6/26/2019

Faculty Inequality of : Donna Lynn Dyess, MD, MBA, FACS Why Patients Get Professor, Departments of Different Treatments Surgery and Physiology University of South Alabama Satellite Conference and Live Webcast Wednesday, June 26, 2019 1:00 – 3:00 p.m. Central Time

Produced by the Alabama Department of Public Health Video Communications and Distance Learning Division

Breast cancer statistics BREAST CANCER STATISTICS Genetic testing •1 in 8 women get •7 out of 8 will not get breast cancer breast cancer •12.4% pppopulation •87.3% pppopulation will Models for risk assessment: lifetime risk never get breast cancer Tyrer Cuzik, Gail •10% of women with •90% of women that get breast cancer have a breast cancer do not Receptors in breast cancer family history have a family history

PROBABILITY OF DEVELOPING RISK OF DEATH FROM BREAST CANCER BY AGE+ BREAST CANCER:

•Birth to 49 years •2.0 % (1 IN 51) Findings at 5 year •5050--5959 years •2.3 % (1 IN 43) diagnosis Distribution Mortality •60-69 years •3. 5 % (1 IN 29) Localized to breast •> 70 years •6.7 % (1 IN 15) 62% 1% •BIRTH TO DEATH •12.4 % (1 IN 8) Regional 31% 15% Metastatic 6% 73%

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RISK OF BEING ALIVE WITH BREAST CANCER: GENETICS?? Findings at 5 year diagnosis Distribution survival •I have breast cancer –Do I carry the ? Localized to •Cancer runs in my family ––wewe must breast 62% 99% have a bad gene! Regional 31% 85% •If I have one cancer, does that mean I Metastatic 6% 27% will get another type of cancer?

OUTLINE GENETICS IN CANCER •55--10%10% of all malignancies are due to •Identify guidelines for referring highly penetrant hereditary cancer patients for cancer genetic counseling predisposition syndromes •Discuss panel testing •Over 602 have been identified as associated with increased risk of cancer development

http://cancer.sanger.ac.uk/census#cl_analysis

HEREDITARY CANCER SYNDROMES RARE HEREDITARY CANCER MOST COMMON/STUDIED SYNDROMES WITH NCCN . Hereditary Breast and Ovarian Cancer GUIDELINES Syndrome (BRCA1 and BRCA2) •LiLi--FraumeniFraumeni Syndrome (TP53) • Incidence: 1 in 300 (BRCA1) to 1 in 800 (BRCA2) •Sarcomas, breast cancer, adrenocortical • Ashkenazi Jewish (()1 in 40) carcinomas, leukemia, many types of brain tumors, melanoma, cancers of the . Hereditary Nonpolyposis Colorectal Cancer aka lung, GI tract, genitourinary tract, Lynch Syndrome (MLH1, MSH2, MSH6, PMS2 and thyroid, ovaries, uterus EPCAM) • Incidence: 1 in 440

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RARE HEREDITARY CANCER RARE HEREDITARY CANCER SYNDROMES WITH NCCN SYNDROMES WITH NCCN GUIDELINES GUIDELINES • (PTEN) •Case reports of in CS patients reports •Breast cancer, endometrial cancercancer,, only endometrioid type follicular or papillary , GI •PtPeutzz--Jeg her (STK11) or ganglioneuromas, colon •Breast, colon, small bowel, gastric, cancer, renal cell carcinoma ovarian/cervical/uterineovarian/cervical/uterine,, testicular, •Lifetime risk of endometrial carcinomas pancreatic cancers of 13–13–1919 %

NCCN GUIDELINES

Most current INDICATIONS FOR •Genetic/Familial High-High-RiskRisk REFERRAL TO GENETIC Assessment: Breast and Ovarian COUNSELOR •Version 3.20193.2019--JanuaryJanuary 18, 2019 •Genetic/Familial High-High-RiskRisk Assessment: Colorectal •Version 1.20181.2018--JulyJuly 12,2018

