Genetics in Breast Cancer: An overview. Dr. Michael Raff Genomics Institute and Medical Genetics Service MultiCare Health System
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1 Genetics in Breast Cancer: An overview Dr. Michael Raff Genomics Institute and Medical Genetics Service MultiCare Health System
2 Basics Mutations in hereditary and somatic regulatory genes lead to cancer The process of transformation from normal cell to invasive cancer is called carcinogenesis The process of carcinogenesis can take place over many years (5-20) 2
3 Cancer Risk Factors Aging Family history Rare hereditary cancer syndromes Hormonal factors in gender-specific cancers Infectious agents (HPV, HBV) Radiation Environmental toxins Modifiable risk factors: high-fat, low-fiber diet low intake of fruits and vegetables inactivity alcohol use smoking
4 Breast Cancer Most common cancer in women Second most common cancer death in American women Lifetime risk of developing breast cancer is 12-14% (1 in 7-8 women)
5 A Comprehensive Family History At least 3-generations for each lineage Specify exact biological relationship Age, or age/cause of death All cancers and age at diagnosis (determine if primary, recurrence, or metastatic cancer) Location of primary cancers, stage, laterality, treatment Pertinent chemoprevention/surgeries* Predisposing conditions/precursor lesions Pertinent physical findings
6 More Comprehensive Family History Current health status/significant illnesses (e.g., Hodgkin s) Reproductive history/issues (e.g., infertility, DES exposure) Congenital abnormalities (e.g., Down syndrome) Environmental exposures (e.g., radiation, chemicals, second-hand smoke, excessive sun) Race/Ethnicity (including if Ashkenazi Jewish ancestry)
7 The Value of Family History Information Probability of hereditary cancer predisposition Cancer risks for referred individual and family members Cancer cases needing confirmation/documentation Need for consultation with cancer genetics experts Genetic testing Family members already tested If no testing yet, determining who to test Need for screening, prevention, support services Eligibility for research study participation
8 When to suspect an inherited cancer predisposition Earlier age at diagnosis than expected Cancer in at least two close relatives in the same lineage Evidence of autosomal dominant transmission Two or more primary tumors in an individual Constellation of tumors characteristic of a specific syndrome Multiple rare cancers in single lineage Male breast cancer Bilaterality
9 When to be suspicious even if the family history is not too concerning No (or limited) family cancer history, but Limited family structure Little information about the family Relatives are young Early age at diagnosis (single case indicator) Few females to detect pattern of sex-limited cancers Skipped generations (incomplete penetrance) Risk-reducing chemoprevention/surgeries Possibility of new mutations (less common)
10 Skipping Generations Individuals inherit susceptibility to cancer, not cancer itself Many, but not all carriers, develop cancer (rare exceptions such as familial polyposis) Cancer may appear to skip generations
11
12 Differences in Risk Perception Personal/family experience with and communications about cancer Personality traits, coping style, risk tolerance level Perceptions, beliefs, attitudes about health and illness Age, education, occupation Cultural, social, religious norms
13 When to do a genetic test? When there is a reasonable likelihood of identifying a cancer predisposing mutation When there is a genetic test available that can be adequately interpreted When the results will influence the individual s or the family s healthcare
14 Genes Implicated in Breast Cancer BRCA1 20%-40% BRCA2 10%-30% ATM 4% TP53 <1% CHK2 <1% PTEN <1% Unknown genes 25%-65%
15 When to Get a Genetics Clinic Appointment Any personal or family history of breast cancer: diagnosed < age 50 (< age 55 if Ashkenazi Jewish ancestry), especially if limited family history bilateral, with first cancer < age 50 in a male at any age DCIS < breast and ovarian cancer: any woman with both one of each cancer in two close relatives, diagnosed at any age ovarian cancer: personal history of ovarian cancer in two or more close relatives, diagnosed any age
16 Methods to Estimate Risk Risk for Developing Breast Cancer Probability of Carrying a BRCA mutation Claus Model Gail Model BRCAPRO Tyrer-Cuzick BOADICEA Couch Model Myriad Model BRCAPRO Tyrer-Cuzick BOADICEA
