Mismatch repair status and surgical approach in apparent early-stage endometrial cancer.

OBJECTIVE: To test the hypothesis that mismatch repair (MMR) status (as an accurate surrogate marker for microsatellite stability) modifies the effect of surgical approach on oncological outcome for apparent early-stage endometrial cancer. METHODS: Observational data from a large prospective population study on endometrial cancer were analyzed using target trial methodology and doubly robust methods, including propensity score matching and adjusted regression analyses. Laparoscopy was compared with laparotomy, stratified by MMR status on outcomes of recurrence and site, and recurrence-free, overall, and disease-specific survival. RESULTS: After matching, there were 400 patients for analysis, with 200 in each treatment group. The mean age was 62 years and mean body mass index was 32 kg/m2. Most patients had early-stage disease (stage I n=362 (90%)) and endometrioid histology (n=363 (91%)). Adjuvant pelvic radiation was administered to 11%, adjuvant vaginal brachytherapy to 13% and adjuvant chemotherapy to 5% of patients. Five-year recurrence-free survival did not differ significantly between modes of surgery across the cohort (p=0.7) or within MMR strata (MMR-proficient p=0.9, MMR-deficient p=0.6). Similarly, there was no significant difference in overall or disease-specific survival by mode of surgery across the cohort or within MMR strata. There was no significant difference in the HR for recurrence for those treated with laparoscopy stratified by MMR status (MMR-proficient HR=0.99 (95% CI 0.28 to 3.58); MMR-deficient HR=0.83 (95% CI 0.24 to 2.87)), even when restricted to endometrioid subtype. CONCLUSION: In this study, there was no evidence of a difference in survival outcomes according to mode of surgery and MMR status.

Uterine transposition for fertility preservation in pelvic cancers.

OBJECTIVE: To review rates of uterine preservation and gonadal function, surgical outcomes, and pregnancy outcomes in patients undergoing surgical uterine transposition. METHODS: A structured search and analysis of the published literature on uterine transposition was conducted. Information on study type, sample size, patient characteristics, clinical indications, details of the surgical technique, trans-operative and post-operative results, success rates in preserving reproductive organ function and fertility were extracted. RESULTS: A total of 18 cases were reported to date. Patients' median age was 29 (range 3-38) years. Rectal cancers accounted for 9 (50%) cases of published cases of uterine transposition, followed by 6 (33%) cervical squamous cell carcinomas, 1 (6%) vaginal squamous cell carcinoma, 1 (6%) sacral yolk sac tumor, and 1 (6%) pelvic liposarcoma. The median time for uterine transposition to the upper abdomen was 150 (range 80-360) min, and 90 (range 80-310) min for organ reimplantation in the pelvis. Cervical ischemia occurred in 5 (27.8%) cases, being the most commonly reported complication. The median follow-up time was 25 months, and three patients achieved spontaneous pregnancies resulting in successful gestations, out of five patients who were reported as having tried. One patient experienced recurrence and succumbed to the tumor during treatment. CONCLUSIONS: Uterine transposition is a feasible and safe surgical approach that offers patients undergoing pelvic radiotherapy an option to preserve gonadal and uterine function, with the potential for spontaneous pregnancy.

Consensus on surgical technique for sentinel lymph node dissection in cervical cancer.

OBJECTIVE: The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. METHODS: A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. RESULTS: Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. CONCLUSION: Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.

Pre-post feasibility trial of a telephone-delivered exercise intervention for patients during chemotherapy for recurrent ovarian cancer: the ECHO-R trial protocol.