INDICATIONS FOR REFERRAL INDICATIONS FOR REFERRAL TO GENETIC COUNSELOR TO GENETIC COUNSELOR • Single case of: •Personal OR family history of: • Ovarian cancer *Particularly breast, •Cancer* diagnosed at a young age (<50) • Sarcoma gastrointestinal, melanoma, uterine, •Multiple primary cancers in the same • Medullary thyroid cancer renal, thyroid, • Retinoblastoma urinary tract, iidiidlndividual • Wilm’s tumor sarcoma •Cancer* in 2 or more close relatives • Adrenocortical carcinoma • Choroid plexus carcinoma •Combination of certain cancers* in a • / family • Multiple (>10) adenomas *Particularly breast, gastrointestinal, melanoma, uterine, renal, • Hamartomatous polyps, juvenile polyps or serrated thyroid, urinary tract, sarcoma polyps (any number at any age)

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TOP 10 CANCER MOST LIKELY TO BE DUE TO GERMLINE MUTATION •What is panel testing ? 1. Adrenocortical carcinoma (LiFraumeni and BWS) •Testing several genes for changes at 2. Carcinoid tumors (MEN I) one time 3. Diffuse gastric cancer (Hereditary Diffuse Gastric Cancer) •Why is panel testing performed? 4. Fallopian tube (BRCA) 5. Leiomyosarcoma (HLRCC, Lynch, Rb) •GGtienetic tttiesting for bbtreast cancer 6. Medullary thyroid carcinoma (MEN 2) 7. Paraganglioma/pheo (MEN 2, VHL, NF1, PGL) usually tests for mutations in BRCA1 8. Renal cell carcinoma-carcinoma-chromophobe, hybrid and BRCA2 genes; there are at least oncocytotic, oncocytoma histology (Britt-(Britt-HoggHogg--Dube)Dube) 9. Sebaceous carcinoma (Lynch) 10 other genes that predispose a 10.10.SexSex cord tumor with annular tubule (PJS) patient to breast cancer. Banks et al. Familial Cancer 2013;12:1-18.

HEREDITARY CANCER PANELS* HEREDITARY CANCER PANELS* Pancreatic cancer panels (13-(13-16)16) Multiple labs offering similar but different panels Malignant Melanoma panels (2(2--4)4) High risk breast cancer panels (5-(5-77 genes included) Lymphoma/leukemia panels (13) Expanded breast cancer panels (17-(17-23)23) Prostate cancer panels (5)  / panels (9(9--12)12) Breast/ovarian cancer panels (21-(21-23)23) Hereditary cancer panels (25-(25-6161 genes) Gynecological (ovarian/uterine) cancer panels Universityyg of Washington: AKT1, APC, ATM, ATR, AXIN2, (9(9--24)24) BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK1, CHEK2, CTNNA1, FAM175A High risk Colorectal cancer panels (7-(7-12)12) (Abraxas), FH, FLCN, GALNT12, GEN1, GREM1, HOXB13, Expanded colorectal cancer panels (16(16--22)22) MEN1, MLH1, MRE11A, MSH2 (+EPCAM), MSH6, MUTYH, NBN, NF1, PALB2, PALLD, PIK3CA, PMS2, POLD1, POLE, Renal cancer panels (12-(12-19)19) POT1, PRKAR1A, PRSS1, PTCH1, PTEN, RAD51B, RAD51C, Brain/CNS cancer panels (17(17)) RAD51D, RB1, RET, RINT1, RPS20, SDHB, SDHC, SDHD, SLX4, SMAD4, SMARCA4, STK11, TP53, VHL, and XRCC2 **AsAs of 7/10/15 **AsAs of 7/10/15

INFORMED CONSENT: RISKS & GETTING TESTING COVERED LIMITATIONS OF GENETIC TESTING • AL Medicaid does not cover genetic testing • Not all mutations are detectable • Contact labs to find one that is willing to • Negative result in your patient is only fully perform testing for free for Medicaid patients informative if a mutation has been identified in • Medicare only covers genetic testing in another family member individuals affected by cancer and meet criteria • Ie, negative results does not always mean the • Invitae will tes t unaffected Medicare for free cancer is not genetic (at this time) • Many of the main labs will offer significant • Uncertain significance of some variants (mutations) financial assistance • Unproven efficacy of most interventions • Myriad, Ambry, Invitae, GeneDx • Emotional impact and need to inform family • Look for patient assistance applications online members

