HEREDITARY CANCER SYNDROME REVIEW Alix d’angelo, mgc, cgc February 13, 2017

SYNDROME OVERVIEW Breast CRC Gyn

HEREDITARY BREAST CANCER

SYNDROMES WITH BREAST CANCER Hereditary Breast and Ovarian Cancer syndrome (BRCA1, BRCA2) Li-Fraumeni syndrome (p53) Cowden syndrome (PTEN) Peutz-Jeghers syndrome (STK11) Hereditary Diffuse Gastric Cancer (CDH1)

HBOC Jews: 1in 40 compared to 1 in 400 in general population. Dutch and Icelanders have founder mutations too BRCA1: 185delAG, 5382insC BRCA2: 6174delT Also an up to 60% lifetime risk of a second primary breast cancer Elevated melanoma risk for BRCA2, but exact risk not known. Annual skin and eye exams by specialist may be appropriate. Screening for breast cancer- annual MRI (25) and mammography (30). Prophylactic mastectomy. Male breast cancer- no formal recs, semiannual clinical breast exam, consideration of baseline mammography followed by annual mammogram if gynecomastia is present. Ovarian- US and CA-125 semiannually at 35. Prophylactic salpingo-oophorectomy. Prostate- annual PSA and exam at 40. Pancreas- imaging in research setting

RECOMMENDATIONS FOR WOMEN SCREENING SURGERY Prophylactic bilateral mastectomy Reduces breast cancer risk by 90-95% Prophylactic bilateral salpingo- oophorectomy by 35-40yo or 40- 45yo Reduces ovarian cancer risk by ~85% Reduces breast cancer risk by ~50% Annual Mammogram and Breast MRI MRI beginning at 25yo; mammo at 30yo Transvaginal ultrasound and CA-125 Every 6 months beginning at 30yo NOT PROVEN EFFECTIVE at detecting ovarian cancer at an early stage MRI with contrast. Can start imaging earlier if there is a breast cancer <30yo in the family. Screening is in addition to clinical breast exams every 6-12 months starting at 25yo. Considerations of just salpingectomy in premenopausal women followed by postmenopausal oophorectomy.

HBOC- Chemoprevention Tamoxifen Raloxifene Selective estrogen receptor modulator Originally used to prevent and treat osteoporosis in postmenopausal women Studies show may be more effective than tamoxifen in women who have not had a hysterectomy Partial estrogen antagonist ~50% reduction in risk of breast and contralateral breast cancers Predicted to be more helpful in women with BRCA2 mutations Tumors are less likely to be estrogen receptor negative than BRCA1 In the initial STAR study that compared the two drugs, tamoxifen was more effective in reducing breast cancer within a given period of time. However, tamoxifen increases the risk of uterine cancer, and in the same study, about double the number of women on tamoxifen developed uterine cancer compared to those on raloxifene. Both increase the risk of blood clots, so have to take medical history into account when deciding whether chemoprevention is appropriate. Aromatase inhibitors (i.e. anastrozole) in postmenopausal women. http://www.cancer.gov/types/breast/research/benefit-risk-tool

HBOC- PARP Inhibitors Resistance Mechanisms Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian CancerCell Rep. 2016 Jan 6. pii: S2211-1247(15)01487-4 Resistance Mechanisms Secondary mutations restoring BRCA function microRNAs regulating NHEJ repair rescues HR deficiency PARP senses DNA damage (SSB) and recruits HR machinery. If PARP is inhibited, this doesn’t happen and genomic instability rises, resulting in synthetic lethality. Inhibition also stimulates the error-prone NHEJ pathway, also leading to increased genomic instability.

RECOMMENDATIONS FOR MEN Clinical breast exams every 6-12 months beginning at 35 years-old Consider mammogram at 40 years-old (no longer explicitly in guidelines) PSA blood test annually beginning at 45 years-old Recommended for BRCA2; “Consider” for BRCA1

Li-Fraumeni syndrome (p53) Core Cancers Other Cancers Sarcomas Breast cancer Brain tumors Adrenocortical carcinomas Lung Gastrointestinal Others Skin Genitourinary Sarcomas- mostly osteosarcomas and rhabdomyosarcomas. NOT some types like Ewing sarcomas. Breast cancer typically hormone receptor positive. Brain tumors like glios, medullos and CPCs. Breast cancer screening is similar to BRCA1/2, but perhaps at an earlier age depending on family history. Increased colonoscopy screening Neuroblastomas Thyroid Leukemias and lymphomas

