Simple But Complicated: Genetic Testing in Hereditary Gynecologic Cancers

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Edwin Robbins
6 years ago
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1 Simple But Complicated: Genetic Testing in Hereditary Gynecologic Cancers Robert Resta, MS, Licensed/Certified Genetic Counselor, Hereditary Cancer Clinic, Swedish Medical Center, Seattle, WA

2 Nota Bene Most patients with a significant personal and family history of cancer will have normal genetic testing Even in a high risk genetics clinic, ~80-90% of patients will have a normal genetic test result Ergo, for most patients, genetic testing will be uninformative The only true negatives occur in families where a pathogenic mutation has been identified Ideally, genetic testing should always start with an affected relative

3 Nota Bene Most apparently hereditary cancers are due to mystery genes, polygenic factors, an as yet undiscovered genetic mechanism, and/or some as yet unidentified environmental causes All patients with suspected hereditary cancer but who have normal genetic test results should bank their DNA Genetic testing is a key opportunity for identifying and implementing risk reducing/screening strategies for the patient and the family

4 Hereditary Gynecologic Cancer BRCA1/2 Update Lynch Syndrome Update Uncommon Stuff New Stuff Tests, Labs, Insurance Coverage, Who To Test

5 BRCA1/2 Primarily, but not exclusively, serous epithelial ovarian cancer Many but not all cases originate in fallopian tubes Lifetime risk ~20% (BRCA2) & ~40% (BRCA1) Wide variability in risk estimation due to study differences, age, family history, mystery factors At least 25% of BRCA+ women do not meet standard testing criteria May be associated with a small risk of serous papillary uterine cancer

6 BRCA 1/2 Should be offered to all women with ovarian cancer, regardless of age at dx because of potential for treatment with PARP inhibitors Breast, pancreatic, melanoma, male breast, young onset and aggressive prostate cancer Autosomal dominant men can transmit mutations to sons or daughters and it does not skip generations New mutations are very rare Homozygous BRCA2 mutations = Fanconi Anemia Homozygous BRCA1 usually embryolethal

7 4 High Risk Ethnic Populations 1. Ashkenazi Jews 2. Icelanders 3. Bahamians 4. East Greenland Eskimos

8 Lynch Syndrome (HNPCC) 5 different genes MLH1, MSH2, MSH6, PMS2, EPCAM Colon, uterine, ovarian, stomach, small intestine, skin, urinary tract cancers, and probably a few others Cancer risks vary significantly with each gene. Much lower cancer risks for MSH6 and PMS2.

9 Lynch Cancer Risks By Gene

10 Lynch Syndrome At least 25% of Lynch patients do not meet family history criteria Particularly common in women with synchronous/metachronous uterine and colon cancer Homozygotes present in childhood with Constitutional Mismatch Repair Deficiency (hematologic, brain, GI tumors in childhood and can mimic neurofibromatosis) No ethnic over-representation, though some specific mutations are more common in certain populations

11 Lynch Syndrome Uterine Cancer Uterine cancers can be endometrioid, mucinous clear cell, serous, carcinosarcoma Lower uterine segment cancers more likely to be Lynch Other pathologic features are not strongly predictive of Lynch Younger age of onset, except for MSH6 and PMS2 related uterine cancer Tumors typically demonstrate abnormal expression of one or more mismatch repair proteins (MMRP) by immunohistochemistry Many centers perform MMRP on uterine tumors, usually below a certain age though universal screening is reasonable

12 Lynch Syndrome Ovarian Cancer Ryan NAJ et Gynec. Oncol study of 53 cases Histopathology: 53% endometrioid, followed by serous, clear cell, carcinosarcoma, and mixed Average age of onset = 51 85% detected at Stage I/II Possibly overall better prognosis (80% survival at 5 years) Effectiveness of mismatch repair protein screening not well studied

13 Lynch Syndrome Ovarian/Uterine Cancer Moller P et al. Gut 2017;66; European study of 1942 mutation carriers followed prospectively with active surveillance 10 year crude survival of uterine cancer = 98% (95% CI, 88-99%) 10 year crude survival of ovarian cancer = 89% (95% CI, 60-97%) but small number (19) Is hysterectomy/bso warranted?

Rare Stuff Peutz-Jeghers (STK11) Multiple GI hamartomatous polyps, primarily small intestine Adenoma malignum of the cervix SCTAT (sex cord tumors with

14 Rare Stuff Peutz-Jeghers (STK11) Multiple GI hamartomatous polyps, primarily small intestine Adenoma malignum of the cervix SCTAT (sex cord tumors with annular tubules) Breast, pancreatic, GI cancers Lip/mouth freckling (tends to disappear in adulthood) Image from

15 Rare Stuff DICER1 Primarily children and young adults Sertoli Leydig cell tumors Cervical Embryonal Rhabdomyosarcoma Pleuropulmonary blastoma Cystic nephroma Multinodular goiter Autosomal dominant

16 Rare Stuff Cowden Syndrome Uterine Cancer (20-30%), Breast Cancer (40-60%), Renal Cancer, Thyroid Cancer (35%) Trichilemommas, acral keratoses, macrocephaly, uterine malformations, fibroids, cerebellar dysplastic gangliocytoma, developmental delay/autism, intestinal polyposis Mutations in PTEN gene Autosomal dominant Probably under-diagnosed

17 Rare Stuff Small Cell Carcinoma of the Ovary, Hypercalcemic Type Aggressive, young onset (average age = 24) Poor survival (33% survival with Stage 1 disease) ~40% of cases the result of SMARCA4 mutations SMARCA4 involved in chromatin remodeling SMARCA4 one cause Coffin-Siris syndrome (developmental disability, dysmorphology) Interestingly, ovarian cancer patients with SMARCA4 mutations don t have Coffin-Siris syndrome and Coffin-Siris patients are not at increased risk of small cell ovarian ca

18 New Stuff Newer Ovarian Cancer Genes Located in the Fanconi Anemia DNA double strand repair pathway; BRCA 1/BRCA2 in same pathway RAD51C RAD51D BARD1 BRIP PALB2??