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WHO GETS GENETIC TESTING? INDICATIONS FOR REFERRAL TO GENETIC COUNSELOR •Patient with cancer – Medical Oncologist will arrange for testing if indicated OR •Patient without cancer: When should the provider order •Primary provider must determine if genetic testing???? genetics testing is a consideration •Primary provider must counsel patient on seeking testing

RISK ASSESSMENT TOOLS FACTORS FOR RISK ASSESSMENT •BB--RSTRST –Breast Cancer Genetics Referral •Age Screening Tool • •https://www.breastcancergenescreen.org Height and weight •Race •Ibis ((yTyrer Cuzick) •http://www.emshttp://www.ems--trials.org/riskevaluator/trials.org/riskevaluator/ •Age at menarche •Gail – Breast Cancer Risk Assessment Tool •Age at first birth •https://bcrisktool.cancer.gov/ •History of breast biopsy •Family history

FAMILY HISTORY PATERNAL FAMILY HISTORY •Primary family •Secondary family •PATERNAL •Father members members FEMALE • •Mother •Cousin Paternal family RELATIVES member with •Sister •Aunt genetic mutation •Daughter •Grandmother

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RISK ASSESSMENT RISK ASSESSMENT TOOLS TOOLS •BB--RSTRST – Breast Cancer Genetics •BB--RSTRST – Breast Cancer Genetics Referral Screening Tool Referral Screening Tool •Ibis (Tyrer Cuzick •Ibis (Tyrer Cuzick) – accurate for at •Gail – Breast Cancer Risk Assessment least 19 years Tool •Gail – Breast Cancer Risk Assessment Tool

TYRER CUZICK RISK ASSESSMENT •Age at menarche TOOLS •Height •BB--RSTRST – Breast Cancer Genetics Referral •Weight Screening Tool •Age at menopause •Age at parturition •Ibis (Tyrer CuzickCuzick)) •Prior breast biopsies and PATH •Family history – who had breast cancer AND at what age •Gail –Breast Cancer Risk Assessment Tool •Hormonal use •EEstimatesstimates the risk of developing invasive •Breast density breast cancer in the next 5 years

RISK OF BREAST American Cancer Society Recommendations for the Early Detection of Cancer in Average- CANCER Risk, Asymptomatic Adults •Population (average) risk (women with no •Women 40-40-5454 years risk factors): 12.7% •Mammography starting at age 45, screened annually •Women should have the opportunity to •Moderate risk: Greater than 12.7% but begin annual screening between 4040--4444 years less than 20% •Women aged 55 years and older •Mammography – biennial screening or continue annually •High risk: 20% or greater •Mammography – continue as long as life expectancy is 10 years or longer

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RISK OF BREAST MODERATE RISK CANCER (LIFETIME RISK 12.712.7--20%)20%) •Population (average) risk (women with • Mammographic screening – start at age 40 no risk factors): 12.7% • Lifestyle behaviors • Alcohol – limit to no more than one drink per day • Lose weihtight – BMI >28 increases ri sk in a •Moderate risk: Greater than 12.7% but postmenopausal woman less than 20% • Regular exercise – 30 minute brisk walks 5 times weekly • Vitamin D (1000 IU daily) •High risk: 20% or greater • Healthy diet – limit red meat to 3 servings/week

RISK OF BREAST HIGH RISK (GREATER THAN CANCER 20% LIFETIME RISKRISK)) • Enhanced screening: yearly breast MRI in •Population (average) risk (women with addition to mammogram no risk factors): 12.7% • Alternate mammogram and MR every 6 months • Lifestyle behaviors • Prevention •Moderate risk: Greater than 12.7% but • Tamoxifen – only therapy for PREMENOPAUSAL less than 20% women • Raloxifen –more favorable than Tamoxifen • AI’s – Exemestane and anastrozole •High risk: 20% or greater • Surgery –not a candidate unless a BRCA mutation in family

