Wednesday, November 12, 2014

BRCA gene mutation and Mass SCREENING

In 1990, Mary Claire King discovered the BRCA 1 & 2 gene mutations and their association with breast cancer. The prevalence was found in the Ashkenazi Jewish population predominantly, in Long Island, NY and there were some Peruvian women who tested positive in the original data.

BRCA genes are DNA repair genes. Any mismatch and these segments of the exome are activated in the cell cycle checkpoint control to maintain genomic stability and transcriptional integrity.

The BRCA 1 stands for “Breast Cancer 1 early onset.” The recent estimates of a woman’s lifetime risk of developing breast cancer with the BRCA 1 mutation was 28%-60% by age 70. Additionally women with the BRCA 1 gene mutation also carry a 39% risk of ovarian cancer during their lifetime. BRCA 1 gene is located on Chromosome 17q12-21. Those carrying the BRCA 2 mutation have a 40% risk at age 70. Women who carry the BRCA 2 gene have a 15% lifetime risk of developing ovarian cancer by age 70 also. BRCA 2 gene is located on Chromosome 13. The breast cancer penetrance has increased for those born after 1960 (40%) as compared to those born before 1940 (7.5%). BRCA 1 mutations also have some clinically relevant features that defy the established histo-pathologic paradigm. Breast Cancers with BRCA mutations are mostly basal-type, have no correlation between size and nodal metastasis, they are usually Estrogen Receptor negative, yet respond to SERMs and Tamoxifen also prevents secondary cancers that are ER negative in this subset of individuals.

Let us dissect the populace under the BRCA gene mutation stress a bit: Overall independent of BRCA gene mutation, 12% of women will develop Breast Cancer and 1.4% will develop Ovarian Cancer during their lifetime. In the general population based on at least one limited study of 1220 cases the estimates of 0.7% of the population is a carrier for the BRCA 1 and 1.3% for BRCA 2 is of some significance.  Given that estimate and the Breast Cancer penetrance at age 80 of 48% (CI 7-82) for BRCA 1 and 74% (CI 7-14) BRCA 2 and Ovarian Cancer penetrance at a similar age of 22% (CI 6-65) for both BRCA 1 & 2 should give us a moment of pause.

So let us look at this through the lens of Mary Claire King’s recent recommendations in the JAMA article where she advocates that all women at age 40 should be tested for the BRCA genes. In this age of Cost Controls and the Healthcare taking 17.9% of the GDP, some considerations should be made to the costs that all experts tout so vociferously. U.S. currently spends $6,000,000,000 on Breast Cancer annually. 

Based on the population statistics as of Census 2010 there are 156,964,212 (50.6%) women in the United States. The mixed gender population ages 25-44 years is calculated at 82,134,554 and thus 50.6% of that translates to 41,724,353 women. Dr. King recommends that all women by age 40 should be tested for the BRCA gene. The cost of the BRCA test is averaged at $2000 per test. The expense for such a testing would put the cost to the healthcare industry at $83,448,708,000.00. With two predicates to keep in mind: One that the incidence of BRCA carriers in the general population is 1.98% that means that $826,142.00 would yield a positive result and the rest of the expensed monies wasted. But even at that, the second predicate suggests that with the maximum 60% actual breast cancer penetrance in the carriers that would mean only $495,628.00 spent would actually identify the breast and ovarian cancer cases for prevention. 

So it should come as no surprise that logic would dictate that the BRCA gene mutation analysis should be carried out ONLY in high risk families with established evidence of breast, ovarian, colon, prostate and pancreatic malignancies in their members at a young age. And patients who develop breast cancer at a younger age without known family history should also consider being tested for BRCA mutations in hopes of isolating variants of the BRCA genes that may function as disease promoter and consequently may help other family members in making preventative decisions.
Bayesian modeling in various ethnic population shows marked variations of BRCA penetrance. The BRCAPRO and BOADICEA analysis again confirms sensitivity to family analysis data rather than large population based determination. Two large population studies done in the US suggest BRCA 1 mutation in patients younger than 65 years was found in 3.5% of Hispanics, 1.4% in African Americans, 0.5% in Asian American, 2.9% in non-Ashkenazi whites and 10.2% in Ashkenazi Jewish individuals. Additionally 10-15% of the fully sequenced BRCA 1 & 2 population shows Variant of Uncertain Significance (VUS) in the form of SNPs and missense DNA mutations in the intron regions. These VUS however may or may not have any deleterious consequences to the patient. This would also create a dilemma for the genetic counselors and for the patients from such wide-berth screening. Another source of BRCA gene silencing comes from hyper-methylation, which like the hereditary version of the mutation has similar effect of breast cancer promotion. The exact incidence however remains unknown and testing might reveal this anomaly of which little data is available.
Just based on the current data 40% of the BRCA 1 mutated individuals who will never develop breast cancer will be subjected to potential emotional and physical harm and those with BRCA 2 mutated that number will rise to 60%. These percentages would falsely constitute a Type I or False Positive Error in potential Breast Cancer penetrance among patients and create confusion sometime even among physicians and counselors. With the ultimate goal of genetic testing of individuals being to reduce the risk of cancer that they are predisposed to as a consequence of the BRCA mutation, screening the entire population would have far reaching deleterious consequences both emotionally and physically to the individual.

In the end I am at odds with Mary Claire King’s recommendation of population screening for BRCA 1 and 2 mutations in women aged 40 and younger (even though I laud her for her pioneering work of BRCA discovery)!


D Gareth Evans et al. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: Risks of breast/ovarian cancer quoted should reflect the cancer burden in the family. BMC Cancer 2008, 8:155 ( )

Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer. 2000 Nov;83(10):1301-8.  ( )

Narod SA. Modifiers of risk of hereditary breast and ovarian cancer. Nature Review Cancer 2:113-123, 2002.

Chappuis PO, Nethercot V, and Foulkes WD. Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Seminars in Surgical Oncology 18:287-295, 2000

High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes

Frank TS, Deffenbaugh AM, Reid JE, et al.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20 (6): 1480-90, 2002

Malone KE, Daling JR, Doody DR, et al.: Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 66 (16): 8297-308, 2006.

John EM, Miron A, Gong G, et al.: Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA 298 (24): 2869-76, 2007.

Narod SA, Dube MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, Provencher D, Heimdal K, Moller P, Robson M, et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute 94:1773-1779, 2002.

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