OBJECTIVES 8/25/2017. An attempt to organize the chaos

Transcription

1 High Risk for Breast Cancer and Genetics: Who? What? Where? When? An attempt to organize the chaos Presented at Winds of Change Conference November 3, 2017 by Carol Hager, MSN, CRNP and Allison Haener, MSN, CRNP OBJECTIVES Describe basic genetic concepts related to Hereditary Breast & Ovarian Cancers [HBOC]. Define NCCN guidelines for genetic testing related to HBOC. Summarize the process of evaluation, education, and counseling of individuals seen in the High Risk Clinic. Categorize the recommendations for individuals seen in the High Risk Clinic including risk reducing medications-risk and benefits. 1

2 The Elements of Risk Personal Modifiable Environmental Genetic Breast cancer risks that may be modified Physical environment Exposure to toxins Smoking Radiation Diet & alcohol Obesity Hormones & hormone use Breast feeding Risks that can t be modified Sex Age Reproductive history Prior cancers Dense breasts Abnormal cells on biopsy Family history Heredity BRCA 1 & 2 Other genes 2

3 Hereditary Cancer Predisposition 2 or more closely related individuals with the same or related types of cancer Cancer diagnoses at a younger than expected age (before age 50) Multiple primary tumors in an individual Several affected generations in the same bloodline Unusual or rare tumors Ethnicity 3

4 The Stats Average risk of breast cancer 1:8 women 1.7% annually; 12% of breast cancers ER+ Incidence of female breast cancer by age CDC

5 Who to test? NCCN criteria Personal history of CA Ovarian cancer Breast cancer w/ known FH of mutation Early age dx Triple neg <60yo 2 breast primaries Breast CA any age and >1 close relative w/ breast <50 yo >1 close relative w/ invasive ovarian >2 close relatives w/ breast/pancreatic any age Pancreatic ca any age Population at inc risk Ashkenazi Jewish descent Personal or FH of multiple primary in same individual No personal history of CA Close relative with: 1 st /2 nd degree relative w/ breast <45 yo FH mutation >2 breast primaries in indiv >2 indiv w/ breast primaries on same side of family, 1 dx < 50yo Ovarian CA Male breast CA FH 3 or more CA Breast, pancreatic, prostate, melanoma, sarcoma, brain tumor Leukemia, gastric, colon, endometrial, thyroid, renal Others less commonly What Test? Single site testing-known mutation BRCA 1/2 HBOC panels Multigene panels 5

6 Where to test? Telmedicine In person sites Regionally Pittsburgh & Cleveland RCC [or other regional cancer center] VA has their own telemedicine Any provider can order informed consent Genetic counseling highly recommended pre & post testing When to test? Urgently-to help determine surgical intervention if dx w/ breast/ovarian ca & strong FH Non-urgent Personal risk based on FH Family members at risk Generally not <21yo Possible Test Results Positive Result Negative Result Uncertain Variant Increased Cancer Risk Risk based on Family History Cancer Risk not yet known* *Testing for the specific variant can be offered to appropriate family members to evaluate the clinical significance of the variant; most labs will notify providers if VUS upgraded or downgraded 6

7 Post testing & counseling Results w/ significance & impact on management Surgery Reproduction Long term follow up Informing & testing at risk family Support groups & research studies BRCA mutations Autosomal dominant 1 parent w/ mutation may pass on The abnormal gene dominates 50/50 chance of inheritance If gene not inherited, cannot pass on the mutation or disease [risk goes back to family & personal/modifiable/environmental risk] If child dx; look at parents first if possible Additional risk associated w/ BRCA 1/2 BRCA 1 2-3% of developing new breast ca each year Lifetime risk of 2 nd primary breast cancer up to 64% Risk of ovarian ca up to 44%; BSO risk by 95% and risk of second breast ca in premenopausal women Male breast ca up to 7% Prostate ca 20-32% Pancreatic ca 2-5%? Cervical & colon 7