RISKRISK--REDUCINGREDUCING SURGERY – IN MUTATION CARRIERS •Bilateral prophylactic mastectomy (risk reduction) CALCULATORS ARE NOT •decreases risk of breast cancer greater than TO BE USED FOR 90% PATIENTS WITH A •Risk reducing salpingosalpingo--oophorectomyoophorectomy (RRSO) PERSONAL HISTORY OF •Decreases breast cancer risk by 50% BREAST CANCER •BRCA1 ––byby age 35 •BRCA2 ––byby age 40 •Decreases ovarian cancer risk by 80%

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PATHOLOGY OF BREAST CANCER BREAST CANCER 1. Breast mass –biopsy is sent to pathology 2. Slides are made –pathology confirms = breast cancer diagnosis of cancer = BREAST cancer 3. Slides are stained to determine if there are certain receptors: = breast CANCER •Estrogen •Progesterone •HER2

RECEPTORS HER2: HUMAN HUMAN EPIDERMALEPIDERMAL • Cell receptors – found inside and on the RECEPTORRECEPTOR 2 surface of cells – normal breast and cancer cells • Gene that can play a role in the development of breast cancer • Cell receptors receive messages from substances • HER2 gene makes HER2 proteins – these are receptors on in the bloodstream, telling the cells what to do breast cells • Normal: HER2 receptors help control how a healthy cell • Cell hormone receptors: Estrogen (E), grows, divides, and repairs itself progesterone (P) • 25% breast cancer: HER2 gene mak es too many copi es of • If cells have hormone receptors, E and P attach and itself (HER2 amplification), extra HER2 genes tell breast cells provide instructions to help cells grow and function to make too many HER2 receptors (HER2 overexpression), and makes breast cells grow and divide in an uncontrolled way • Normal breast cells –E and P help growth • HER2 positive cancers grow faster, are more likely to spread • Cancer cells – E and P stimulate growth of cancer and come back • 2/3 of breast cancers have receptors for Estrogen, • HER2 positive cancer cells have 40-40-100100 X as many HER2 Progesterone, or Both receptors on the cell surface

HER2 HER2 POSITIVE BREAST • Healthy breast cells –HER2 stimulates cell CANCER – GOOD OR BAD? growth •HER2 positive tumors • Breast cancer cells with too much HER2: cells grow and divide too quickly •More aggressive • TOO much HER2 (receptors) is bad – •Increased risk of recurrence cancer cells grow rapidly •More likely to metastasize (especially • HERCEPTIN: blocks the HER2 receptors to the brain) • HER2 positive –Herceptin is a effective drug •Found in younger women • HER2 negative – Herceptin doesn’t treat the cancer

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BREAST CANCER -- INVASIVE ER/PR/HER2 Hormone (ER/PR) HER2 •Hormone positive means Estrogen positive, Progesterone positive, or both •Hormone positive •HER2 positive positive •Hormone negative •HER2 negative •Hormone positive, HER2 negative •Hormone positive, HER2 positive •Hormone negative, HER2 positive •Hormone negative, HER2 negative

CANCER TREATMENTS TRIPLE NEGATIVE • blockade – blocking the receptors BREAST CANCER on a cancer cell prevents hormones and •Estrogen negative HER2 from stimulating cell growth •Progesterone negative •Hormonal therapy: Tamoxifen, Anastrazole (Arimidex), Letrozole (Femara) – block the •HER2 negative effect of estrogen and progesterone on cancer cells, slowing or stopping growth •Herceptin, Perjeta, Tykerb, Kadcyla: blocks HER2 receptors

TRIPLE NEGATIVE WHO GETS TRIPLE CANCER NEGATIVE CANCER • 1010--20%20% of breast cancers are triple negative • Hormones are not stimulating the cancer’s growth, •Anyone so cancer is not going to slow down by giving •Younger people – more likely to be hormonal therapy • HER2 is not stimulating cancer growth, so found in women younger than 50 years HerceptinHerceptin--typetype drugs don’t work •African American and Hispanic women • Triple negative cancers are more aggressive than other types •People with BRCA1 mutation(70% of • Triple negative cancers more likely to spread cancers in BRCA1 patients are triple beyond the breast • Triple negative cancers more likely to recur – negative return after treatment

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