John R. McLaughlin

Uptake of clinical genetic testing for ovarian cancer in Ontario: A population-based study

BACKGROUND Approximately 13% of ovarian cancers in Canada are attributable to a mutation in BRCA1 or BRCA2. In 2001, genetic testing for BRCA1 and BRCA2 became freely available to all women in Ontario with a diagnosis of invasive ovarian cancer. It is unknown what proportion of women with ovarian cancer receive genetic testing as a result of this recommendation. METHODS Patients in Ontario who had been diagnosed with epithelial ovarian cancer from 2002 to 2004 were identified using the Ontario Cancer Registry. Information was collected on demographic and risk factors, including information on previous testing for BRCA1 and BRCA2. Women were asked to provide a blood sample for genetic testing or to provide a genetic test result if clinical testing had been done. Genetic testing for BRCA1 and BRCA2 mutations was conducted on all blood samples. RESULTS Of the 416 women, 80 women (19%) had undergone previous clinical genetic testing for BRCA1 and BRCA2. Of these 80 women, 30% had a positive genetic test result, compared to 5% of 336 women who had not had clinical genetic testing (p<0.0001). Sixty percent of all mutations were identified within this group of 80 women. CONCLUSIONS Genetic testing is available in Ontario to all women with invasive ovarian cancer. However, only a small proportion of women are being referred for testing. This study suggests that increased public awareness directed at physicians and at women with cancer may expand the use of genetic testing.

Dietary patterns and colorectal cancer recurrence and survival: a cohort study

Objective To examine the association between dietary patterns and colorectal cancer (CRC) survival. Design Cohort study. Setting A familial CRC registry in Newfoundland. Participants 529 newly diagnosed CRC patients from Newfoundland. They were recruited from 1999 to 2003 and followed up until April 2010. Outcome measure Participants reported their dietary intake using a food frequency questionnaire. Dietary patterns were identified with factor analysis. Multivariable Cox proportional hazards models were employed to estimate HR and 95% CI for association of dietary patterns with CRC recurrence and death from all causes, after controlling for covariates. Results Disease-free survival (DFS) among CRC patients was significantly worsened among patients with a high processed meat dietary pattern (the highest vs the lowest quartile HR 1.82, 95% CI 1.07 to 3.09). No associations were observed with the prudent vegetable or the high-sugar patterns and DFS. The association between the processed meat pattern and DFS was restricted to patients diagnosed with colon cancer (the highest vs the lowest quartile: HR 2.29, 95% CI 1.19 to 4.40) whereas the relationship between overall survival (OS) and this pattern was observed among patients with colon cancer only (the highest vs the lowest quartile: HR 2.13, 95% CI 1.03 to 4.43). Potential effect modification was noted for sex (p value for interaction 0.04, HR 3.85 for women and 1.22 for men). Conclusions The processed meat dietary pattern prior to diagnosis is associated with higher risk of tumour recurrence, metastasis and death among patients with CRC.

Height, weight, BMI and ovarian cancer survival.

OBJECTIVES Ovarian cancer is a highly fatal gynecologic malignancy. Prognosis is primarily based on clinicopathologic features. There is interest in the role of modifiable factors including overweight and obesity, although data to date have been inconclusive. Here we evaluate the relationship between body size and ovarian cancer survival among 1423 women diagnosed with epithelial ovarian cancer in a large population-based study. METHODS Information on risk factors and characteristics was collected by telephone. Vital status was determined both by computerized record-linkage and by chart review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for height, weight and body mass index (BMI) in association with ovarian cancer-specific mortality. RESULTS Height, weight and BMI 5 years prior to diagnosis did not significantly predict ovarian cancer survival in this study. The HR for ovarian cancer-specific mortality for women with a weight of >61 kg compared with >50-55 kg was 0.91 (95%CI 0.71-1.20). The HR among women with a BMI≥30 kg/m2 compared to 18.5-<25 kg/m2 was 1.11 (95%CI 0.87-1.42). These findings did not vary by histologic subtype. CONCLUSIONS Our results do not support a role of height, adult weight or adiposity in ovarian cancer prognosis.

