Family Hist.+ Genotyping may change risk estimates

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"Genotyping Plus Family History May Change Breast Cancer Risk Estimates Elsevier Global Medical News. 2009 Oct 21, S Boschert
 SAN FRANCISCO (EGMN) - Combining genotyping with family history may better identify women at risk of developing breast cancer, a preliminary study of 160 women suggests. Overall, 29% of women had a potentially clinically significant change in estimated risk based on genotyping plus family history, compared with family history alone, Amy Martin and her associates reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology. The investigators calculated genotype relative risks using the three most significant single nucleotide polymorphisms (SNPs) that have been identified as risk factors for breast cancer. Combining these genotype-based estimates with risk estimates based on family history increased the risk level for 17% of women in the study, and decreased the risk level for 12%.  In recent years, genetic risk factors for breast cancer have been identified beyond BRCA1 and BRCA2, which carry high risk for breast cancer but affect relatively few people. Each of the newer genetic risk markers (multifactorial polymorphisms) confers a relatively small increased risk, but they can be found in many people, and appear to increase risk cumulatively in people who have multiple polymorphisms, said Ms. Martin, lead investigator in the study and a medical student at the University of Dundee (Scotland). The three polymorphisms used in the study are rs2981582 in FGFR-2 (fibroblast growth factor receptor type 2), rs3803662 near TNRC9 (trinucleotide repeat containing 9), and rs889312 near MAPKKK1 (mitogen-activated protein kinase kinase kinase 1). Clinicians in the United Kingdom conventionally stratify risk for breast cancer based on family history as being low risk (less than a 3% chance in 10 years), medium risk (4%-7% risk), or high risk (8% or greater risk over 10 years), and consider screening or treatment choices based on that risk category.  The study suggests that 11% of women would shift from low-risk to medium-risk status - and 3% would shift from low-risk to high-risk status - if genotyping information were combined with family history, said Dr. Jonathan N. Berg, also of the university and a coauthor of the study, during a poster presentation of the findings. Combining family history and genotyping could shift 11% of medium-risk women to low-risk status, and 3% of medium-risk women to high-risk status, he added. Among patients at high risk based on family history, the addition of genotyping information could shift 1% down to medium-risk status. The risk for breast cancer appeared to be 48% lower in women with none of the susceptibility alleles at the targeted loci, or 60%-308% higher in women with one to five of the alleles, the investigators calculated. The preliminary findings need to be confirmed in larger studies and clinical trials, Dr. Berg said. Dr. Jeffrey N. Weitzel, chief of clinical cancer genetics at City of Hope in Duarte, Calif., who was the invited discussant, said the study "deserves replication and validating in other populations, but it's certainly promising."  The findings reminded him of similar modeling that's been done in prostate cancer, in which SNPs in combination with family history can produce a strong cumulative risk (up to a 9.5-fold increased risk for prostate cancer in the presence of five SNPs plus a family history of prostate cancer). By far, the most significant factor in those modeling studies was family history, he noted. Dr. Weitzel wondered if modeling based on SNPs might be useful in cases in which no family history of breast or prostate cancer is available, a question that would require more research.  The investigators reported having no conflicts of interest related to this study. Dr. Weitzel has received honoraria from Myriad Genetics Inc., which develops cancer drugs and genetic tests for predisposition to cancer."