INTRODUCTION: The benefits of exercise in reducing treatment-related morbidity and improving quality of life following a primary diagnosis of cancer have been well documented and have led to exercise being recommended by oncology societies for all people with a cancer diagnosis. However, these recommendations are derived from research typically involving cohorts with more common cancers and relatively good prognosis, such as breast and prostate. Evidence from these cancers may not apply to women with recurrent ovarian cancer. Therefore, the primary objective of this trial is to evaluate the feasibility and safety of a home-based, telephone-delivered exercise intervention for women undergoing chemotherapy for recurrent ovarian cancer. METHODS AND ANALYSIS: The Exercise During Chemotherapy for Recurrent Ovarian Cancer (ECHO-R) trial is a single-arm, phase II, pre/postintervention trial of a 6-month, telephone-delivered exercise intervention (consistent with recommended exercise oncology prescription). The target sample size is 80 women who are currently undergoing (or are scheduled to receive) chemotherapy for recurrent ovarian cancer. Recruitment is through participating hospital sites in Queensland, Australia, or via self-referral. The exercise intervention comprises 12 telephone sessions over a 6-month period delivered by trial-trained exercise professionals and supplemented (where feasible) by five sessions face to face. Exercise prescription is individualised and works towards an overall goal of achieving a weekly target of 150 min of moderate-intensity, mixed-mode exercise. Assessments via self-administered survey and physical fitness and function tests occur at baseline and then at 6 and 9 months postbaseline. Data to inform feasibility and safety are recorded as case notes by the exercise professional during each session. ETHICS AND DISSEMINATION: Ethics approval for the ECHO-R trial was granted by the Metro North Human Research Ethics Committee (HREC/2020/QRBW/67223) on 6 November 2020. Findings from the trial are planned to be disseminated via peer-reviewed publications and both national and international exercise and oncology conferences. TRIAL REGISTRATION NUMBER: ACTRN12621000042842.

Feasibility and safety of a surgical training program in total laparoscopic hysterectomy: Results of a pilot trial.

BACKGROUND: It is widely accepted total laparoscopic hysterectomy (TLH) and vaginal hysterectomy are less invasive procedures compared to total abdominal hysterectomy (TAH). However, rates of TAH remain unreasonably high. AIM: To pilot-test a model of training for practising obstetricians and gynaecologists (O&Gs) in TLH. MATERIALS AND METHODS: Training of participating O&Gs was conducted across four hospitals in Queensland, Australia, while other O&Gs were observed as contemporary controls. Type of hysterectomy, details of the surgery, including adverse events, were collected from hospital medical records. RESULTS: Eleven O&Gs completed the pre-intervention and intervention training periods, and nine completed the post-intervention follow-up. TLH rates increased from 24% prior to 75% during and 68% after intervention. Overall, the uptake rate of TLH showed a two-fold increase during the intervention period (2.08, 95% CI: 1.16-8.56, P < 0.001) and a 12% increase was retained during the follow-up period (1.12, 95% CI: 0.54-4.02, P = 0.427). Pre-intervention, across all sites, 24% of hysterectomies were performed via TAH by the participating specialist trainees, which decreased to 13% during the intervention and 14% during follow-up. The rate of adverse events decreased from 13.5% at pre-intervention, to 6.4% during and 4.2% post-intervention. By comparison, no change in surgical approach or rate of adverse events was observed in the control group. CONCLUSIONS: The implementation of a formal and structured surgical training program teaching TLH resulted in important benefits to trainees, patients and society in the four trial hospitals.

Experience of practicing obstetrician-gynecologists in a surgical training program in total laparoscopic hysterectomy.

