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THIS COULD BE YOU ONE DAY SOON: Starting out in your new OB/Gyn practice You meet Lori, a new patient, for her annual well-woman visit:

LORI: 37-year old Caucasian female good general health family history: mother: HTN, osteopenia dx ed 65 father: colon polyps dx ed 68 PGM: breast cancer dx ed 55 sister: recently dx ed with breast cancer at 42

FUN FACT #1: F A M I LY H I S T O R Y W A S T H E F I R S T G E N E T I C T E S T.

CASE #1 LORI S PEDIGREE

Family histor Lifestyle y Cancer Risk Environmen t Gene s

FUN FACT #2: A L L C A N C E R I S G E N E T I C, BUT F E W C A N C E R S A R E I N H E R I T E D.

STAGES OF CANCER DEVELOPMENT Normal cell Mutation in Gene A Increased proliferation Mutation in Gene B Early neoplasia Mutation in Gene C Progressive neoplasia Carcinoma Continuing cascade of mutations Metastasis

ALL CANCERS HAVE GENETIC ORIGINS Somatic mutations Germline Mutations Occur in non-germline tissues (breast, colon, lung, blood, etc.) Not inherited sporadic Start out in egg and sperm cells Heritable Once inherited, mutation is present in all cells of the body 90-97% of all cancers 3-10% of all cancers

THE WORLD OF CANCER GENETIC TESTING Direct-to-consumer Tumor testing (somaticbased) Germline genetic testing

GERMLINE GENETIC TESTING WHO? WHY? Myriad, Ambry, GeneDx, Prevention, etc. WHAT? DNA sequencing and deletion/duplication analysis of genes associated with inherited cancer syndromes To guide screening, prophylaxis, risk management, and identify at-risk family members LIMITATIONS not every cancer risk gene is known possibility of unclear results cannot prevent / screen for all cancer risks more questions than answers anxiety / distress

CASE #1 LORI S PEDIGREE

NATIONAL COMPREHENSIVE CANCER NETWORK www.nccn.org Mission statement: Our mission, as an alliance of leading cancer centers devoted to patient care, research, and education, is improve the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Clinical Practice Guidelines in Oncology Patient Guidelines CEU programs

NCCN GUIDELINES FOR HEREDITARY BREAST/OVARIAN ASSESSMENT personal history of ovarian cancer at any age personal history of breast cancer <45 triple negative breast cancer two primary breast cancers two or more family members with breast and/or ovarian cancer, especially <50

CONSIDER GENETIC TESTING BUT FOR WHO? Lori? Lori s sister?? Someone else???

FUN FACT #3: IDEALLY, GENETIC TESTING SHOULD BE PERFORMED ON AN AFFECTED INDIVIDUAL.

SO WHAT TESTING DO WE OFFER THIS FAMILY? Back in the day (<5 years ago), we had only a small handful of cancer genes we routinely tested for. Myriad Labs held the patent on the BRCA1 and BRCA2 genes and was the only lab who could do the testing. On June 13, 2013, the Supreme Court struck down the patent, ruling that genes are not patentable. On June 14, 2013, every genetic testing laboratory was offering BRCA1 / 2.

Introduction of NGS technologies

NGS MULTIGENE PANELS Benefits -- assess any number of genes at once (typically anywhere from 15 50) -- clarify patient s risk (and those of other carriers of familial variant) -- guide medical management Challenges -- turnaround time may be several weeks delayed decision-making -- limited literature on many genes / variants -- interpreting results for unaffected family members -- variants of unknown significance -- informed consent -- follow up in the case of variant reclassification

DISTRIBUTION OF PATHOGENIC VARIANTS IN HBOC FAMILIES Citation: Castera, L. et al. Nextgeneration sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014 Feb 19

GENES AND CANCER SITES

FUN FACT #4: I T I S V E R Y U N L I K E LY Y O U W I L L E V E R O R D E R G E N E T I C T E S T I N G F O R A S I N G L E G E N E / C A N C E R S Y N D R O M E

CASE #2 COLON POLYPS 57-year old male first colonoscopy at 56 -- multiple polyps throughout colon -- pathology: tubular adenomas and mucosal polyps with muscle overgrowth follow-up colonoscopy (6 months later) -- multiple polyps in each colon segment -- uncountable polyps in transverse colon -- pathology: tubular adenomas and hyperplastic polyps

TESTING STRATEGY genetics evaluation if >10 adenomas present, test for FAP / MAP conventional approach: -- sequencing and rearrangement testing of APC, MUTYH genes -- if polyp NOT adenomatous, assess whether patient meets NCCN criteria for less common polyposis syndrome, such as Cowden, Peutz-Jehger, or Juvenile Polyposis syndrome.

