METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models.
RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537).
CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.
Objective: To evaluate mainstream genetic testing using cancer-based criteria in patients with cancer.
Design, Setting, and Participants: A quality improvement study and cost-effectiveness analysis of different BRCA testing selection criteria and access procedures to evaluate feasibility, acceptability, and mutation detection performance was conducted at the Royal Marsden National Health Service Foundation Trust as part of the Mainstreaming Cancer Genetics (MCG) Programme. Participants included 1184 patients with cancer who were undergoing genetic testing between September 1, 2013, and February 28, 2017.
Main Outcomes and Measures: Mutation rates, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were the primary outcomes.
Results: Of the 1184 patients (1158 women [97.8%]) meeting simple cancer-based criteria, 117 had a BRCA mutation (9.9%). The mutation rate was similar in retrospective United Kingdom (10.2% [235 of 2294]) and prospective Malaysian (9.7% [103 of 1061]) breast cancer studies. If traditional family history criteria had been used, more than 50% of the mutation-positive individuals would have been missed. Of the 117 mutation-positive individuals, 115 people (98.3%) attended their genetics appointment and cascade to relatives is underway in all appropriate families (85 of 85). Combining with the equivalent ovarian cancer study provides 5 simple cancer-based criteria for BRCA testing with a 10% mutation rate: (1) ovarian cancer; (2) breast cancer diagnosed when patients are 45 years or younger; (3) 2 primary breast cancers, both diagnosed when patients are 60 years or younger; (4) triple-negative breast cancer; and (5) male breast cancer. A sixth criterion-breast cancer plus a parent, sibling, or child with any of the other criteria-can be added to address family history. Criteria 1 through 5 are considered the MCG criteria, and criteria 1 through 6 are considered the MCGplus criteria. Testing using MCG or MCGplus criteria is cost-effective with cost-effectiveness ratios of $1330 per discounted QALYs and $1225 per discounted QALYs, respectively, and appears to lead to cancer and mortality reductions (MCG: 804 cancers, 161 deaths; MCGplus: 1020 cancers, 204 deaths per year over 50 years). Use of MCG or MCGplus criteria might allow detection of all BRCA mutations in patients with breast cancer in the United Kingdom through testing one-third of patients. Feedback questionnaires from 259 patients and 23 cancer team members (12 oncologists, 8 surgeons, and 3 nurse specialists) showed acceptability of the process with 100% of patients pleased they had genetic testing and 100% of cancer team members confident to approve patients for genetic testing. Use of MCGplus criteria also appeared to be time and resource efficient, requiring 95% fewer genetic consultations than the traditional process.
Conclusions and Relevance: This study suggests that mainstream testing using simple, cancer-based criteria might be able to efficiently deliver consistent, cost-effective, patient-centered BRCA testing.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7).
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.
METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.
RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.
CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.
METHODS: One hundred fifty-three orthopaedic residents were recruited and randomly assigned to either the LAC or CAC. They were allocated 2 practice sessions, with 20 minutes each, to practice 4 given arthroscopic tasks: task 1, transferring objects; task 2, stacking objects; task 3, probing numbers; and task 4, stretching rubber bands. The time taken for participants to complete the given tasks was recorded in 3 separate tests; before practice, immediately after practice, and after a period of 3 months. A comparison of the time taken between both groups to complete the given tasks in each test was measured as the primary outcome.
RESULTS: Significant improvements in time completion were seen in the post-practice test for both groups in all given arthroscopic tasks, each with P < .001. However, there was no significant difference between the groups for task 1 (P = .743), task 2 (P = .940), task 3 (P = .932), task 4 (P = .929), and total (P = .944). The outcomes of the tests (before practice, after practice, and at 3 months) according to repeated measures analysis of variance did not differ significantly between the groups in task 1 (P = .475), task 2 (P = .558), task 3 (P = .850), task 4 (P = .965), and total (P = .865).
CONCLUSIONS: The LAC is equally as effective as the CAC in basic arthroscopic skills training with the advantage of being cost-effective.
