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Understanding BRCA2 Mutations: Breast Cancer Risk and Prognosis

Explore the impact of BRCA2 mutations on breast cancer risk and prognosis, including inherited tendencies, genetic factors, and treatment effects. Learn about the Icelandic BRCA2 founder mutation, risk factors, and survival outcomes for carriers. Gain insights into the role of hormone status, genetic testing, and personalized risk assessment for better decision-making regarding surveillance and treatment options.

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Understanding BRCA2 Mutations: Breast Cancer Risk and Prognosis

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  1. Breast Cancer Risk and Prognosis in BRCA2 Mutation Carriers • Brjóstaheill Samhjálp kvenna • Nordic Congress on Breast Cancer • Grand Hotel Reykjavik Iceland 16 - 18 September 2016 • Laufey Tryggvadóttir, Clinical Professor Faculty of Medicine, UI • Managing Director, Icelandic Cancer Registry

  2. Breast cancer in families • Breast Cancer Familiy database founded • Icelandic Cancer Society 1975 • Increased risk among mothers, sisters and daughters • Increased risk of prostate cancer

  3. Inherited tendency for breast cancer • The Family Database of the Icelandic Cancer Society • The discovery of the “Breast Cancer Gene 2” - BRCA2 – 20 years ago

  4. BRCA1 and BRCA2 genes • Code for proteins that protect us from breast cancer • Inherited defects (mutations) multiply breast cancer risk • BRCA1 mutations are rare in Iceland • One single BRCA2 mutation is relatively common

  5. The Icelandic BRCA2 founder mutation • Frequency • 6-7% women with breast cancer • 0,8% of Icelanders are borne with the mutation

  6. The risk in mutation carriers is determined by genetic and environmental factors in addition to the mutation

  7. 2006

  8. Breast Cancer Risk before age 70 according to year of diagnosis Year of Icelandic Estimated for BRCA2 diagnosis women mutation carriers 1920 1.8 18.6 (11.0-29.5) 1930 2.1 22.1 (13.7-33.8) 1940 2.5 26.3 (17.0-39.1) 1950 3.0 31.4 (20.6-46.0) 1960 3.6 37.2 (24.7-54.0) 1970 4.4 44.2 (29.4-64.1) 1980 5.2 52.1 (34.3-76.2) 1990 6.3 61.5 (39.8-90.7) 2000 7.5 71.9 (45.9-100)

  9. Explanations Diagnostics Reproductive patterns Age at menarche OCs and HRTs Calorie-dense food Obesity Physical inactivity Alcohol

  10. Age at breast cancer diagnosis – BRCA2 carriers

  11. Age at breast cancer diagnosis – BRCA2 carriers 21% 33%

  12. Factors that predict breast cancer risk and age at onset in BRCA carriers • Other genetic factors • Reproductive history, physical activity, calorie intake • Mammographic breast density • Increased knowledge of effects of risk factors in carriers • –> individual measures for predicting risk and age at onset

  13. Conclusions – risk prediction • Large variation in breast cancer risk among BRCA carriers • -> Risk prediction models could be improved • Better help in decision making regarding surveillance and/or age at risk-reduction surgery

  14. 2007

  15. 2013

  16. Unexpected results • BRCA2 mutation carriers had worse prognosis – but only if tumors were hormone positive • Women without BRCA2 mutations: • Hormone positive tumours predict considerably better survival than hormone negative tumours • BRCA2 mutation carriers: • Hormone positive tumours predict considerably worse survival than hormone negative tumours

  17. Effects of prognostic factors and treatment on breast cancer survival • in BRCA2 mutation carriers • 285 carriers & 570 non-carriers • Genetic testing of 3,577 breast cancer cases in 1995-2012 • Patients diagnosed 1935-2012

  18. Recently published online

  19. Results Adding 153 BRCA2 carriers with known ER status to 109 BRCA2 carriers from previous study Positive hormone status associated with worse survival among carriers Effect present in the era before the introduction of hormone therapy (1935-1979) and after (1980-2012)

  20. Breastcancer-specificsurvival - totalperiod Non-carriersN=503 BRCA2mutationN= 262 ER+

  21. Breastcancer-specific survival BRCA2 carriers Diagnosed 1935-1979 N=81 Diagnosed 1980-2012 N=181 ER+

  22. Effects of treatment in BRCA2 carriers with breast cancer Strong protective effect of chemotherapy Strong protective effect of mastectomy (vs lumphectomy) No effect seen for hormone treatment

  23. Conclusions – prognosis of patients • Previous Icelandic findings confirmed - adverse outcomes associated with ER+ tumours among BRCA2 carriers • Not explained by response to hormone treatment • Differentnature of ER+ tumoursinmutation carriers • Specific effects of treatment in mutation carriers • -> important to know mutation status at diagnosis • Needs confirmation in other populations • Better understanding of the biology is needed

  24. Thankyou

  25. Different nature of tumours • No mutation • Hormone positive -> 42% lymph node involvement -> smaller tumours • Hormone negative -> 51% lymph node involvement • -> larger tumours • BRCA2 mut • Hormone positive -> 63% lymph node involvement • -> larger tumours • Hormone negative -> 32% lymph node involvement • -> smaller tumours

  26. BRCA2mutations 10-fold risk of female breast cancer 100-fold risk of male breast cancer 7-fold risk of ovarian cancer Threefold risk of prostate cancer 7-fold risk of pancreatic cancer

  27. Age at breast cancer diagnosis

  28. Breastcancer-specific survival non-carriers Diagnosed1935-1979 N=150 Diagnosed 1980-2012 N=353 ER+

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