BACKGROUND: Advanced surgical techniques, such as total laparoscopic hysterectomy, are often challenging to acquire beyond fellowship training programs for practicing obstetrician-gynecologists. A lack of formative data currently exist for continuing medical education programs, limiting our understanding of how improvement in surgical skills and training programs occur. OBJECTIVE: This study aimed to investigate how practicing obstetrician-gynecologists acting as trainees experience a program that aims to teach them total laparoscopic hysterectomy, and to assess whether their surgical skills improve according to data from formative assessment tools and qualitative data from open-ended survey questions and in-depth interviews. STUDY DESIGN: We report a process analysis of formative data collected during a pilot implementation trial of a surgical training program targeting practicing obstetrician-gynecologists. Eleven consultant obstetrician-gynecologists and 4 experienced surgical mentors participated in 4 hospitals in Queensland, Australia. Total laparoscopic hysterectomy was performed in 700 patients over the course of the study. A total laparoscopic hysterectomy surgical mentorship training program of 10 training days with up to 3 total laparoscopic hysterectomy procedures per day was performed. Both the obstetrician-gynecologists and the surgical mentor completed a formative assessment questionnaire analyzing the trainee's performance after each surgical procedure. Mentors were formatively assessed by the Structured Training Trainer Assessment Report (STTAR) and at the completion of the study by the mini-STTAR, a summative assessment of quality of mentorship. Obstetrician-gynecologists, mentors, hospital leaders, and surgical administrative staff participated in qualitative interviews about the training program. RESULTS: Over time, there was a demonstrated improvement in trainee performance reported by both mentors and trainees in all competency assessment tool domains as the case number increased, with mentors consistently rating trainees' performance higher than the trainees themselves. Most trainees were satisfied with their mentor in all 31 areas during formative assessment, and at the end of the training, structure, attributes, and role modeling were all rated high (average score >4.5; range, 3.79-5.00), whereas training behavior was rated slightly lower at 4.1 (range, 3.79-4.45). Qualitative interviews demonstrated that the trainees found the training to be a beneficial, hands-on experience. CONCLUSION: Formative assessment clearly documented improvement in surgical skills during a total laparoscopic hysterectomy training program for consultant obstetrician-gynecologists.

Efficacy of exercise interventions for women during and after gynaecological cancer treatment - a systematic scoping review.

PURPOSE: To systematically synthesise evidence of exercise intervention efficacy for physical/psychosocial outcomes that matter to women during/following treatment for gynaecological cancer. METHODS: Five databases were searched (PubMed, EMBASE, CINAHL, PsychInfo, Scopus). Exercise-only intervention studies that included women during/ following treatment for any gynaecological cancer, with/ without control comparison, on any physical or psychosocial outcome(s), were included and qualitatively appraised using the Revised Cochrane Risk of Bias tool and a modified Newcastle-Ottawa Scale. RESULTS: Seven randomised controlled trials (RCTs), three single-arm pre-post studies, and one prospective cohort study satisfied were included (11 studies). Most studies were completed following treatment (91%), included combined (aerobic and resistance; 36%) and aerobic (36%) training, were fully/mostly (63%) unsupervised, and had a moderate-to-high risk of bias. Overall, 33 outcomes (64% objectively-measured) were assessed. Improvements were observed in aerobic capacity (V̇O2 Peak +1.6 mL/kg/min, 6-minute walk distance +20-27 m), lower- (30-second sit-to-stand +2-4 repetitions) and upper-limb strength (30-second arm curl +5 repetitions; 1RM grip strength/chest press +2.4-3.1 kg), and agility (timed up-and-go -0.6 seconds). However, changes in quality of life, anthropometry/body composition, balance and flexibility were inconsistent. There was no evidence to support worsening of outcomes. CONCLUSION: Preliminary research into the role of exercise post-gynaecological cancer suggests an improvement in exercise capacity, muscular strength, and agility which, in the absence of exercise, typically decline following gynaecological cancer. Future exercise trials involving larger and more diverse gynaecological cancer samples will improve understanding of the potential and magnitude of effect of guideline-recommended exercise on outcomes that matter to patients.

Exercise during CHemotherapy for Ovarian cancer (ECHO) trial: design and implementation of a randomised controlled trial.