Li-Fraumeni syndrome (p53) Classic Criteria Proband with a sarcoma <45y First degree relative with cancer <45y First or second degree relative with any cancer <45y or sarcoma at any age But, can consider testing for anyone who has an LFS spectrum tumor <45y, multiple tumors <45y or ACC or CPC at any age. If they have early onset breast cancer and are BRCA1/2 negative. Tumor-specific risk estimates don’t currently exist (except breast which is up to 80%), bc of how rare it is and the diverse spectrum of tumors.

RECOMMENDATIONS FOR WOMEN SCREENING SURGERY Breast MRI and mammogram Annually; MRI beginning at 20yo and mammogram beginning at 30yo Clinical breast exams Every 6-12 months beginning at 20-25yo Prophylactic bilateral mastectomy

OTHER RECOMMENDATIONS Annual comprehensive physical exam including neurological and dermatologic exams Consider colonoscopy every 2-5y beginning at 25yo Annual whole body MRI (including brain MRI) Pediatricians should be aware of childhood cancers AVOID radiation therapy when possible

PTEN- Hamartoma Tumor syndrome Cowden syndrome Bannayan-Riley-Ruvalcaba syndrome Proteus syndrome Proteus-like syndrome Need annual physical with particular attention to skin, thyroid and breasts, urinalysis, baseline thyroid US, breast screening (annual MRI and mammography) at 30y, annual thyroid US, colonoscopy at 35 every 5 yr (or more often if polyps found), renal imaging at 40 every 1-2y. Other findings: Macrocephaly Derm findings (Trichilemmomas, acral keratosis, papillomatous lesions) Intestinal polyps, fibrocytic breasts, uterine fibroids, lipomas, fibromas… Benign goiters and thyroid adenomas (75%)

RECOMMENDATIONS FOR WOMEN SCREENING SURGERY Mammogram and breast MRI Annually beginning at 30-35yo Random endometrial biopsies and/or ultrasound Prompt response to symptoms Prophylactic bilateral mastectomy Reduces breast cancer risk by 90- 95% Prophylactic hysterectomy Upon completion of childbearing

RECOMMENDATIONS FOR MEN AND WOMEN Annual comprehensive exam beginning at 18yo or 5y before the earliest cancer diagnosis in the family Annual thyroid ultrasound starting at time of diagnosis Colonoscopy beginning at 35yo performed every 5y or more frequently if polyps are found Consider renal ultrasound beginning at 40yo (every 1-2 years) May need dermatologic management

Hereditary Diffuse Gastric Cancer (CDH1) Men: 67-80% Women: 56-83% Lobular breast cancer 39-52% Colorectal? Prophylactic gastrectomy at 18-40y Upper endoscopy and biopsies every 6-12 months Breast MRI and mammography similar to BRCA1/2 mutations Different pathology from the intestinal-type gastric cancer which is more common and related to environmental risks such as H pylori infection. Efficacy of screening for gastric cancer is not high, and individuals who underwent PTG were found to have early stage cancer despite screening. Therefore, gastrectomy is preferred.

MODERATE RISK GENES Other genes with elevated but not yet defined risks: BLM FANCC MRE11A MUTYH NF1 RAD50 RAD51C RAD51D XRCC2 These have known moderate risks with clinical guidelines. CHEK2 also warrants male breast screening. New literature says BRIP1 probably just ovarian cancer risk gene.

RECOMMENDATIONS Anecdotally, I’ve seen testing done on families with breast and ovarian cancer come back positive for PMS2 mutation

RECOMMENDATIONS

RECOMMENDATIONS

SYNDROME OVERVIEW

Lynch syndrome/HNPCC Amsterdam II Criteria 3 or more family members with HNPCC-related cancers 1 must be a 1st degree relative of the other 2 2 successive affected generations 1 or more HNPCC-related cancer diagnosed before 50y Exclusion of FAP

Lynch syndrome (HNPCC) + means the combined risk is 6% to age 70y. EPCAM is a regulator of PMS2 expression, so risks are similar. Different studies actually quote MSH6’s endometrial risk as higher (more like 60%). Colonoscopy 1-2yr (may be less if no polyps are found) at 20-25 for MLH1/MSH2, 25-30 got MSH6/PMS2/EPCAM, pancreas surveillance and, prophylactic hysterectomy and BSO or screening