Telomere Length and Mortality Following a Diagnosis of Ovarian Cancer

Background: Telomeres are essential for the maintenance of chromosomal integrity. Telomere shortening leads to genomic instability, which is hypothesized to play a role in cancer development and prognosis. No studies to date have evaluated the prognostic significance of telomere length for ovarian cancer. Methods: We examined whether relative telomere length in peripheral blood leukocytes was associated with survival following a diagnosis of ovarian cancer. We analyzed data from a large population-based study of incident ovarian cancer conducted in Ontario between 1995 and 2004. Telomere length was measured using the quantitative PCR–based relative telomere length assay and vital status was determined by computerized record linkage and by chart review (n = 1,042). Proportional hazard models were used to estimate ovarian cancer–specific survival HRs and 95% confidence intervals (CI) associated with quartiles of telomere length z score. Results: We found no significant relationship between telomere length and ovarian cancer–specific mortality (P log-rank test = 0.55). Compared with women in the lowest quartile of telomere length z score, the HR for women in the highest three quartiles of telomere length z score combined was 0.88 (95% CI, 0.77–1.10). The corresponding estimates for serous and nonserous tumors were 0.68 (95% CI, 0.66–1.13) and 1.13 (95% CI, 0.71–1.79), respectively. Conclusions: Our data provide preliminary evidence that telomere length likely does not predict outcome after a diagnosis of ovarian cancer. Impact: This represents the first study to suggest no prognostic role of telomere length for ovarian cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2603–6. ©2014 AACR.

Interaction between alcohol drinking and obesity in relation to colorectal cancer risk: a case-control study in Newfoundland and Labrador, Canada

BackgroundWhile substantive epidemiological literature suggests that alcohol drinking and obesity are potential risk factors of colorectal cancer (CRC), the possible interaction between the two has not been adequately explored. We used a case-control study to examine if alcohol drinking is associated with an increased risk of CRC and if such risk differs in people with and without obesity.MethodsNewly diagnosed CRC cases were identified between 1999 and 2003 in Newfoundland and Labrador (NL). Cases were frequency-matched by age and sex with controls selected using random digit dialing. Cases (702) and controls (717) completed self-administered questionnaires assessing health and lifestyle variables. Estimates of alcohol intake included types of beverage, years of drinking, and average number of alcohol drinks per day. Odds ratios were estimated to investigate the associations of alcohol independently and when stratified by obesity status on the risk of CRC.ResultsAmong obese participants (BMI ≥ 30), alcohol was associated with higher risk of CRC (OR: 2.2; 95% CI: 1.2-4.0) relative to the non-alcohol category. Among obese individuals, 3 or more different types of drinks were associated with a 3.4-fold higher risk of CRC relative to non-drinkers. The risk of CRC also increased with drinking years and drinks daily among obese participants. However, no increased risk was observed in people without obesity.ConclusionThe effect of alcohol of drinking on CRC seems to be modified by obesity.

Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models.

BackgroundAccurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias.MethodsA cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. Johns, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females.ResultsLifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females compared to their male counterparts (Females = 23.7, 95%CI = (5.6, 137.9); Males = 6.8%, 95% CI = (2.3, 66.2)). However, the risk of developing CRC decreased with age among both genders.ConclusionThe proposed modified segregation-based models used to estimate age-specific risks for HNPCC phenotypes can reduce bias due to ascertainment and missing genotype information as well as provide estimates of absolute and relative risks.

Risk of breast cancer after a diagnosis of ovarian cancer in BRCA mutation carriers: Is preventive mastectomy warranted?

OBJECTIVE Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. METHODS First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality. RESULTS Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer. CONCLUSIONS Among BRCA mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer.

Polycystic ovary syndrome, oligomenorrhea, and risk of ovarian cancer histotypes: Evidence from the Ovarian Cancer Association Consortium

Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies. Methods: We analyzed data from 14 case–control studies including 16,594 women with invasive ovarian cancer (n = 13,719) or borderline ovarian disease (n = 2,875) and 17,718 controls. Adjusted study-specific ORs were calculated using logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression. Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length ≤35 days [OR = 0.70; 95% confidence interval (CI) = 0.58–0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76–0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65–1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors (Pheterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors (Pheterogeneity < 0.0001). Conclusions: Our results suggest that menstrual cycle characteristics influence ovarian cancer risk differentially based on histotype. Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174–82. ©2017 AACR.