COLORECTAL CANCER Sporadic (70%) FAP = Familial adenomatous polyposis MAP= MUTYH-associated polyposis Familial (25%) - Lynch syndrome (3%) - FAP (1%) - MAP (1%) - Rare CRC syndromes (<1%) juvenile polyposis Peutz-Jehgers syndrome serrated polyposis PTEN-related syndrome hereditary diffuse gastric cancer (HDGC)

LIFETIME RISKS FOR COLORECTAL CANCER Cancer Risk (%) 100 90 80 70 60 50 40 30 20 10 0 FAP AFAP MAP General Population

APC / MUTYH negative NOW

COLONEXT NGS PANEL (AMBRY) Gene Syndrome CRC Risk Polyposis Other Associated Cancer(s) STK11 Peutz-Jeghers Up to 40% Yes Breast, pancreas, GI, uterine, cervical CHEK2 CDH1 Hereditary Breast/CRC Hereditary Diffuse Gastric Cancer Increased No Breast Increased No Lobular breast, diffuse gastric PTEN Cowden Increased Yes Breast, thyroid, kidney, uterine TP53 Li-Fraumeni Increased No Breast, sarcoma, brain, leukemia MYH MAP Up to 80% Yes Duodenal, thyroid APC FAP / AFAP Up to 99% Yes Duodenal, thyroid MLH1 MSH2 MSH6 PMS2 EPCAM Lynch Up to 80% No Stomach, brain, Uterine, ovarian, Pancreas, ureter SMAD4 BMPR1A Juvenile Polyposis Up to 50% Yes Stomach

THINGS TO CONSIDER BEFORE TESTING - CLINICIAN Gene / syndrome-specific testing is still available and MAY be a reasonable option in some cases and should be discussed with any patient MSI / IHC should be utilized when Lynch syndrome is suspected Large gene panels can take several weeks to several months for results Large panels may not be feasible when making time-sensitive decisions

THINGS TO CONSIDER BEFORE TESTING - PATIENT Longer turnaround time may delay treatment / surgery Testing may find variants with unclear cancer implications Testing may find variants revealing risk for unrelated cancers Results may have implications for other family members

PTEN HAMARTOMA TUMOR SYNDROME (PHTS) Includes: Cowden syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS) Thyroid cancer (35%) Kidney cancer (33%) Colorectal cancer (9%) Melanoma (6%) Breast cancer (60%) Endometrial cancer (28%) Uterine fibroids Hamartomatous polyps Macrocephaly Thyroid nodules, goiter Trichilemmomas, papillomatous papules Hyperpigmentation Overgrowth Fibrocystic breast disease Autism spectrum disorder Mental retardation (IQ<75) Lipomas

Lipomas, HC 63.9 cm Asperger syndrome macrocephaly LD autism

PTEN WORKUP - JW Subtotal colectomy with IRA path: colon with multiple tubular adenomas and hamartomatous polyps Double balloon enteroscopy -- glycogenic acanthosis, ileal and jejunal polyps Thyroid ultrasound innumerable nodules Recommendations: Yearly physical Yearly thyroid ultrasound Yearly derm exam Continue GI screening based on polyp burden Genetic testing for first degree relatives > age 18 Derm exam unremarkable MRI of the abdomen unremarkable

CASE #3 - HBOC 46 year old woman with a newly diagnosed left breast cancer ER/PR+ invasive ductal carcinoma Referred for genetic risk assessment by patient request -- wants risk estimate to help her decide about bilateral mastectomy

CANCER RISKS IN HBOC BRCA1 Breast cancer: 54-90% 2nd breast cancer: 27% within 5 years Ovarian cancer: 24-40% BRCA2 Breast cancer: 41-87% 2nd Breast cancer: 12% within 5 years Ovarian cancer: 8.4-18%

CANCER RISKS IN HBOC

FUN FACT #5 A LWAY S A S K A B O U T B O T H S I D E S O F T H E FA M I LY W H E N TA K I N G A FA M I LY H I S T O R Y!