INTRODUCTION: Epidemiological evidence supports an association between higher levels of physical activity and improved cancer survival. Trial evidence is now needed to demonstrate the effect of exercise in a clinical setting. The Exercise during CHemotherapy for Ovarian cancer (ECHO) trial is a phase III, randomised controlled trial, designed to determine the effect of exercise on progression-free survival and physical well-being for patients receiving first-line chemotherapy for ovarian cancer. METHODS AND ANALYSIS: Participants (target sample size: n=500) include women with newly diagnosed primary ovarian cancer, scheduled to receive first-line chemotherapy. Consenting participants are randomly allocated (1:1) to either the exercise intervention (plus usual care) or usual care alone, with stratification for recruitment site, age, stage of disease and chemotherapy delivery (neoadjuvant vs adjuvant). The exercise intervention involves individualised exercise prescription with a weekly target of 150 minutes of moderate-intensity, mixed-mode exercise (equivalent to 450 metabolic equivalent minutes per week), delivered for the duration of first-line chemotherapy through weekly telephone sessions with a trial-trained exercise professional. The primary outcomes are progression-free survival and physical well-being. Secondary outcomes include overall survival, physical function, body composition, quality of life, fatigue, sleep, lymphoedema, anxiety, depression, chemotherapy completion rate, chemotherapy-related adverse events, physical activity levels and healthcare usage. ETHICS AND DISSEMINATION: Ethics approval for the ECHO trial (2019/ETH08923) was granted by the Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Zone) on 21 November 2014. Subsequent approvals were granted for an additional 11 sites across Queensland, New South Wales, Victoria and the Australian Capital Territory. Findings from the ECHO trial are planned to be disseminated via peer-reviewed publications and international exercise and oncology conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry (ANZCTRN12614001311640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367123&isReview=true).

The potential role of GLP-1 receptor agonist targeting in fertility-sparing treatment in obese patients with endometrial malignant pathology: a call for research.

INTRODUCTION: Most patients diagnosed with endometrial hyperplasia or cancer are obese. Obesity, along with polycystic ovarian syndrome (PCOS) and type-2 diabetes mellitus (T2DM), may act synergistically to increase risk of malignant endometrial pathology. Incidence of malignant endometrial pathology is increasing, particularly in reproductive aged women. In patients who desire future fertility, the levonorgestrel intrauterine device (LNG-IUD) is often utilized. If the first-line progestin therapy fails, there is not an effective second-line adjunct option. Moreover, pregnancy rates following fertility-sparing treatment are lower-than-expected in these patients. AREAS COVERED: This clinical opinion provides a summary of recent studies exploring risk factors for the development of malignant endometrial pathology including obesity, PCOS, and T2DM. Studies assessing efficacy of fertility-sparing treatment of malignant endometrial pathology are reviewed, and a potential new adjunct treatment approach to LNG-IUD is explored. EXPERT OPINION: There is an unmet-need for a personalized treatment approach in cases of first-line progestin treatment failure. Glucagon-like peptide 1 receptor agonists are a class of anti-diabetic agents, but may have a role in fertility-sparing treatment of obese patients with malignant endometrial pathology by reducing weight, decreasing inflammation, and decreasing insulin resistance; these changes may also improve chances of subsequent pregnancy. This hypothesis warrants further exploration.

Common analgesics and ovarian cancer survival: the Ovarian cancer Prognosis And Lifestyle (OPAL) Study.

BACKGROUND: Most women with ovarian cancer (OC) are diagnosed with advanced disease. They often experience recurrence after primary treatment, and their subsequent prognosis is poor. Our goal was to evaluate the association between use of nonsteroidal antiinflammatory drugs (NSAIDs), including regular and low-dose aspirin, and 5-year cancer-specific survival after an OC diagnosis. METHODS: The Ovarian cancer Prognosis And Lifestyle study is a prospective population-based cohort of 958 Australian women with OC. Information was gathered through self-completed questionnaires. We classified NSAID use during the year prediagnosis and postdiagnosis as none or occasional (<1 d/wk), infrequent (1-3 d/wk), and frequent (≥4 d/wk) use. We measured survival from the start of primary treatment: surgery or neoadjuvant chemotherapy for analyses of prediagnosis use, or 12 months after starting treatment (postdiagnosis use) until the earliest of date of death from OC (other deaths were censored) or last follow-up to 5 years. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) and applied inverse-probability of treatment weighting to minimize confounding. We also calculated restricted mean survival times. RESULTS: Compared with nonusers and infrequent users, we observed better survival associated with frequent NSAID use prediagnosis (HR = 0.73, 95% CI = 0.55 to 0.97) or postdiagnosis (HR = 0.65, 95% CI = 0.45 to 0.94). Estimates were similar for aspirin and nonaspirin NSAIDs, new and continuous users and in weighted models. These differences would translate to a 2.5-month increase in mean survival by 5 years postdiagnosis. There was no association with acetaminophen. CONCLUSIONS: Our findings confirm a previous study suggesting NSAID use might improve OC survival.