CLINICAL RELEVANCE: In view of the scarcity in commercial arthroscopic devices for trainees, this low-cost device, which trainees can personally own and use, may provide a less expensive and easily available way for trainees to improve their arthroscopic skills. This might also cultivate more interest in arthroscopic surgery among junior surgeons.
METHODS: Breast cancer patients were recruited from three Malaysian hospitals between June and November 2017. We compared the proportion of patients who rated PROs as very important (scored 7-9 on a 9-point Likert scale) between Malaysian patients and data collected from patients in HICs via the ICHOM questionnaire development process, using logistic regression. A two-step cluster analysis explored differences in PROs among Malaysian patients.
RESULTS: The most important PROs for both cohorts were survival, overall well-being, and physical functioning. Compared with HIC patients (n = 1177), Malaysian patients (n = 969) were less likely to rate emotional (78% vs 90%), cognitive (76% vs 84%), social (72% vs 81%), and sexual (30% vs 56%) functioning as very important outcomes (P
METHODS: We established PN in a dedicated breast clinic of a Malaysian state-run hospital. We compared diagnostic and treatment timeliness between navigated patients (n = 135) and patients diagnosed in the prior year (n = 148), and described factors associated with timeliness.
RESULTS: Women with PN received timely mammography compared with patients in the prior year (96.4% v 74.4%; P < .001), biopsy (92.5% v 76.1%; P = .003), and communication of news (80.0% v 58.5%; P < .001). PN reduced treatment default rates (4.4% v 11.5%; P = .048). Among navigated patients, late stage at presentation was independently associated with having emotional and language barriers ( P = .01). Finally, the main reason reported for delay, default, or refusal of treatment was the preference for alternative therapy.
CONCLUSION: PN is feasible for addressing barriers to cancer care when integrated with a state-run breast clinic of an LMIC. Its implementation resulted in improved diagnostic timeliness and reduced treatment default. Wider adoption of PN could be a key element of cancer control in LMICs.
METHODS: We conducted a cross-sectional study of 2,377 Malaysian women aged 40-74 years. Physical activity information was obtained at screening mammogram and mammographic density was measured from mammograms by the area-based STRATUS method (n = 1,522) and the volumetric Volpara™ (n = 1,200) method. Linear regression analyses were performed to evaluate the association between physical activity and mammographic density, adjusting for potential confounders.
RESULTS: We observed that recent physical activity was associated with area-based mammographic density measures among postmenopausal women, but not premenopausal women. In the fully adjusted model, postmenopausal women with the highest level of recent physical activity had 8.0 cm2 [95% confidence interval: 1.3, 14.3 cm2] lower non-dense area and 3.1% [0.1, 6.3%] higher area-based percent density, compared to women with the lowest level of recent physical activity. Physical activity was not associated to volumetric mammographic density.
CONCLUSIONS: Our findings suggest that the beneficial effects of physical activity on breast cancer risk may not be measurable through mammographic density. Future research is needed to identify appropriate biomarkers to assess the effect of physical activity on breast cancer risk.
METHODS: We developed a decision analytic model to estimate the lifetime costs and quality-adjusted life-years (QALYs) accrued through BRCA mutation testing or routine clinical surveillance (RCS) for a hypothetical cohort of 1000 early-stage breast cancer patients aged 40 years. In the model, patients would decide whether to accept testing and to undertake risk-reducing mastectomy, oophorectomy, tamoxifen, combinations or neither. We calculated the incremental cost-effectiveness ratio (ICER) from the health system perspective. A series of sensitivity analyses were performed.
RESULTS: In the base case, testing generated 11.2 QALYs over the lifetime and cost US$4815 per patient whereas RCS generated 11.1 QALYs and cost US$4574 per patient. The ICER of US$2725/QALY was below the cost-effective thresholds. The ICER was sensitive to the discounting of cost, cost of BRCA mutation testing and utility of being risk-free, but the ICERs remained below the thresholds. Probabilistic sensitivity analysis showed that at a threshold of US$9500/QALY, 99.9% of simulations favoured BRCA mutation testing over RCS.
CONCLUSIONS: Offering BRCA mutation testing to early-stage breast cancer patients identified using a locally-validated risk-assessment tool may be cost effective compared to RCS in Malaysia.