Genetic susceptibility and survival: Application to breast cancer

Inherited mutations of the BRCA1 and BRCA2 genes are known to confer an ele vated risk of both breast and ovarian cancers. The effect of carrying such a mutation on survival after developing breast or ovarian cancer is less we ll understood. We investigate the relationship between BRCA1 and BRCA2 carr ier status and survival after breast cancer. We obtained data from the Canc er and Steroid Hormone Study, a large population-based study including more than 4,000 breast cancer cases. Patient data include extensive information about breast and ovarian cancer in relatives. We obtained follow-up inform ation about patients via record linkage with the Surveillance, Epidemiology , and End Results registry, with maximum follow-up of 15 years. In the abse nce of genetic testing for each individual, presence or absence of mutation at a breast cancer susceptibility gene is captured by a pair of binary lat ent variables whose marginal probability depends on the patient's family hi story of breast and ovarian cancer. We estimate the effect of genotype on s urvival using a Cox proportional hazards model, treating genetic status as a latent variable and controlling for stage at diagnosis, histology, whethe r radiation treatment was administered, the individual's smoking history, b ody mass, race, and age at diagnosis. Inference is accomplished using a Mar kov chain Monte Carlo algorithm to draw a ample from the posterior distribu tion of model parameters accounting fur sampling error, uncertainty in the genotype of study participants, and uncertainty in estimates of genetic par ameters. An analysis that does not discriminate between BRCA1 and BRCA2 est imates the genetic effect on survival after breast cancer for women carryin g a mutation at either site. We find evidence that survival of nonirradiate d mutation carriers is better than that of noncarriers; we estimate the pro bability of improved survival to be .990. As a byproduct of this analysis, we estimate that a study based on 901 women with known mutation status woul d yield estimates of genetic effect on survival with comparable uncertainty to that obtained in the combined-gene analysis. An analysis assessing the separate effects of the two genes indicates that carriers of either mutatio n may have an improved prognosis. We estimate the probability of improved s urvival among nonirradiated BRCA1 carriers to be .841, and that among nonir radiated BRCA2 carriers to be .924. However, substantial uncertainty remain s about the magnitude of the BRCA2 effect.