Results from a large Dutch study shows that women with breast cancer who had a BRCA1 mutation had significantly worse overall and recurrence-free survival rates compared with patients without BRCA mutations, but no evidence for a difference in survival was found between patients with BRCA2 mutations and those without a BRCA mutation. The data was presented during the Annual Meeting of the American Association for Cancer Research(AACR) held in Washington, D.C., April 6-10, 2013.

Germline mutations inBRCA1are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. Mutations in BRCA2 are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer. [1][2] Mutations in BRCA1 and BRCA2 appear to be responsible for disease in 45% of families with multiple cases of breast cancer only and in up to 90% of families with both breast and ovarian cancer. [3][4]Hereditary breast and ovarian cancer (HBOC) syndrome due to germline mutations in the BRCA1 and BRCA2 genes is characterized by an autosomal dominant pattern of inheritance. Women with a BRCA mutation have alifetime risk of breast cancer of 50 to 85% and a 15 to 40% chance of developing ovarian cancer. Current evidence shows that there is also an increased risk of a second breast cancer diagnosis.

Survival differences
Previous studies investigating survival differences between women with BRCA1 or BRCA2 mutations and those without a BRCA mutation, or noncarriers, have been inconsistent,” noted Marjanka M. K. Schmidt, Ph.D., a group leader in the Experimental Therapy Division of the Netherlands Cancer Institute (NKI-AVL) in Amsterdam. ?We have analyzed data from one of the largest, least biased, BRCA1/2-genotyped breast cancer cohorts,? she said.

Schmidt and colleagues evaluated BRCA status and survival in 5,518 patients who had been diagnosed with breast cancer before the age of 50 and had been treated at any one of 10 cancer clinics in the Netherlands. They found that 3.6% of the patients had a BRCA1 mutation and 1.2% had a BRCA2 mutation.

BRCA1 and lower ER+ tumors
Researchers tested patients? samples for 78 different inherited BRCA1 or BRCA2 mutations and linked these to long-term outcome during a mean follow-up of 11.3 years. The proportion of ER-positive (ER+) tumors was similar between non-carriers? tumors (86%) and tumors from patients with a BRCA2 mutation (81%) but was low among tumors from patients with BRCA1 mutations (29%).

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Higher incidence of breast cancer
The data revealed that women with a BRCA1 mutation were 1.5 times more likely to have a breast cancer recurrence (HR 1.5; p=0.004)and were 1.2 times more likely to die from breast cancer compared with non-carriers (HR1.2; p=0.07)There was no evidence for worse survival among patients with BRCA2 mutations compared with non-carriers.

In preliminary analyses, the effect of BRCA1 on survival remained after the researchers adjusted for tumor characteristics. ?However, in our review, we also found that the effects were attenuated when tumor characteristics were adjusted for,? Schmidt noted. ?So part of the worse survival in BRCA1 mutation carriers is likely explained by tumor characteristics and part by the mutation itself.?

Treatment focus
The differences in survival between BRCA1 mutation carriers and non-carriers might indicate that treatment should depend, in part, on which mutation a woman has, according to Schmidt.?Currently, patients are treated on the basis of their tumor characteristics, not on their BRCA status, aside from prophylactic measures and, for example, PARP (poly ADP ribose polymerase)inhibitors in clinical trials,? she said. ?If we could show that BRCA status, independent of tumor characteristics, is predictive of prognosis, this could be taken into account in prediction models and could facilitate treatment decisions.?

Remaining questions
Although this study is an important indicator of the differences between BRCA1 and BRCA2, it does not convey whether treatment may change the actual outcomes.BRCA-associated breast cancers are usually high grade, hormone receptor- and HER-2 negative and often express topoisomerase IIa.Generally, patients with BRCA-associated cancers have a worse prognosis in the absence of treatment, but once they are given treatment their prognosis is, in many cases, the same or potentially even better than non-carriers. [5][6][7][8] However, while this is so for BRCA2-associated cancers, a number of studies reviewing survival forBRCA1-associated breast cancer based on mutation analysis do not report better survival rates and many have reported no differences at all. [9][10][11] Some studies have reported worse prognosis.

