Jill Stopfer, MS, CGC Abramson Cancer Center University of Pennsylvania

Jill Stopfer, MS, CGC Abramson Cancer Center University of Pennsylvania

Aging Family history Early menarche Late menopause Nulliparity Estrogen / Progesterone use after menopause More than two alcoholic beverages per day Protective Factors for Breast Cancer At least four or more hours a week of exercise Breastfeeding Maintaining ideal body weight (especially after menopause) Having children prior to age 30

15%-20% 5% 10% 5% 10% Breast Cancer Ovarian Cancer Sporadic Family clusters Hereditary

Can find genetic risk in some families Can sort out who does, and who does not, have genetic risk for cancer Can tailor health care to lower cancer risk and maximize chances for cure Can spare those without genetic risk for cancer from unnecessary procedures and worry

Hereditary Cancer Syndromes One important gene associated with major cancer risk Clear pattern of inheritance Genetic testing often available 5-10% of breast and ovarian cancer cases overall Certain features of the family history can suggest this Moderate Risk Genes Each gene may increase risk, but less dramatically It may require a set of genes, or genetic profile, to significantly raise risk Multifactorial Inheritance Genes, environment, lifestyle risk factors, random cell errors

Multiple generations of cancer Young age at diagnosis More than one cancer in the same person Cancers that run together such as breast / ovarian, or colon / uterine Rare cancers BR 51 OV 53 Brain 50 BR 29 OV 72 BR 35

Family history may guide: Screening recommendations Diagnosis of hereditary cancer condition Suggestions for genetic testing Potentially life saving interventions Specific cancer types and ages at diagnoses Every detail need not be shared

Multiple cases of early onset breast cancer (<50) Ovarian cancer (with family history of breast or ovarian cancer) Breast and ovarian cancer in the same woman Bilateral breast cancer Ashkenazi - Eastern European Jewish heritage Male breast cancer

Breast cancer 60%-70% Second primary breast cancer 40%-50% Ovarian cancer 30-45% Increased risk of other cancers: Male breast cancer: 1-5% Pancreatic 2-3%

breast cancer (60%-80%) ovarian cancer (10%-20%) male breast cancer (5-10%) Other increased risks: Prostate: 15-25% Earlier ages Pancreatic: 3-5% Melanoma: 3-5%

An estimated 1 in 40 Ashkenazi Jews carries a BRCA1 or BRCA2 mutation BRCA1 185delAG Prevalence = ~1% 5382insC Prevalence = ~0.15% BRCA2 6174delT Prevalence = ~1.5%

Contrast enhanced MRI using Gadolinium Rapid enhancement of tumor relative to normal tissue Data suggests improved sensitivity Picks up smaller cancers Sensitivity 83-100% Decreased specificity Specificity ranges from 37-96% False positives are a major concern

Surveillance Options for Ovarian Cancer No proven methodology Annually or semiannually, starting at 30 35 Transvaginal ultrasound w/color Doppler imaging CA-125

Chemoprevention of Breast Cancer Tamoxifen 49% reduction of breast cancer incidence in high-risk women (mean follow-up of 4 years) Limited data are available for BRCA-mutation carriers Participation in ongoing studies is critical Other options (Raloxifene, Aromatase Inhibitors) Fisher, JNCI, 1998

Chemoprevention of Ovarian Cancer Oral Contraceptives In general population, OCs reduce risk of ovarian cancer 40% to 50% after 3 years cumulative use

Prophylactic Mastectomy Removes most but not all breast tissue Reduces breast cancer risk in women with a family history by 90% Total (simple) mastectomy removes more breast tissue than subcutaneous mastectomy

Prophylactic Oophorectomy Eliminates risk of primary ovarian cancer; however, peritoneal carcinomatosis may still occur Laparoscopic oophorectomy reduces postsurgical morbidity Induces surgical menopause In BRCA-mutation positive women >85% risk reduction Also reduces risk of breast cancer by 50-70%

Can do. Annual Endoscopic ultrasound Magnetic cholangiopancreatography (MRCP) If suspicious findings noted, can do ERCP Tissue biopsy Pancreatic resection Offered to those with BRCA2 + Fam hx Panc CA 2 or more cases pancreatic ca in close relatives Peutz Jeghers syndrome

Treatment selection: PARP inhibitors in BRCA1/2 carriers Endogenous damage BER repair intermediates PARP SSB repair BER Rad51 HR SSB PARP inhibitors DNA replication BRCA1/2 BRCA1/2 Rad51 strand invasion BRCA1/2 deficiency Error prone repair NHEJ or SSA Replication fork collapse Cytotoxicity

BR 51 Stom 53 Brain 50 Liver 72 BR 29 BR 58 BR 35

BR 51 OV 53 Brain 50 OV 72 BR 29 BR 58 BR 35

BR 51 OV 53 Brain 50 OV 72 B1 Neg B1 BR 29 Neg Neg Neg B1 BR 58 B1 Neg BR 35 B1 Neg Neg B1

Colon 68 Prostate 60 Colon 60 Lung 70 Ovary 30 Ovary 36 Ovary 51 Breast 40 Breast 61 Renal cell 55 40y 43y 46y 38y 31y

Colon 68 B1 Prostate 60 Colon 60 B1 Lung 70 B1 Ovary 51 Ovary 30 Ovary 36 B1 Breast 40 Breast 61 Renal cell 55 B1 40y 43y 46y 38y 31y

Colon 68 B1 Prostate 60 Colon 60 B1 Lung 70 B1 Ovary 51 Ovary 30 Ovary 36 B1 Breast 40 Breast 61 Renal cell 55 B1 40y BSO 46y 38y 31y Ovary 46 Stage IV BSO

Not all mutations can be seen using current lab methods Most breast and ovarian cancer risk is not due to a mutation in a single gene like BRCA1/2

Pros More extensive searching Could find mutation in gene not suspected based on family history More economical Cons Many genes on panels not well characterized Uncertain medical management of findings More testing but possibly increased uncertainty

Payment for testing Confidentiality Discrimination Health and Life Insurance Legislation HIPAA and GINA

Pre-test genetic counseling Family history assessment at least three generations Collection and review of medical records Determination of best person in the family to initiate testing Explanation of natural history of condition to test Explanation of inheritance, and who else may be at risk Explanation of opportunities for intervention to lower risk Genetic testing Typically a blood test or swish and spit kit Insurance pre-authorization Result Disclosure Positive, Negative, Variant of Uncertain Significance Medical Recommendations