RECOMMENDATIONS FOR MEN AND WOMEN Colorectal cancer Colonoscopy every 1-2y beginning at 20-25yo Gastric and small bowel cancer Consider EGD with extended duodenoscopy every 3-5y beginning at age 30-35yo Only in selected individuals/families or those of Asian descent Urothelial cancer Consider annual urinalysis beginning at 30-35yo CNS cancers Consider annual neurologic exam beginning at 25-30yo Aspirin use may decrease CRC risk. No guidelines for pancreatic cancer risk, but can consider research protocols with EUS and MRCP.

RECOMMENDATIONS FOR WOMEN SCREENING SURGERY Endometrial biopsies and transvaginal ultrasound Not proven effective Transvaginal ultrasound and CA- 125 Prophylactic hysterectomy Consider upon completion of childbearing Prophylactic bilateral salpingo- oophorectomy

CHEMOTHERAPY and MSI Microsatellite instability (MSI-H) 90% of Lynch syndrome related tumors (data on colon and endometrial cancers) 10-15% of sporadic colorectal tumors Data shows stage II MSI-H tumors have better prognosis 5-FU use is contraindicated in stage II MSI-H tumors 5-10% false negative rate for Lynch with MSI and IHC testing.

Familial Adenomatous Polyposis (FAP) Mutations in APC 100s-1000s of colon polyps 10-99 for attenuated form (AFAP) Nearly 100% risk of CRC in classic form ~70% risk in AFAP Elevated risk for thyroid (1-12%), gastric, small bowel (4-12%)and other GI cancers Osteomas, supernumerary teeth, desmoid tumors, CHRPE CHRPE= congenital hypertrophy of the retinal pigment epithelium. Mean age of cancer diagnosis is 39y. Certain variants called Gardner (epidermoid cysts, desmoid tumors) and Turcot that also have an increased risk of CNS tumors like Medulloblastoma. Genotype-phenotype correlations exist. Colonoscopy at 10-15y, colectomy and upper endoscopy, thyroid exam

COLORECTAL RECOMMENDATIONS SCREENING SURGERY Annual flex sigmoidoscopy or colonoscopy beginning at 10- 15yo Can continue until polyp burden becomes unmanageable Colectomy or proctocolectomy (dependent on several factors) Still need screening after surgery Colectomy  endoscopic eval of rectum every 6-12 mos

EXTRACOLONIC RECOMMENDATIONS

MUTYH- associated polyposis Autosomal recessive inheritance Similar presentation to AFAP 10-99 polyps 43-99% lifetime risk of CRC Similar extracolonic features as FAP but not completely defined Carriers may have increased risk for late-onset CRC Also, a new gene called NTHL1 that is autosomal recessive and similar presentations

RECOMMENDATIONS

Peutz-Jeghers syndrome (STK11) Clinical Diagnostic Criteria ≥2 PJS-type hamartomatous polyps Characteristic mucocutaneous pigmentation and a family history of PJS Any number of PJS polyps and a family history of PJS Any number of PJS polyps and characteristic mucocutaeous pigmentation Pigmentation on mouth, lips, nose, eyes, genitalia or fingers

Peutz-Jeghers syndrome

Juvenile Polyposis syndrome Specific histology 5-100+ polyps in lifetime Lifetime CRC risk: 68% Lifetime gastric cancer risk: 21% Pancreas cancer? Hamartomatous mucus-filled cystic glands among other features and are missing the muscle fibers and proliferative characteristics of adenomas. JPS can be clinically diagnosed if 5+ polyps are in the colon, many are anywhere in the GI tract, or if there are any number of polyps and a family history. Need colonoscopies and upper endoscopies annually at 15y, and CBC to monitor for bleeding and anemia.