17 Claus Model Statistical model to calculate cumulative breast cancer risk based on family history Data derived from a Study conducted by the CDC Risk estimates determined from the family history of 4,730 individuals with breast cancer (age 20-54) and matched controls in US Family history of breast cancer is the only risk factor considered
18 Application of the Claus Model
19 Claus Model Example
20 Gail Model Data from 284,780 women in the Breast Cancer Detection Demonstration Project 2,852 Breast cancer individuals; 3,146 controls followed for 35 years Risk factors assessed: Family history of breast cancer in a 1st degree relative Late age at first live birth Early menarche (first menstrual cycle) Multiple benign breast biopsies The model estimates breast cancer risk over 10- yr intervals
21 Gail Model Incorporates Age Age at menarche Age at first live birth Number of previous breast biopsies If a biopsy showed atypical hyperplasia Number of first-degree relatives with breast cancer Ethnic background (White, Hispanic, Black) Does not incorporate Other cancers, such as ovarian cancer Second-degree relatives Males with breast cancer Paternal history Age at diagnosis of relatives breast cancer
22 Gail Model Illustration Patient Age: 42 Menarche: 13 Age of 1st live-birth: n/a Breast biopsies: 1 Atypical hyperplasia: 0 Mother/sisters/daughters with breast cancer: 1 Ethnicity: White 5 Year Risk This Patient (age 42) = 2.1% Average woman (age 42) = 0.7% Lifetime Risk This patient (to age 90) = 22.1% Average woman (to age 90) = 12.2%
23 Tyrer-Cuzick Model Incorporates risk factors: Age Age at menarche Age at first live birth Age at menopause (if postmenopausal) Personal history of atypical hyperplasia/ LCIS/ ovarian cancer Height BMI (body-mass index) Hormone replacement therapy use Breast or ovarian cancer in 1st, 2 nd and 3 rd degree relatives; bilateral breast cancer in 1 st degree relatives Genetic test results (if performed)
24 Risk Model Comparisons Model Calculations: Gail 22.1% Claus 24.8% Tyrer-Cuzick 23.8% General pop 12.2%
25 Couch Model University of Pennsylvania study of 169 breast cancer families seen in clinic for genetic counseling Factors that increased likelihood of a BRCA1 mutation: lower average age of onset of BC in a family Ashkenazi Jewish ancestry Ovarian cancer Family member with both breast and ovarian cancer This model considers only family history
26
27 Myriad Model
28 BRCAPRO Model A model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCA2, on the basis of family history of breast and ovarian cancer in first-and second-degree relatives Also considers oophorectomy, hormone receptor status of tumors (ER, PR), and genetic testing results The model integrates a Bayesian calculation based on the relationships of the family members with cancer, the ages at onset of the diseases, and the ages of family members who do not have the diseases
29 Boadicea Model One of the most validated of the models Model considers: current age, age of death, age of diagnoses year of birth (cohort effect) breast/bilateral breast/ovarian cancer half siblings pancreatic/ prostate cancer fractions of Jewish ancestry genetic test results male breast cancer Model does not consider pathology
30 BRCA1 and BRCA2 Testing Two genes that, if mutated, increases the risk for breast and ovarian cancer Test results may be: Positive for a mutation Negative for a mutation Undetermined due to a variant of unknown significance (VUS)
31 VUS in Gene Testing A VUS finding does not allow us to refine the cancer risk Occurs in approx. 10% of BRCA tests There is a large database of VUS that are constantly being reevaluated
32 Genetic Information Non-Discrimination Act (GINA) GINA became federal law in 2008 Protects individuals from genetic discrimination (misuse of genetic information) by insurers and employers Protected information includes: genetic test results, documentation of genetic services and genetic counseling, family health history Includes inadvertently obtained genetic information Includes protection of insurance eligibility and coverage terms No protection regarding eligibility for life, disability, or LTC insurance
33 Thank you for listening! Dr. Michael Raff MultiCare Genomics Institute and Medical Genetics Service
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