Groin Surveillance by Serial Ultrasonography Rather Than Sentinel Node Biopsy or Inguinofemoral Lymphadenectomy for Patients with Vulvar Cancer: A Pilot Study.

A pilot study was conducted to determine whether 3-monthly groin ultrasonography could eliminate groin dissection after a negative bilateral groin ultrasound in three groups of patients: (i) Those with a unifocal stage 1B squamous cell carcinoma of up to 20 mm in diameter. (ii) Those with an ipsilateral squamous cell carcinoma of any size which extended to within 1 cm either side of the midline. These patients underwent ipsilateral inguinofemoral lymphadenectomy and ultrasonic surveillance of the contralateral groin. (iii) Patients with multifocal invasive lesions with the largest individual focus 20 mm or less in diameter. Three additional patients were added because they either refused groin dissection or were considered unfit for surgery. All ultrasonically positive nodes were confirmed histologically. Thirty-two patients were entered, and no patients were lost to follow-up. Forty-three groins were followed. With a median follow-up of 37 months, three positive nodes (9.4%) were detected. One patient died of her recurrence (3.1%), and 39 groins (90.7%) were preserved. The overall sensitivity of ultrasonic surveillance was 100% (95% CI: 44-100%), with a specificity of 97% (95% CI: 83-99%) and a negative predictive value of 100% (95% CI: 88-100%). This pilot justifies a larger study on serial ultrasonography in lieu of groin dissection in selected patients with vulvar cancer.

Role of adjuvant therapy in intermediate-risk cervical cancer patients - Subanalyses of the SCCAN study.

OBJECTIVE: The "intermediate-risk" (IR) group of early-stage cervical cancer patients is characterized by negative pelvic lymph nodes and a combination of tumor-related prognostic risk factors such as tumor size ≥2 cm, lymphovascular space invasion (LVSI), and deep stromal invasion. However, the role of adjuvant treatment in these patients remains controversial. We investigated whether adjuvant (chemo)radiation is associated with a survival benefit after radical surgery in patients with IR cervical cancer. METHODS: We analyzed data from patients with IR cervical cancer (tumor size 2-4 cm plus LVSI OR tumor size >4 cm; N0; no parametrial invasion; clear surgical margins) who underwent primary curative-intent surgery between 2007 and 2016 and were retrospectively registered in the international multicenter Surveillance in Cervical CANcer (SCCAN) study. RESULTS: Of 692 analyzed patients, 274 (39.6%) received no adjuvant treatment (AT-) and 418 (60.4%) received radiotherapy or chemoradiotherapy (AT+). The 5-year disease-free survival (83.2% and 80.3%; PDFS = 0.365) and overall survival (88.7% and 89.0%; POS = 0.281) were not significantly different between the AT- and AT+ groups, respectively. Adjuvant (chemo)radiotherapy was not associated with a survival benefit after adjusting for confounding factors by case-control propensity score matching or in subgroup analyses of patients with tumor size ≥4 cm and <4 cm. In univariable analysis, adjuvant (chemo)radiotherapy was not identified as a prognostic factor in any of the subgroups (full cohort: PDFS = 0.365; POS = 0.282). CONCLUSION: Among patients with IR early-stage cervical cancer, radical surgery alone achieved equal disease-free and overall survival rates to those achieved by combining radical surgery with adjuvant (chemo)radiotherapy.

Collaborative centralization of gynaecological cancer care.