JPS/Hereditary Hemorrhagic Telangectasia Only with SMAD4 mutations, NOT BMPR1A Mucocutaneous telangectasias Vascular malformations Pulmonary, GI, hepatic and cerebral AVMs Need pulse oximetry every 1-2 yrs in first decade, contrast echocardiogram every 5 yrs thereafter; brain MRI after puberty Arteriovenous malformations

RECOMMENDATIONS

RECOMMENDATIONS

GENETIC TESTING Single Gene Phenotype Panel Pan-Cancer Panel Still important when clinical diagnosis can be made Decreases risk of VUS in unrelated gene Will NOT pick up unusual results Only include genes related to specific cancer Different sizes Will pick up some unexpected results Increases risk of VUS Includes all genes related to hereditary cancer # depends on lab Will pick up unexpected results Increases risk of VUS

CHEK2 deletion 2 d. 62y 73y 53y dx. triple neg. breast ca @ 53y 30s dx. “ovarian ca” @ 20s 34y dx. triple neg. breast ca @ 34y 31y

BRCA2 + hx of colon cancer hx of pancreas cancer 60s + tob hx of colon polyps and thyroid cancer uterine fibroids breast cancer 40s hx of thyroid disease breast cancer 30s hx of thyroid disease

MSH2 + 3 d. 82y dx. Ovarian ca @ 45y dx. Bladder and stomach ca @ 77y MVA 85y d. 65 heart disease d. 67y dx. ovarian ca @ 35y dx. breast ca 45y hx of colon polyps and TAH-BSO @ 38y hx of colon polyps TAH-BSO? d. 47y surgical complications d. 23y MVA Mother originally had negative BRCA1/2 sequencing and BART. Several years later, the daughter presented for hx of breast cancer. My colleague recommended that the mother have updated panel testing. 3 34y 32y 20s 42y

BRCA1+ and ATM+ 5 1 maternal cousin with breast ca @ 55y (d. 57y) dx. breast ca @ 51y 70y dx. breast ca @ 50y 75y dx. prostate ca @ 65y 1 maternal cousin with breast ca @ 55y (d. 57y) 1 maternal cousin with “breast tumor” @ 20y (now 40y) 30s 40y 18y 14y

Genetic Counseling Process Review family and medical history Use models for risk assessment when appropriate (i.e. Tyrer-Cusick) Decide on appropriate testing Discuss benefits and risks with patient Follow-up appointment to discuss results and management recommendations

REFERRAL CRITERIA- breast cancer dx A known mutation in a cancer susceptibility gene within the family Early-onset breast cancer Triple negative breast cancer ≤60y Two breast cancer primaries in a single individual Breast cancer at any age AND ≥1 close blood relative with breast cancer ≤50y or ≥1 close blood relative with invasive ovarian cancer at any age or ≥2 close blood relatives with breast cancer and/or pancreas cancer at any age From a population at increased risk Personal and/or family history of three or more of the following Pancreas cancer, prostate cancer (Gleason score ≥7, sarcoma, adrenocortical carcinoma, brain tumors, endometrial cancer, thyroid cancer, dermatologic manifestations, macrocephaly, hamartomatous polyps of the GI tract, diffuse gastric cancer Invasive ovarian cancer Male breast cancer

REFERRAL CRITERIA – no cancer dx Family history of: A known mutation in a cancer susceptibility gene within the family ≥2 breast cancer primaries in a single individual ≥2 individuals with breast cancer primaries on the same side of the family ≥1 invasive ovarian cancer primary First or second degree relative with breast cancer ≤45y Personal and/or family history of three or more of the following: Pancreas cancer, prostate cancer (Gleason score ≥7, sarcoma, adrenocortical carcinoma, brain tumors, endometrial cancer, thyroid cancer, dermatologic manifestations, macrocephaly, hamartomatous polyps of the GI tract, diffuse gastric cancer Male breast cancer

REFERRAL CRITERIA- CRC Individual meets revised Bethesda criteria Individual from a family meeting Amsterdam Criteria Individual with >10 adenomas Individual with multiple GI hamartomatous polyps or serrated polyps Individual from a family with a known hereditary CRC syndrome (mutation known or not) Individual with a desmoid tumor, variant of papillary thyroid cancer or hepatoblastoma Bethesda- CRC dx <50yrs, presence of synchronous or metachronous Lynch-related tumors regardless of age, CRC with MSI-H histology dx at <60yrs, CRC dx in a patient with 1st degree relatives with a Lynch-related cancer, or CRC dx in a patient with multiple 1st or 2nd degree relatives with Lynch-related tumors regardless of age

CONTACT INFO Alix D’Angelo, MGC, CGC Office: CSRB 652 Phone: (504) 568-2668 Email: adange@lsuhsc.edu Fax: (504) 568-2586