Jenny Chang-Claude

Causal Effects of Breast Cancer Risk Factors across Hormone Receptor Breast Cancer Subtypes: A Two-Sample Mendelian Randomization Study

Abstract Background: It is unclear if established breast cancer risk factors exert similar causal effects across hormone receptor breast cancer subtypes. We estimated and compared causal estimates of height, body mass index (BMI), type 2 diabetes, age at menarche, age at menopause, breast density, alcohol consumption, regular smoking, and physical activity across these subtypes. Methods: We used a two-sample Mendelian randomization approach and selected genetic instrumental variables from large-scale genome-wide association studies. Publicly available summary-level Breast Cancer Association Consortium data (n = 247,173; 133,384 cases, 113,789 controls) for the following subtypes were included: luminal A–like (45,253 cases), luminal B–/HER2-negative–like (6,350 cases), luminal B–like (6,427 cases), HER2-enriched (2,884 cases), and triple-negative (8,602 cases). We employed multiple Mendelian randomization methods to evaluate the strength of causal evidence for each risk factor–subtype association. Results: Collectively, our analyses indicated that increased height and decreased BMI are probable causal risk factors for all five subtypes. For the other risk factors, the strength of evidence for causal effects differed across subtypes. Heterogeneity in the magnitude of causal effect estimates for age at menopause and breast density was explained by null findings for triple-negative tumors. Regular smoking was the sole risk factor for which there was no evidence of a causal effect on any subtype. Conclusions: This study suggests that established breast cancer risk factors differ across hormone receptor subtypes. Impact: Our results are valuable for the development of primary prevention strategies, improvement of breast cancer risk stratification in the general population, and identification of novel breast cancer risk factors.

Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Abstract Background Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. Methods A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. Results Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. Conclusions Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

An exercise and nutrition intervention for ovarian cancer patients during and after first-line chemotherapy (BENITA study): a randomized controlled pilot trial

Data on the treatment-supporting effect of modifiable lifestyle factors such as nutrition and physical activity on survival or quality of life (QoL) are scarce in patients with ovarian cancer. Despite a strong rationale for evaluating the effect of a multimodal intervention and multiple studies targeting other cancer sites, randomized controlled trials (RCTs) on the effects of a combined nutrition and exercise intervention on survival and QoL in ovarian cancer patients are rare. No study has investigated the impact of an early intervention during first-line chemotherapy. To evaluate the study design, feasibility, safety, and acceptance of combined nutrition and exercise in patients diagnosed with ovarian cancer during and after first-line chemotherapy. Physical exercise and a cancer-specific nutrition intervention after ovarian cancer diagnosis is feasible, accepted, and safe for patients receiving first-line chemotherapy. A 1:1 RCT with an intervention group and a control group. The intervention group receives an exercise and nutrition program whereas the control group continues to follow the usual care. Inclusion: women ≥18 years of age; women diagnosed with ovarian cancer, tubal cancer, or peritoneal cancer and primary or interval debulking surgery. Exclusion: Eastern Cooperative Oncology Group (ECOG) status of 2 or worse. Recruitment rate, completion rate, side effects, and adherence. n=30 patients (15 per arm) will be recruited. Accrual completion is planned for the end of 2019. Results will be presented in the months following study completion 1 year after recruitment has been finalised. The pilot phase was approved by the ethics committee of the Medical Faculty of Hamburg on December 13, 2017 (PV5456). The study was registered on September 9, 2018 at the German Study Registry for Clinical Studies (DRKS00013231).

Randomised controlled trial testing the feasibility of an exercise and nutrition intervention for patients with ovarian cancer during and after first-line chemotherapy (BENITA-study)

Objectives Advanced ovarian cancer is a severe disease with major side effects caused by peritoneal carcinomatosis, ascites and gastrointestinal involvement as well as exhaustive treatment like debulking surgery and combination chemotherapy. Two most frequently reported side effects are muscle wasting and malnutrition, leading to frailty, decreased health-related quality of life (HRQoL) and cancer-related fatigue (CRF). As muscle wasting and malnutrition often commence during first-line chemotherapy and develop progressively into a refractory state, an early intervention is warranted. This pilot study aimed to evaluate the safety and acceptance of a combined exercise and nutrition intervention during and after first-line chemotherapy. Design The pilot study was conducted as a monocentric 1:1 randomised controlled trial (RCT) with an intervention group (IG) and a control group (CG). Participants were divided by chance into IG or CG. Information on group allocation was conveyed to the study coordinator responsible for making an appointment with the patients for the baseline assessment as well as the physiotherapist and nutritionist responsible for the intervention and outcome assessment in both groups. Participants Eligibility criteria included women ≥18 years of age, diagnosed with ovarian cancer, tubal cancer or peritoneal cancer and primary or interval debulking, scheduled but not started adjuvant or neoadjuvant chemotherapy and sufficient German-language skills. Intervention The IG received a 12-month exercise and nutrition programme, the CG continued to follow usual care. Primary and secondary outcome measures Primary outcomes were recruitment rate, adherence to intervention, completion rate and adverse events. In addition, in-person assessments (eg, HRQoL, CRF, muscle quality and function and dietary intake and quality) were conducted at baseline (T0, before chemotherapy), week 9 (T1, mid-chemotherapy), week 19 (T2, after completion of chemotherapy) and after 12 months of intervention (T3). Results Of 60 eligible patients, 15 patients signed informed consent (recruitment rate=25.0%) and were randomised into IG (n=8) and CG (n=7). Eleven participants completed the study (completion rate, 73.3%), one patient dropped out due to loss of interest, one due to poor health, one was lost to follow-up and one patient died. Conclusion The BENITA (Bewegungs- und Ernährungsintervention bei Ovarialkrebs) study demonstrated the safety and acceptance of an exercise and nutrition intervention integrated into first-line therapy and follow-up care of ovarian cancer. A large multicentre RCT is planned to investigate the effectiveness of the intervention on HRQoL, CRF and survival and to establish means of implementation into oncology guidelines and clinic routine. Trial registration number DRKS00013231.

Reproductive Factors Do Not Influence Survival with Ovarian Cancer

Abstract Background: Previous studies on the association between reproductive factors and ovarian cancer survival are equivocal, possibly due to small sample sizes. Methods: Using data on 11,175 people diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer (ovarian cancer) from 16 studies in the Ovarian Cancer Association Consortium (OCAC), we examined the associations between survival and age at menarche, combined oral contraceptive use, parity, breastfeeding, age at last pregnancy, and menopausal status using Cox proportional hazard models. The models were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study and stratified on stage and histotype. Results: During the mean follow-up of 6.34 years (SD = 4.80), 6,418 patients passed away (57.4%). There was no evidence of associations between the reproductive factors and survival among patients with ovarian cancer overall or by histotype. Conclusions: This study found no association between reproductive factors and survival after an ovarian cancer diagnosis. Impact: Reproductive factors are well-established risk factors for ovarian cancer, but they are not associated with survival after a diagnosis of ovarian cancer.