CASE #3 PEDIGREE

MYRISK (MYRIAD) RESULTS

BOOM! POSITIVE TEST! Deleterious variant - MUTYH gene c.1187g>a (p.gly396asp)

MUTYH GENE involved in base excision repair germline MUTYH mutations impair DNA repair of somatic APC mutations leading to a phenotype similar to FAP RECESSIVE inheritance biallelic carriers are predisposed to: Multiple colorectal adenomas upper GI manifestations stomach cancer, duodenal polyps Early onset colon caner CHRPE Risks for other cancers is unclear (possible increased risk for breast cancer, skin cancer, ovarian cancer)

MUTYH-ASSOCIATED POLYPOSIS MUTYH testing classically bundled with APC accounts for 1% of all CRC accounts for up to 3% of CRC under age 50 monoallelic carriers: - studies conflict on whether cancer risk is increased - carrier rate: 1-2% of the general US population

SO, IN OTHER WORDS Does she have a disease-causing variant? YES. Does it explain her cancer? NO. Does this variant, on its own, affect her risk for cancer? Probably not.

MYRISK RESULTS Deleterious variant - MUTYH gene c.1187g>a (p.gly396asp) Variants of Uncertain Significance (VUS) - BRCA2 c.8447g>a (p.gly2816asp) - STK11 c.1062c>g (p.phe354leu)

FUN FACT #6: S O M E T I M E S I N O U R Q U E S T F O R A N S W E R S W E O N LY F I N D M O R E Q U E S T I O N S.

VARIANT INTERPRETATION Citation: Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J.,... & Voelkerding, K. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine. Medical mgmt. based on personal & family hx. Uncertain results do not influence recommendations for care. Medical mgmt. based on guidelines for gene variant and its associated syndrome(s).

RATES OF UNCERTAIN VARIANTS 40.0% Decline in Rate of BRCA1/2 Variants of Uncertain Significance 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% All Patients Middle Eastern Asian African Native American Latin American Central European Western European 5.0% 0.0% 2002 2006 2008 2012 Eggington et. al. Current Variant of Uncertain Significance Rates in BRCA1/2 and Lynch Syndrome Testing (MLH1, MSH2, MSH6, PMS2, EPCAM), March 2012, ACMG Poster Presentation.

CASE #3 PEDIGREE MUTYH-positive VUS BRCA2 VUS STK11 NO BRCA2 VUS

STK11 GENE associated with Peutz-Jehgers syndrome autosomal dominant ~50% de novo characteristic hyperpigmentation of the mucosa hamartomatous polyps

CANCER RISKS IN PJS Breast - 50% Colorectal - 39% Pancreatic 11-36% Gastric - 29% Small bowel 13% Ovarian - 21% Cervical 10% Uterine - 9% Lung - 15% Testicular -?

RECOMMENDATIONS currently no genetic indication that PR s risk for a second breast cancer is significantly increased. recommended standard breast treatment, screening, and follow-up care based on physician recommendations and family history undergo colonoscopy every 5 years MYH testing recommended for 1 st degree relatives -- to assess for MAP -- high US carrier rate (1-2%)

THIS CASE ILLUSTRATES complex inheritance patterns with some syndromes significant risk of variants of uncertain significance - approximately one-third of panel results - newer genes, less literature, smaller samples - reclassification of many VUS with time challenges for clinicians in sorting out the data challenges for patients trying to make decisions about care

FUN FACT #7: Y O U D O N T N E E D T O K N O W E V E R Y T H I N G. Y O U D O N E E D T O K N O W W H E N T O R E F E R.

A GENETIC COUNSELOR CAN HELP YOU RIGHT PATIENT RIGHT TEST RIGHT LAB RIGHT RESULTS

WHEN TO REFER TO GENETICS triple-negative breast cancer male breast cancer ovarian cancer young onset (< 50) same/related cancer in relatives autosomal dominant inheritance with rare exceptions aggressive prostate cancer - Gleason score 7 multiple primaries multifocal / bilateral cancers rare cancers unusual non-malignant features (i.e., syndromic ) confirmed mutation in relative If uncertain, refer anyway!

LAST FUN FACT: G E N E T I C S A N D O U R U N D E R S TA N D I N G O F M U TAT I O N S I S E V O LV I N G, S O T O D AY S G E N E T I C R E S U LT M U S T A L W AY S B E R E A S S E S S E D A N D I N T E R P R E T E D B A S E D O N C U R R E N T I N F O R M A T I O N A N D S T U D I E S O F M O D I F I E R S, P R O P H Y L A X I S O P T I O N S, A N D P R E V E N T I O N. M I C H A E L H A L L, M D F O X C H A S E C A N C E R C E N T E R P H I L A D E L P H I A, P A

QUESTIONS? My contact information: Carla Bell, MS, LCGC Wesley Medical Center Oncology Department 550 North Hillside Wichita, KS 67214 Direct phone: 316.361.0991 Fax: 501.222.7753 Email: Carla.Bell@WesleyMC.com