This document provides an overview of breast cancer genetics and risk assessment. It discusses that 10-25% of cancers are hereditary while the majority are due to acquired mutations over a lifetime. Highly penetrant genes like BRCA1 and BRCA2 confer large risks, while many low penetrance genes each confer small risks. Risk assessment evaluates family history and can classify risk as average, moderate or high to guide screening and management. Genetic testing of high risk families can identify pathogenic variants to further guide screening and prevention for mutation carriers and their relatives.

1. Breast Cancer Genetics:An Overview Kevin Sweet, MS, CGC Certified Genetic Counselor Clinical Associate Professor Division of Human Genetics Kevin Sweet discloses no significant financial interests or other relationships with commercial interests. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device. The following planning committee members have no significant financial interests or relationships with commercial interests to disclose, their educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an organization other than The Ohio State University: Amy Ehrlich, MA and Henry Zheng, PhD, MBA

3. Each individual type of cancer arises from a single cell that requires varying numbers of gene mutations for progression to the invasive state.

4. Cancer is a term that encompasses a complex group of more than 100 different diseases that all share the primary characteristic of uncontrolled cell growth.

6. First mutation First mutation Second mutation Second mutation Third mutation Third mutation Malignant cell Malignant cell All Cancer is Genetic; Not All Cancer is Inherited Common cancer pathway due to somatic mutation Hereditary cancer pathway, where initial gene mutation is inherited Normal cell

7. Breast Cancer is Common 1in every 8 American women will be diagnosed with breast cancer in her lifetime

8. Risk Factors for Breast Cancer Age Nulliparity Early menarche and late menopause Personal history Atypical hyperplasia Female hormone replacement therapy Family history/genetics

9. Goal: ClassificationWho Needs What? Assessment Intervention Risk Classification Average (70%) Standard screening recommendations Personalized detection/prevention recommendations Family History Moderate (15-20%) Referral for genetic evaluation with personalized screening recommendations High (5-10%)

11. Examples of average risk:

12. One 1st degree relative (parent, sibling, child) diagnosed with breast cancer >50 yrs

13. One or two 2nd degree relatives (aunts, uncles, grandparents) diagnosed >60 yrs

15. Ages of onset not strikingly young (average age breast cancer dx is 62)

16. However, risk for all first degree relatives increased

17. Risk depends on number of family members affected, how closely related, ages of onset

20. 5 year risk of 1.2% / lifetime risk of 20.4%

21. Claus Model: (BreastCa for Palm, version 1.0, copyright 2001) http://www.palmgear.com/index.cfm?fuseaction=software.showsoftware&prodID=29820

22. Lifetime risk of 18.8%The Gail model is limited because it does not incorporate second-degree relatives (e.g. aunts, grandmothers) or the age of onset of breast cancer in the family. The Claus model incorporates up to two relatives with breast cancer, taking into account their ages of onset, but does not include relatives with ovarian cancer or take into account nongenetic risk factors such as age at menarche.

24. Ovarian (or other cancer) risk not increased

25. Screening recommendations:

26. Monthly breast self exam monthly

27. Clinical breast exam every six months

29. which side of the family matters

30. all on one side or some on each – not convergent!

31. Perceived risk does not always equal actual risk

32. genetic counseling/risk assessment may help

34. Frequencies Of And Relative Risks Associated With Commercially Available SNPs For Breast Cancer

35. Commercial GWA Offerings Some commercial GWA companies provide breast cancer risk estimates based on the number of these low penetrance alleles the individual possesses. Each company uses a different specific algorithm to combine the genotype data and produce their risk estimate.

36. Breast Cancer Risk and SNPs RR associated with a risk-increasing SNP allele is often dose–dependent and complex; possessing two copies of the risk-increasing SNP allele often conveys more than twice the risk that possessing one copy of the risk-increasing allele does For example, for the rs2981582 SNP in the FGFR2 gene, the genotype specific RR of breast cancer (individual's risk compared to the risk in the general population) is 0.83 for carriers of two risk-reducing alleles (common allele homozygotes), 1.05 for carriersof one risk-increasing and one risk-reducing allele (heterozygotes) and1.38 for carriers of two risk-increasing alleles (rare allele homozygotes). This projects a lifetime risk of 10%for women who carry one risk-increasing allele and 13% for women who carry two risk-increasing alleles.

