Hereditary Ovarian cancer: BRCA1 and BRCA2. Karen H. Lu MD September 22, 2013

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1 Hereditary Ovarian cancer: BRCA1 and BRCA2 Karen H. Lu MD September 22, 2013

2 Outline Hereditary Breast and Ovarian Cancer (HBOC) BRCA1/2 genes How to identify What it means to you What it means to your family

3 How much ovarian cancer is hereditary? Ovarian Cancer 10-15%

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5 OV OV BR OV age 40

6 Case 1 BR at 52 BR at 49 OV at 49 age 26 age 23 age 17 age 28 age 24 How does genetic testing work? How can her daughters use this information?

7 BRCA1 and BRCA2 BRCA1 BRCA2 BRCA1 Tumor suppressor gene on chromosome 17 Coding Region nucleotides Span 81 KB Genomic DNA ~1200 different mutations reported BRCA2 Tumor suppressor gene on chromosome 13 Coding Region 10,254 nucleotides Span 84 KB Genomic DNA ~1380 different mutations reported

8 Risk of Ovarian and Breast Cancer associated with BRCA1 mutation 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Ovarian Breast General Population BRCA1

9 BRCA1 Breast and Ovarian Cancer Risk Reference: Chen and Parmigiani 2007 JCO 25(11): ; these numbers are only applicable to women who are BRCA1 positive and have never had breast or ovarian cancer

10 BRCA2 Breast and Ovarian Cancer Risk Reference: Chen and Parmigiani 2007 JCO 25(11): ; these numbers are only applicable to women who are BRCA2 positive and have never had breast or ovarian cancer

11 Red Flags for BRCA1/2 Multiple family members with breast cancer and/or ovarian cancer Early onset of breast cancer < 50 years Ovarian, fallopian tube, primary peritoneal cancer Multiple primary cancers in same individual Two primary breast cancers Breast and ovarian cancer Triple negative breast cancer (ER-, PR-, Her2-) Male breast cancer

12 What kind of ovarian cancer most likely with BRCA1 and BRCA2 High grade serous ovarian cancers most suggestive Endometrioid tumors High grade more suggestive than low grade 10-15% of high grade serous ovarian cancers associated with BRCA mutation Germ cell and granulosa cell tumors have no known association with BRCA1/2 mutations BRCA1/2 mutations are quite rare in borderline/lmp (low malignant potential) ovarian tumors and mucinous ovarian cancers Pal T et al. Cancer Dec 15;104(12): ; Risch HA et al. Am J Hum Genet Mar;68(3): Epub 2001 Feb 15

13 BRCA1 and BRCA2 Genetic Testing

14 Click to edit Genetic Master testing title style Benefits unaffected woman Defining risk Preventing cancer Early detection Surgical prevention Benefits ov ca patient Personalized treatment PARP inhibitors Prognostic information Preventing second cancers Breast/ovarian

15 Why are results helpful to daughters? Helps with precision of risk for daughters Test positive, risk reducing options Test negative, general population risk

16 Case 1 BR at 52 BR at 49 OV at 49 age 26 age 23 age 17 age 28 age 24 How does genetic testing work? How can her daughters use this information?

17 Cost of Genetic Testing Type of Test Full analysis BRCA1 and BRCA2 Cost ~$4000 Predictive testing, previously identified familial mutation ~$500 **Covered by Medicare and most insurance companies

18 Insurance Discrimination and Federal Law Genetic Information Non-discrimination Act (GINA) Passed in 2008 Prohibits: Group and individual plans from using genetic information to determine eligibility or premiums Insurance companies from requesting or requiring genetic testing Employers from using genetic information Does not apply to: Long term/disability insurance or life insurance

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20 The Patient Experience 1) Cancer Patient With High Risk Criteria 2) Risk Assessment performed in Care Center 5) Patient Mgmt Treatments Risk Reduction Mgmt 3) Genetic Testing 6) Family Members: Predictive Testing Risk Reduction Mgmt 4) Results Reviewed

21 Significant progressionfree and overall survival advantage for advanced-stage ovarian cancer patients with non-aj BRCA mutations. Survival advantage generalizable for all BRCA mutation carriers.