PURPOSE OF REVIEW: To discuss the benefits of centralization of gynaecological cancer care on patients and the healthcare system and how to overcome its barriers. RECENT FINDINGS: Evidence demonstrates that adherence to clinical practice management guidelines is more likely; the risk of adverse events is lower; survival is improved; in young women fertility preservation is higher; and cost effectiveness is higher; in systems that employ centralized care for women with gynaecological cancer. Barriers to the uptake of centralized models include knowledge, attitude as well as deficient systems and processes, including a lack of governance and leadership. Collaborative centralization refers to a model that sees both elements (centralization and treatment closer to home) utilized at the patient level that addresses some of the barriers of centralized gynaecological cancer care. SUMMARY: Evidence supports centralized gynaecological cancer care, as it results in reduced risks of adverse events, improved survival and higher fertility rates at lower cost to funders. Collaborative centralization is a process that considers both the value of centralization and collaboration amongst healthcare professionals at primary, secondary and tertiary levels of healthcare to benefit patient outcomes.

Toward Incorporating Health-Related Quality of Life as Coprimary End Points in Clinical Trials: Time to Achieve Clinical Important Differences and QoL Profiles.

PURPOSE: Besides morbidity and mortality, quality of life (QoL) is a key outcome of cancer treatments. Trials on the basis of clinical outcomes have expectations that QoL outcomes can be either tolerated or improved. Simultaneously considering QoL and clinical outcomes is challenging with lack of suitable metrics allowing incorporation of QoL as coprimary end points in clinical trial design and utilization of hierarchical hypothesis testing. METHOD: We propose combining time to achieving a minimal clinically important difference (MCID) and probabilities of a MCID occurring in each QoL domain to provide QoL metrics analogous to those used for clinical end points. For QoL domains of interest, these yield QoL profiles, time to MCID, and number needed to treat. Incorporation of QoL as coprimary end points in clinical trial designs through hierarchical hypothesis testing can easily be achieved. The noninferiority designed Laparoscopic Approach to Carcinoma of the Endometrium trial, evaluating laparoscopic versus open abdominal surgery for endometrial cancer with Functional Assessment of Cancer Therapy-General QoL domains, is used to illustrate the usefulness of these metrics. RESULTS: This analysis revealed that laparoscopic surgery had a significant shorter time to MCID for physical and functional well-being QoL domains (physical mean: 1.5 months, 95% CI, 0.5 to 2.6; P = .002; and functional mean: 1.4 months; 95% CI, 0.4 to 2.4; P = .003) than abdominal surgery, but little difference between the two approaches for psychologic social and emotion well-being. Probability profile plots show a consistent > 2-fold higher chance of attaining a MCID for physical and functional well-being over time for laparoscopic compared with abdominal surgery. CONCLUSION: This analysis reinforces the potential value of novel MCID metrics and their usefulness in raising the profile of QoL outcomes to complement clinical end points. The methods will allow health professionals to counsel patients about QoL outcomes and clinical outcomes simultaneously.

Germline BRCA variants, lifestyle and ovarian cancer survival.

OBJECTIVE: Women with ovarian cancer who have a pathogenic germline variant in BRCA1 or BRCA2 (BRCA) have been shown to have better 5-year survival after diagnosis than women who are BRCA-wildtype (non-carriers). Modifiable lifestyle factors, including smoking, physical activity and body mass index (BMI) have previously been associated with ovarian cancer survival; however, it is unknown whether these associations differ by germline BRCA status. METHODS: We investigated measures of lifestyle prior to diagnosis in two cohorts of Australian women with invasive epithelial ovarian cancer, using Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In the combined studies (n = 1923), there was little association between physical activity, BMI or alcohol intake and survival, and no difference by BRCA status. However, the association between current smoking status before diagnosis and poorer survival was stronger for BRCA variant carriers (HR 1.98; 95% CI 1.20-3.27) than non-carriers (HR 1.18; 95% CI 0.96-1.46; p-interaction 0.02). We saw a similar differential association with smoking when we pooled results from two additional cohorts from the USA and UK (n = 2120). Combining the results from all four studies gave a pooled-HR of 1.94 (95% CI 1.28-2.94) for current smoking among BRCA variant carriers compared to 1.08 (0.90-1.29) for non-carriers. CONCLUSIONS: Our results suggest that the adverse effect of smoking on survival may be stronger for women with a BRCA variant than those without. Thus, while smoking cessation may improve outcomes for all women with ovarian cancer, it might provide a greater benefit for BRCA variant carriers.