19 Data presented at the 2017 Annual Meeting on Women s Cancer by the Society of Gynecologic Oncology (SGO) 2017 Annual Meeting on Women s Cancer by the Society of Gynecologic Oncology (SGO), National Harbor, MD

20 Mutation Rate by Ovarian Cancer Type

21 Ovarian Cancer Genes and Age at Diagnosis

22 NCCN Guidelines For Ovarian Cancer Risk Genes

23 Sweating The Details (Where The Devil Resides) How Do I Decide Which Gene(s) To Test For? What about Insurance Coveage? Which Lab Do I Use? Which patients do I test? How much will it cost patients?

24 Oh, make me wanna holler The way they do my life Make me wanna holler The way they do my life - Inner City Blues by Marvin Gaye and James Nyx, Jr

Deus ex machina Massively Parallel Sequencing To The Rescue Massively parallel sequencing allows for testing for multiple genes in one fell swoop All ovarian and uterine cancer genes can be analyzed

25 Deus ex machina Massively Parallel Sequencing To The Rescue Massively parallel sequencing allows for testing for multiple genes in one fell swoop All ovarian and uterine cancer genes can be analyzed in one fell swoop at no greater cost than single gene analysis Unless a known mutation is segregating in a family, the vast majority of genetic tests are gene panels encompassing 10, 20, 30, or more genes

26 Two Types Of Gene Panels Panels focused on a specific type of cancer (e.g., ovarian cancer genes only, breast cancer genes only, etc.) Broad cancer based panels that include genes for cancers that the patient/family does not appear to be at risk for Good arguments can be made for either approach, and in the long run, it probably does not matter too much

27 BUT Multicancer panels turn up lots of surprises Yurgelun MD et al. Gastroenterology 2015; 149: patients tested for Lynch syndrome with a 25 gene panel 9% tested positive for Lynch syndrome 5.6% tested positive for non-colon genes, including 15 BRCA mutations, only one third of whom met NCCN criteria for BRCA testing

28 More Surprises Susswein LR et al. Genetics in Medicine 2016; 18: ,000 patients tested with multigene panel Of colon cancer patients/fam hx, looking patients, 15% tested positve Of that 15%, 28% tested positive for a breast/ovarian gene Of breast cancer patients/fam hx, 10% tested positive Of that 10%, ~8% tested positive for a colon cancer gene

29 Downsides to Multigene Panels For some patients, TMI Much higher incidence of finding variants of uncertain significance (~30%) Almost all such variants should be ignored for clinical purposes There can be significant differences between labs in the interpretation of variants (not necessarily reflective of the quality of the lab itself)

30 Insurance Coverage All insurers cover hereditary cancer genetic testing, including Medicare and, in Washington, Medicaid Each insurer, however, uses different family history/medical history criteria to determine eligibility Calling the insurer to verify coverage not uncommonly gets you a wrong answer (~25% of the time, in my experience) The bigger, established labs will verify insurance coverage before initiating testing Genetic Nondiscrimination Act (GINA) of 2007

31 Cost Of Genetic Testing Significant differences between labs in cost of testing Prices range from $250 - $6,000 for pretty much the same test Some insurers require using only certain labs The larger well known labs all provide good quality tests If patient meets insurer s criteria for coverage, cost to the patient is usually negligible (in my experience, less than $100 and often no out of pocket) Many labs will do insurance preverification and are far better at it than you or your staff

32 Who Should Consider Genetic Testing? Unaffected Patients NCCN 2017 Guidelines

33 Who Should Consider Genetic Testing? Affected Patients All patients with serous ovarian cancer, regardless of age or ethnicity or family history All patients with uterine cancer with abnormal expression of the mismatch repair proteins (Lynch syndrome) All patients with uterine cancer and one other primary cancer (esp., colon, breast, ovarian)

34 BRCA Testing For All? By one estimate, only ~49,000 of the ~350,000 female BRCA mutation carriers in the US have been identified Because a substantial minority of BRCA mutation carriers have no risk factors, screening only high risk women results in missed opportunities for cancer risk reduction/prevention In a few communities, pilot programs have been successful in offering BRCA screening to all Ashkenazi women Some have argued that with dropping cost of genetic testing into affordable range, all women age should undergo BRCA testing, regardless of medical or family hx Controversial, but thought-provoking

GYNplus: A Genetic Test for Hereditary Ovarian and/or Uterine Cancer

GYNplus: A Genetic Test for Hereditary Ovarian and/or Uterine Cancer Causes of Hereditary Ovarian and Uterine Cancer uterine cancer ovarian cancer Sporadic 75-90% Sporadic 70-80% Hereditary, 5% Lynch syndrome