8 BRCA 2 Increased risk breast ca 50-87% Increased risk ovarian ca 27% Increased risk 2 nd breast primary up to 50% Pancreatic ca 2-5% Melanoma 5% Male breast 7% Prostate 20-32% Small inc risk for ca of: GB/bile duct, stomach, ocular melanoma Unaffected BRCA carrier risk of Ovarian BRCA 1 BRCA 2 JCO [2007]:25[11] Other mutations impacting breast / ovarian ca Increased breast risk ATM, CCH1 [lobular], CHEK2, NBN, NF1, PALB2, STK11, TP53 Increased ovarian risk BRIP1, RAD51C, RAD51D, STK11 Other elevated risk Gastric-- CDH1 Cowden syndrome [PTEN] Li-Fraumeni syndrome [TP53] 8

9 Cowden syndrome Rare, autosomal dominant, associated w/ PTEN Multiple hamartomas of various tissue which are generally benign Increased risk of cancers of breast, thyroid, endometrial/uterine, renal Li-Fraumeni syndrome Rare, autosomal dominant, assoc w/ P53 Predisposed to sarcoma, breast, leukemia, adrenal cancers **avoid radiation exposure inc risk of radiation induced cancers Dominant vs Recessive Genes Management Options BRCA 1 BRCA 2 and other High Risk genetic mutations 9

10 Breast Cancer Surveillance Chemoprevention Preventive Surgery Monthly breast self-exams Annual or semiannual clinical breast exams beginning at age 25 Yearly mammography and breast MRI beginning at age 25 or 5-10 before the earliest age of diagnosis in the family Medication such as Tamoxifen can reduce the risk of breast cancer by 50% in women with an increased risk for breast cancer There is limited information about whether or not Tamoxifen is effective for BRCA1 carriers Preventive mastectomy reduces the risk of breast cancer by at least 90% in women with BRCA mutations Ovarian Cancer Surveillance Chemoprevention Preventive Surgery Annual or semiannual transvaginal ultrasound and testing for CA- 125 to detect ovarian cancer beginning around the age of 30 Oral contraceptives have been associated with a 60% reduction in the risk of ovarian cancer Removal of the ovaries and fallopian tubes reduces the risk of ovarian cancer by at least 96% Recommended between the ages of 35 and 40 May also reduce breast cancer in pre-menopausal women Other cancer risks Melanoma-routine skin & opthalmology Prostate-PSA & screening at 40 Colon-initiate colonoscopies at 40 Pancreatic-awareness, EUS in high risk program 10

11 Risk based on family history Tyer-Cuzick Combines factors such as: Age Extended family history of breast/ovarian cancer Child birth History breast bx & path Age of menarche & menopause Use of hormones Heritage Height/weight and compared to a standard risk Claus Based on family history of breast/ovarian, patient age, and ages of those effected by breast/ovarian cancer Results at 5 and lifetime; if >20% suggest use of MRI to be added to yearly screening w/ mammograms 11

12 Tyer-Cuzick Combines factors such as: Age Extended family history of breast/ovarian cancer Child birth History breast bx & path Age of menarche & menopause Use of hormones Heritage Height/weight and compared to a standard risk Hughes Risk Model 12

13 At Risk Pathology Atypical ductal hyperplasia Atypical lobular hyperplasia Lobular carcinoma in situ Level of Increased Risk Relative Risk Explained Usual risk of average woman 5yr=1.7% Lifetime=12% ADH/ ALH = 4 LCIS= 10 Normal-Abnormal-Cancer Normal Hyperplasia Mild dysplasia Carcinoma in situ (severe dysplasia) Cancer (invasive) 13

14 Breast Cancer Risk Reduction Women w/ lifetime risk >20% --h/o LCIS/ADH/ALH Clinical encounter/exam q 6-12 mos Annual screening mammo/ tomo at time of dx >30yo Consider MRI w/ mammo* >25 yo Risk reduction strategies including meds Breast self awareness Women w/ lifetime risk >20% based on FH Clinical encounter/exam q 6-12 mos Eval for genetic referral Annual screening w/ mammo/tomo 10 yr prior to youngest FH >30yo Recommend annual MRI 10 yr prior to youngest FH >25 yo Risk reduction strategies Breast self awareness Role of estrogen in breast cancer Cause cell proliferation increase risk of cell error development of cancer cell Feed existing cancer cells Risk Reduction Medication Tamoxifen- SERM, premenopausal or postmenopausal Raloxifene-SERM, postmenopausal Exemestane-Aromatase Inhibitor, postmenopausal 14

