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Importance Evidence suggests that low vitamin D status may increase the risk of cancer. Objective To determine if dietary supplementation with vitamin D 3 and calcium reduces the risk of cancer among older women. Design, Setting, and Participants A 4-year, double-blind, placebo-controlled, population-based randomized clinical trial in 31 rural counties (June 24, 2009, to August 26, 2015—the final date of follow-up). A total of 2303 healthy postmenopausal women 55 years or older were randomized, 1156 to the treatment group and 1147 to the placebo group. Duration of treatment was 4 years. Interventions The treatment group (vitamin D 3 + calcium group) received 2000 IU/d of vitamin D 3 and 1500 mg/d of calcium; the placebo group received identical placebos. Main Outcomes and Measures The primary outcome was the incidence of all-type cancer (excluding nonmelanoma skin cancers), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. Results Among 2303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2064 (90%) completed the study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D 3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D 3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, −0.06% to 3.46%]; P = .06). Kaplan-Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D 3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D 3 + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D 3 + calcium group and 2 in the placebo group). Conclusions and Relevance Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D 3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention. Trial Registration clinicaltrials.gov Identifier:NCT01052051

ContextIdentifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.ObjectiveTo develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.Design, Setting, and PatientsExternal validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.Main Outcome MeasureAbility of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.ResultsIn the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.ConclusionsMMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.

Background: Linkage to chromosome 17q has been identified in hereditary breast cancer and hereditary breast/ovarian cancer syndrome. A hereditary breast/ovarian cancer syndrome kindred was identified that yielded a highly significant lod score (4.20) when 17q markers were studied, enabling us to identify those who probably carried the cancerassociated gene among the high-risk members of the family. Methods: High-risk members of the hereditary breast/ ovarian cancer syndrome kindred were offered counseling on the basis of 17q markers. Family members responding positively received one-to-one genetic counseling in a structured setting. Subjects were educated before disclosure, and the immediate impact of this information was assessed after disclosure. Results: We provided genetic counseling on the basis of linkage findings to 32 relatives (four men and 28 women). Women who were told they were linkage positive expressed an increased motivation for surveillance and prophylactic surgery. Most women who were told they were linkage negative indicated that they would not proceed with prophylactic surgery but would continue careful surveillance. To date, there has been no evidence of serious emotional disturbances resulting from this disclosure. We believe that this experience can be used by cancer geneticists and physicians in developing protocols for genetic counseling in cancer-associated hereditary disorders. Conclusions: Physicians must understand current developments in cancer genetics and linkage so that they can be applied to genetic counseling and treatment of high-risk patients. (Arch Intern Med. 1993;153:1979-1987)

To the Editor.— The article by Eddy et al 1 provides evidence that healthy asymptomatic women between the ages of 40 and 49 years do not show sufficient health or economic benefit from mammography to offset the costs and risks. They contend that the costs for screening this cohort are high and that relatively few lives would be saved. Their data indicate that mammography screening in that decade would carry a risk of radiation-induced cancer of the breast of about 1 in 25 000. They conclude that a more prudent approach is to initiate mammography at age 50 years. The matter of hereditary breast cancer (HBC) was totally ignored in these reports. This is surprising since HBC accounts for approximately 9% of the total breast cancer burden 2 and its average age of onset is approximately 44 years. 3,4 Indeed, we recently described a subset of HBC that is characterized