Studies also confirm that in many casesstage I breast cancer inBRCA1carriers has a poor prognosis andsmall node-negative tumors. [12][13] Finally, women who have a BRCA1-mutation tend to develop triple negative breast cancers (breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and HER2/neu) which are known to have a worse prognosis. Unknown is if this impact the prognosis independent of that of BRCA1-mutation status.

For more information:
[1]Brose MS, Rebbeck TR, Calzone KA, et al.: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94 (18): 1365-72, 2002. [Pubmed Abstract]
[2]Thompson D, Easton DF; Breast Cancer Linkage Consortium.: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002. [Pubmed Abstract]
[3]Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993 [Pubmed Abstract]
[4]GeneReviews? [Internet].Pagon RA, Bird TD, Dolan CR, et al., editors.Seattle (WA):University of Washington, Seattle; 1993
[5]Johannsson OT, Idvall I, Anderson C, Borg ?, Barkardottir RB, Egilsson V, Olsson H. Tumour biological Features ofBRCA1-induced Breast and Ovarian Cancer. Eur J Cancer1997, 33 (3): 362-71.[PubMedAbstract]
[6]Lynch BJ, Holden JA, Buys SS, Neuhausen SL, Gaffney DK:Pathobiologic Characteristics of Hereditary Breast Cancer.Hum Pathol1998,29:1140-4.[PubMedAbstract]
[7] Di Leo A, Cardoso F, Durbecq V, Giuliani R, Mano M, Atalay G, Larsimont D, Sotiriou C, Biganzoli L, Piccart MJ:Predictive molecular markers in the adjuvant therapy of breast cancer: state of the art in the year 2002.Int J Clin Oncol2002,7(4): 245-53.[PubMedAbstract]
[8] Hagen AI, Bofin AM, Ytterhus B, Maehle LO, Kjellevold KH, Myhre HO, M?ller P, L?nning PE:Amplification of TOP2A and HER-2 genes in breast cancers occurring in patients harbouringBRCA1germline mutations.Acta Oncol2007,46(2):199-203.[PubMedAbstract]
[9]Verhoog LC, Brekelmans CTM, Seynaeve C, Bosch LMC, Dahmen G, Van Geel AN, Tilanus-Linthorst MMA, Bartels CCM, Wagner A, Ouweland A, Devilee P, Meijers-Heijboer EJ, Klijn J.Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1.Lancet1998,351:316-21.[PubMedAbstract]
[10]Robson M, Gilewski T, Haas B, Levin D, Borgen P, Rajan P, Hirschaut Y, Pressmann P, Rosen PP, Lesser ML, Norton L, Offit K:BRCA-Associated Breast Cancer in Young WomenJ Clin Oncol1998,16(5):1642-9.[PubMedAbstract]
[11]Eerola H, Vahteristo P, Sarantaus L, Kyyronen P, Pyrhonen S, Blomqvist C, Pukkala E, Nevanlinna H, Sankila R:Survival of breast cancer patients inBRCA1, BRCA2, and non-BRCA1/2 breast cancer families: a relative survival analysis from Finland.Int J Cancer2001,93(3):368-72.[PubMedAbstract]
[12] Hagen AI, Tretli S, M?hle L, Apold J, Ved? N, M?ller P. Survival in Norwegian BRCA1 mutation carriers with breast cancer. Hereditary Cancer in Clinical Practice 2009, 7:7 doi:10.1186/1897-4287-7-7 [[PubMed Abstract]]
[13]Rennert G, Bisland-Naggan S, Barnett-Griness O, Bar-Joseph N, Zhang S, Rennert HS, Narod SA. Clinical Outcomes of Breast Cancer in Carriers of BRCA1 and BRCA2 Mutations.New Engl J Med2007,357:115-23.[PubMedAbstract]

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