15 NSABP P-1 Trial Tamoxifen is utilized in breast cancer patients with hormone positive disease adjuvantly to reduce the risk of contralateral breast cancer. If we identify a woman at high risk based on the Gail algorithm, will utilizing Tamoxifen for 5 prevent invasive breast cancer in women at increased risk? NSABP P-1 Trial YES! Out of a population of 13,388 women 35 and older with a 5 year risk of developing breast cancer >1.66% in the next 5 or hx of LCIS Tamoxifen reduced the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50% Also reduced in women with a hx of LCIS (56%) or atypical hyperplasia (86%) Tamoxifen: Considerations Tamoxifen is a SERM, that works as an estrogen antagonist on breast tissue and an agonist on uterus, bone, liver, and coagulation system Endometrial cancer: Relative risk 2.53 per 1000 Thromboembolic events (DVT & CVA): Relative risk 1.59 per 1000 Cataract development: Relative risk 1.14 per 1000 SSRIs are strong inhibitors of CYP2D6 Decrease effectiveness of Tamoxifen Nearly all antidepressants interfere with Tamoxifen- except Effexor 15

16 Tamoxifen: Considerations Undergoing surgery or immobility- temporarily discontinue Contraindicated: Prior history of DVT or PE Prior history of stroke Women who are or may become pregnant or breastfeeding Caution with smokers NSABP Study of Tamoxifen and Raloxifene STAR Trial Can raloxifene be utilized for breast cancer risk reduction? YES Antagonistic activities on breast and uterine tissue and agonist on bone. Fewer noninvasive breast cancers in the tamoxifen group than raloxifene but the difference did not reach statistical significance Raloxifene does not reduce the risk of noninvasive breast cancer Can lower the risk of invasive breast cancer in postmenopausal women with a higher Gail risk, LCIS NSABP Study of Tamoxifen and Raloxifene STAR Trial Less significant risk of thromboembolic events and cataracts and no endometrial cancer risk Raloxifene group experienced fewer cases of PE and DVT 30% less No difference in number of fractures Risk of cataracts was less in raloxifene group Raloxifene does not increase endometrial cancer risk 16

17 NSABP Study of Tamoxifen and Raloxifene STAR Trial White non-hispanic with a uterus NSABP Study of Tamoxifen and Raloxifene STAR Trial White non-hispanic without a uterus Also tables available for black and Hispanic women online Google Breast Cancer Prevention Trial: STAR trial, study of tamoxifen and raloxifene Raloxifene- postmenopausal population only Single (very small- <30 participant) trial examining raloxifene in premenopausal women Increase in ovarian cysts Without larger studies to further examine the efficacy and safety, it should not be prescribed in premenopausal women. 17

18 Long term efficacy European IBIS-I trial- tamoxifen continues to reduce the risk of breast cancer at a median of 16 yr follow up 2010 updated analysis (STAR trial) with a median follow up of 81 months Benefits of tamoxifen were greater, risks with raloxifene were lower, raloxifene retains 76% the effectiveness of tamoxifen General consensus: Even when taken for only 5, likely protective for 10 or more MAP.3 trial Primary outcome- incidence of invasive breast cancer utilizing exemestane for breast cancer risk reduction Elevated 5 year risk according to Gail model, ALH, ADH, LCIS in postmenopausal women Relative risk reduction 65% - invasive breast cancer NOT associated with an increased risk of thromboembolic, cardiovascular events, or other cancers Exemestane: Considerations A possible rare side effect is worsening age related bone loss Check baseline DEXA and repeat in 2 18

19 Side Effects Vasomotor side effects (hot flashes/night sweats) similar in all three Tamoxifen-vaginal discharge/dryness, menstrual irregularities Raloxifene- leg cramps Exemestane- arthralgias Summary Not everyone is appropriate for genetic testing stress to patients it is a good thing if you don t meet criteria to test [NCCN guidelines] Counseling should precede and follow genetic testing; informed consent a must There is more than 1 facet of risk; personal, family and heredity Not all risk reduction is surgical 19