicted PFS (CRS 1 and 2 v 3: median, 12 v 18 months; adjusted hazard ratio, 3.60; 95% CI, 1.69 to 7.66; P < .001). CRS 3 also predicted sensitivity to first-line platinum therapy (94.3% negative predictive value for progression < 6 months). A Web site was established to train pathologists to use the CRS system. CONCLUSION: The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research.

Risk reducing salpingectomy and delayed oophorectomy in high risk women: views of cancer geneticists, genetic counsellors and gynaecological oncologists in the UK.

Risk-reducing-salpingectomy and Delayed-Oophorectomy (RRSDO) is being proposed as a two-staged approach in place of RRSO to reduce the risks associated with premature menopause in high-risk women. We report on the acceptability/attitude of UK health professionals towards RRSDO. An anonymised web-based survey was sent to UK Cancer Genetics Group (CGG) and British Gynaecological Cancer Society (BGCS) members to assess attitudes towards RRSDO. Baseline characteristics were described using descriptive statistics. A Chi square test was used to compare categorical, Kendal-tau-b test for ordinal and Mann-Whitney test for continuous variables between two groups. 173/708 (24.4%) of invitees responded. 71% respondents (CGG = 57%/BGCS = 83%, p = 0.005) agreed with the tubal hypothesis for OC, 55% (CGG = 42%/BGCS = 66%, p = 0.003) had heard of RRSDO and 48% (CGG = 46%/BGCS = 50%) felt evidence was not currently strong enough for introduction into clinical practice. However, 60% respondents' (CGG = 48%/BGCS = 71%, p = 0.009) favoured offering RRSDO to high-risk women declining RRSO, 77% only supported RRSDO within a clinical trial (CGG = 78%/BGCS = 76%) and 81% (CGG = 76%/BGCS = 86%) advocated a UK-wide registry. Vasomotor symptoms (72%), impact on sexual function (63%), osteoporosis (59%), hormonal-therapy (55%) and subfertility (48%) related to premature menopause influenced their choice of RRSDO. Potential barriers to offering the two-stage procedure included lack of data on precise level of benefit (83%), increased surgical morbidity (79%), loss of breast cancer risk reduction associated with oophorectomy (68%), need for long-term follow-up (61%) and a proportion not undergoing DO (66%). There were variations in perception between BGCS/CGG members which are probably attributable to differences in clinical focus/expertise between these two groups. Despite concerns, there is reasonable support amongst UK clinicians to offering RRSDO to premenopausal high-risk women wishing to avoid RRSO, within a prospective clinical trial.

Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer.

BACKGROUND: Cervical cancer is the second commonest cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide. Sources suggest that a very high proportion of new cervical cancer cases in developing countries are at an advanced stage (IB2 or more) and more than a half of these may be stage III or IV. Cervical cancer staging is based on findings from clinical examination (FIGO) staging). Standard care in Europe and US for stage IB2 to III is non-surgical treatment (chemoradiation). However in developing countries, where there is limited access to radiotherapy, locally advanced cervical cancer may be treated with a combination of chemotherapy and hysterectomy (surgery to remove the womb and the neck of the womb, with or without the surrounding tissues). It is not certain if this improves survival. Therefore, it is important to systematically assess the value of hysterectomy in addition to radiotherapy or chemotherapy, or both, as an alternative intervention in the treatment of locally advanced cervical cancer (stage IB2 to III). OBJECTIVES: To determine whether hysterectomy, in addition to standard treatment with radiation or chemotherapy, or both, in women with locally advanced cervical cancer (stage IB2 to III) is safe and effective compared with standard treatment alone. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL, MEDLINE, EMBASE and LILACS up to February 2014. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that compared treatment protocols involving hysterectomy versus radiotherapy or chemotherapy, or both, in women with advanced stage (IB2 to III) cervical cancer presenting for the first time. DATA COLLECTION AND ANALYSIS: We assessed study eligibility independently, extracted data and assessed risk of bias. Where possible, overall and progression or disease-free survival outcomes were synthesised in a meta-analysis using the random-effects model. Adverse events were incompletely reported so results of single trials were described in narrative form. MAIN RESULTS: We included seven RCTs (1217 women) of varying methodological quality in the review; most trials were at moderate or high risk of bias.Three were multi-centre trials, two were single-centre trials, and in two trials it was unclear if they were single or multi-centre. These trials compared the following interventions for women with locally advanced cervical cancer (stages IB2 to III):hysterectomy (simple or radical) with radiotherapy (N = 194) versus radiotherapy alone (N = 180); hysterectomy (simple or radical) with chemoradiotherapy (N = 31) versus chemoradiotherapy alone (N = 30); hysterectomy (radical) with chemoradiotherapy (N = 111) versus internal radiotherapy with chemoradiotherapy (N = 100); hysterectomy (simple or radical) with upfront (neoadjuvant) chemotherapy (N = 298) versus radiotherapy alone (N = 273).One trial (N = 256) found no difference in the risk of death or disease progression between women who received attenuated radiotherapy followed by hysterectomy and those who received radiotherapy (external and internal) alone (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.61 to 1.29). This trial also reported no difference between the two groups in terms of adverse effects (18/129 grade 3 or 4 adverse effects in the hysterectomy and radiation group and 19 cases in 18/121 women in the radiotherapy alone group). There was no difference in 5-year tumour-free actuarial survival (representation of the probable years of survivorship of a defined population of participants) or severe complications (grade 3) in another trial (N = 118) which reported the same comparison (6/62 versus 6/56 in the radiation with surgery group versus the radiotherapy alone group, respectively). The quality of the evidence was low for all these outcomes.One trial (N = 61) reported no difference (P value > 0.10) in overall and recurrence-free survival at 3 years between chemoradiotherapy and hysterectomy versus chemoradiotherapy alone (low quality evidence). Adverse events and morbidity data were not reported.Similarly, another trial (N = 211) found no difference in the risk of death (HR 0.65, 95% CI 0.35 to 1.21, P value = 0.19, low quality evidence), disease progression (HR 0.70, 95% CI 0.31 to 1.34, P value = 0.24, low quality evidence) or severe late complications (P value = 0.53, low quality evidence) between women who received internal radiotherapy versus hysterectomy after both groups had received external-beam chemoradiotherapy.Meta analysis of three trials of neoadjuvant chemotherapy and hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received neoadjuvant chemotherapy plus hysterectomy had less risk of death than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93, I(2) = 0%, moderate quality evidence). However, a significant number of the participants that received neoadjuvant chemotherapy plus hysterectomy had radiotherapy as well. There was no difference in the proportion of women with disease progression or recurrence between the two groups (RR 0.75, 95% CI 0.53 to 1.05, I(2) = 20%, moderate quality evidence).Results of single trials reported no apparent (P value > 0.05) difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between the two groups (low quality evidence).Quality of life outcomes were not reported in any of the trials. AUTHORS' CONCLUSIONS: From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with locally advanced cervical cancer who are treated with radiotherapy or chemoradiotherapy alone. The overall quality of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The quality of the evidence for neoadjuvant chemotherapy and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate, with evidence from other comparisons of low quality. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials that assess medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.