37. High (hereditary) Risk Family Breast, dx 40 d. 40 Breast, dx 44 d. 48 50-70% lifetime risk for breast cancer Increased risk for other cancers Breast Cancer and Ovary, 42, 55 d. 58 Breast, dx 49

38. Breast Cancer Gene VariantsWith High Penetrance 5-10% of all breast cancer are strongly hereditary, with high penetrance and an autosomal dominant single gene determinant Always co-segregated with the disease in families See multiple generations of affected family members Gene mutation found equally in males and females Mutation carriers will have a heterozygous genotype, which means they will have a 50% risk of passing on the gene mutation to each of their offspring

39. Highly Penetrant Genes For Breast Cancer

41. Dominant deleterious mutations in either gene increase cancer risk dramatically

44. Half of all women with hereditary breast cancer risk inherited it from their father

45. Ovarian cancer is not a factor in breast cancer risk

46. Ovarian cancer is an important indicator of hereditary risk, although it is not always present

47. The most important thing in the family history is the number of women with breast cancer

49. BRCA2-Associated Cancers: Risk by Age 70 breast cancer (50-85%) male breast cancer (6%) ovarian cancer (10-20%) Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)

51. 5-8% of all women with breast cancer

52. 18% of women with breast cancer <50 and one close relative with breast cancer <50

53. 2% of all women of Ashkenazi Jewish ancestry

55. Interpreting Test Results: Positive for a BRCA Deleterious Mutation Mostly frameshift and nonsense mutations Any mutation that prevents a functioning protein from being made is assumed to be deleterious, even if it has not been seen before Hundreds of deleterious mutations have been described in BRCA1 and BRCA2

56. Interpreting Test Results: No Mutation Detected If there is a known BRCA mutation in the family: The risk of cancer is the same as that of the general population, despite a strong family history If there is not a known BRCA mutation in the family: A negative result rules out most, but not all, causes of hereditary breast and ovarian cancer Some unusual types of abnormalities in the BRCA genes, such as very large deletions, are not detected on standard analysis

57. Interpreting Test Results: Variants of Uncertain Significance (VUS) Result seen in 5-10% of all BRCA test reports Mostly amino acid substitutions, also some variants in non-coding introns VUS have uncertain clinical significance so associated cancer risk unknown VUS may be further characterized by additional studies

60. 50% risk for each of her daughters Ruth 45 28 37 18 22

61. Case 2: After Testing, Ruth has a Deleterious Mutation in the BRCA1Gene English/Irish German Dx 42 d. 49 60 58 Dx 55 d. 56 Key BRCA1(+) BRCA1(+) -Breast CA Ruth 45 37 28 -Ovarian CA BRCA(-) BRCA1(-) 18 22

62. Surveillance-BRCA1 and BRCA2 Mutation Carriers Mammograms are not completely sensitive -MRI may be more sensitive, but less specific -Begin use of imaging at 25 Breast physical examination is recommended -Encourage monthly breast self-exams (begin at 18) -Clinician performed exams 2-4 times per year (begin at 25) Frequency of interval cancers suggests that six-month screening intervals may be preferable Modified from Burke W et al. JAMA. 1997; 277:997-1003. Scheuer L et al. J ClinOncol. 2002; 20: 1260-1268. Warner E et al. J ClinOncol. 2001; 19:3524-3531.

63. Ovarian Cancer: Chemoprevention Oral Contraceptives 40% to 50% risk reduction in general population after 3 years cumulative use Limited data available for BRCA-mutation carriers; preliminary study showed a 60% risk reduction with ≥6 years use May increase breast cancer risk CASH study NEJM 316:650, 1987; Ursin Cancer Res 57:3678, 1997; Narod NEJM 339:424, 1998

64. Prophylactic Oophorectomy Decreases risk of ovarian cancer by as much as 80% (primary peritoneal carcinoma may still occur) Reduces risk of breast cancer by 60% if done prior to age 40 and by 50% if done prior to age 50 Induces surgical menopause Laparoscopic procedure reduces postsurgical morbidity Consider complete hysterectomy for management of menopause – unopposed, low-dose estrogen Rebbeck NEJM 346(21):1660, 2002; Kauf NEJM 346(21):1660, 2002; Rebbeck et al JNCI 101(2):80-7, 2009

66. may want to consider oophorectomy

67. Ruth’s daughters are negative for their mother’s BRCA mutation

68. general population risk for breast and ovarian cancer

69. follow American Cancer Society screening guidelines

70. cannot pass the family’s BRCA mutation to their children

71. Ruth’s sister (mutation positive)

73. Some family members may want this information and some may not

74. Genetic testing, when informative, can help individuals

75. make decisions about early detection and risk-reduction

76. relieve anxiety about cancer risk (if negative)

77. Informed decision-making imperative

79. Li-Fraumeni Syndrome As the TP53 gene is one of the key gatekeepers for cell cycle maintenance and regulation, germline mutation leads to very high risk for single and multiple primary cancers in mutation carriers. Osteosarcomas and soft tissue sarcomas are the signature cancers of LFS, although early onset breast cancer (20-30s), brain tumors, leukemias, lymphoma and adrenal tumors are also seen regularly.

80. Cowden Syndrome Caused by germline mutations in the PTEN gene Mutation carriers are at increased risk for breast and thyroid cancer (30% and 10% increase in risk, respectively). As a tumor suppressor gene, PTEN is a key regulator of cell signaling pathways; disruption leads to both benign and malignant cellular overgrowth. Cowden syndrome is part of the more comprehensive PTENhamartoma tumor syndrome which also includes Bannayan-Riley-Ruvalcaba syndrome and Proteus-like syndrome.