22 Results Overall Survival By BRCA Mutation Status p < BRCA + Sporadic controls GOG182 controls Months BRCA Mutation GOG Sporadic Sporadic

23 PARP inhibition and tumor-selective synthetic lethality DNA damage (SSBs) DNA replication (accumulation of DNA DSBs) PARP PARP inhibition Normal cell with functional HR pathway HR-deficient tumor cell (e.g. BRCA 1/2 -/- ) HR-mediated DNA repair Cell survival Tumor-selective cytotoxicity Cell death Impaired HRmediated DNA repair DSB, double-strand break; HR, homologous recombination SSB, single-strand break Farmer H et al. Nature 2005;434: Bryant HE et al. Nature 2005;434: McCabe N et al. Cancer Res 2006;66:

24 Movement towards universal testing of all ovarian cancers testing Family history often not helpful Paid for by most insurance companies, including Medicare In busy practices, how often are ovarian cancer patients with substantial risk criteria being referred? In 2007, 48% (Meyer et al, OBGYN)

25 The Patient Experience 1) Cancer Patient With High Risk Criteria 2) Risk Assessment performed in Care Center 5) Patient Mgmt Treatments Risk Reduction Mgmt 3) Genetic Testing 6) Family Members: Predictive Testing Risk Reduction Mgmt 4) Results Reviewed

26 Time Magazine s 10 Best Buzzwords of 2007 #3 previvor: n. person who does not have cancer but possesses a genetic predisposition to develop the disease; a pre-survivor

27 Management of Risk Screening Chemoprevention Surgical Prevention ***Prophylactic Bilateral Salpingo-oophorectomy (BSO) remains the only proven means of decreasing risk of ovarian cancer in women with BRCA1/2 mutations

28 Increased Breast Screening Breast self exam (or self awareness) starting at age 18 Clinical breast exams every 6 months starting at age 18 Yearly mammograms, alternating with yearly breast MRI, starting at age 25 (or earlier depending on family history) NCCN practice guidelines V

29 Risk Reducing Breast Surgery Prophylactic bilateral mastectomy 90-95% reduction in risk Prophylactic bilateral salpingo-oophorectomy ~50% reduction in breast cancer risk Only if performed before menopause Meijers-Heijboer H et al. N Engl J Med. 2001;345: Hartmann LC et al. JNCI. 2001;93: Kauff et al. N Engl J Med Rebbeck et al. N Engl J Med. 2002

30 Increased Ovarian Screening Transvaginal ultrasound and CA-125 every 6 months starting at age 35 (or 5-10 years earlier than the earliest ovarian cancer diagnosis in the family) NCCN practice guidelines V No proven strategy or benefit

31 Chemoprevention: Ovarian Cancer Oral contraceptives 50% reduction in ovarian cancer risk in general population Conflicting evidence in BRCA population OCPs may increase risk of breast cancer Risks and benefits must be carefully weighed and individualized management plans are warranted Modan B et al. N Engl J Med. 2001;345: Narod S et al. N Engl J Med. 1998;339: Narod S et al. JNCI. 2002;94:

32 Risk Reducing Ovarian Surgery Prophylactic bilateral salpingo-oophorectomy (BSO) with serial sectioning Up to 96% risk reduction Residual ~1% risk for primary peritoneal cancer

33 Timing of Procedure BRCA1: % risk of ovarian cancer by age 50. BRCA2: early 40 s 2-3% risk of ovarian cancer by age 50. Oophorectomy after menopause is not associated with a decrease in breast cancer risk. 3 1 King MC, et al. Science Satagopan J, et al. Clin Cancer Res Rebbeck TR, et al. J Natl Cancer Inst. 1999

34 Conclusions 10-15% of ovarian cancer is hereditary BRCA1/2 are two tumor suppressor genes responsible for the majority of hereditary breast and ovarian cancer Genetic testing is recommended for high grade serous ovarian cancer After BRCA1 or BRCA2 found, family members can test

35 Making Cancer History for the Family