Clinical Implications for Intervention

Transcription

1 Hereditary Breast and Ovarian Cancer Syndromes: Clinical Implications for Intervention Muhieddine Seoud, MD, FACOG, FACS American University of Beirut Medical Center MEMAGO 1rst meeting, Ankara, March 2016

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3 Hereditary breast and ovarian cancer (HBOC): Objectives 1. Review the changing prevalence of HBOC syndromes 2. Emphasize the importance of history taking in familial cancer syndromes 1. Identify and select appropriate genetic counseling/testing/companion diagnostics to evaluate germline and somatic mutations of such patients 1. Present available data on lifetime risk of various mutations in various cancers 1. Summarize the current recommendations for risk reducing interventions 1. Take home message

4 HBOC: Facts The hallmarks of hereditary cancer syndromes: 1. Multiple affected family members 2. Early age of onset 3. Multiple and/or bilateral primary cancers Multiple syndromes associated with increase risks 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

5 Case report: Ms. C.S. : 3 cancers in one, all missed 52 years old single female presenting with abdominal carcinomatosis Sister had serous ovarian cancer at age 43 At age 47: Myomectomy for an 18 cm myoma Left 2 cm breast mass: no Work up and no FU 6 months later, left triple negative breast cancer: Lumpectomy and SLN chemo/radio/no tamoxifen Right adnexal mass observed stable At age 52: Abdominal carcinomatosis bilateral ovarian cancers stage IIIC Referred for management 2 cm thyroid nodule discovered FNA thyroid papillary cancer

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7 Case report: Ms. N.S.

8 Patient Cancer Family History No Yes Does the family history raise red flags? No Yes: Hereditary Cancer Testing Negative or VUS Positive Mutation General Population Familial Risk Hereditary Risk

9 HBOC: Facts ~ 20 30% of patients carry a germline mutations in DNA repair pathways 8 10% have a family history of the ds and may carry mutations in BRCA ½ 8 10% without family history of the ds and may carry mutations in BRCA ½ ~ 22% of patients in a breast surgery practice may be appropriate for BRCA testing Tumors may carry somatic mutations in BRCA BRCAness: Tumors may carry mutations in other proteins associated with DNA repair Caveats: 1. Unknown risk from specific mutations: (VUS) 2. Unknown impact on prognosis & response rates for some of these mutations 1. Alsop K et al. J Clin Oncol 2012;30: Liu et al. Clin Cancer 2014; Lodhia K et al. Ann Oncol 2015;26;ii31 Pennongton KP et al. Clin Cancer Res 2014;20:764 75

10 HBOC: Rates of VUS decreasing 1. Alsop K et al. J Clin Oncol 2012;30: Liu et al. Clin Cancer 2014; Lodhia K et al. Ann Oncol 2015;26;ii31 Pennongton KP et al. Clin Cancer Res 2014;20:764 75

11 HBOCS: Patients with an increased likelihood of having an inherited predisposition Women AFFECTED with: 1. High grade EOC/TC/PPC 2. BCA 45 years 3. BCA with: close relative b with BCA 50 yrs close relative b with EOC/TC/PPC 4. BCA 50 years with a limited family history c 5. BCA with 2 close relatives b with BCA at any age 6. BCA with 2 close relatives b with pancreatic cancer, prostate cancer (GS 7) 7. 2 breast 1ries, with the 1rst dx < 50 ys 8. Triple negative BCA 60 years 9. BCA and Ashkenazi Jewish ancestry 10. Pancreatic cancer with 2 close relatives b with BCA, prostate cancer (GS 7) b Close relative is defined as a first degree (parent, sibling, offspring), second degree (grandparent, grandchild, uncle, aunt, nephew, niece, half sibling) or third degree (first cousin, great grandparent or great grandchild) relative c Limited family history includes fewer than 2 first or second degree female relatives of female relatives surviving beyond 45 years.

12 HBOCS: Patients with an increased likelihood of having an inherited predisposition Women UNAFFECTED with cancer, but with: A 1rst degree or several close relatives that meet one of the above criteria A close relative b carrying a known BRCA1 or BRCA2 mutation A close relative with male breast cancer b Close relative is defined as a first degree (parent, sibling, offspring), second degree (grandparent, grandchild, uncle, aunt, nephew, niece, half sibling) or third degree (first cousin, great grandparent or great grandchild) relative.

13 Hereditary susceptibility to ovarian/breast cancer 2002 BRCA2 (30%) Lifetime risk 15-30% BRCA1 (65%) Lifetime risk 30-60% HNPCC (7%) Hereditary (10%) Sporadic (90%) Rebbeck TR, Lynch HT, et al. NEJM 2002

14 Summary of Mutation Carriers: GOG 218 and % of mutation carriers had mutations in non BRCA 1/2 genes

15 Summary of Cancer Associated Mutations: GOG 218 and

16 Each cancer site is associated with multiple hereditary cancer syndromes: 23 Genes panel: APC, ATM, BARD1, BMPRIA, BRCA1, BRCA2, BRIP1, CDKN2A, CDK4, CHECK2, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTNE, RAD1C, RAD1D, SMAD4, STK11 and TP53

17 High Risk 3 x higher > general population Absolute risk ~ > 5% Multiple supporting studies Elevated risk Risk Does not meeting HR criteria Single study Contradictory data

18 HBOCS: Facts Women with Lynch HNPCC syndrome: Mutations in DNA mismatch repair genes: MLH1, MSH2, MSH6, or PMS2 MSI 25 50% lifetime risk of colorectal cancer (lower than male counterparts) Cancer Lifetime Risk MLH1 MSH2 MSH6 PMS2 Endometrial 20 54% 21 49% 16 71% 15% OVC/FT/PC by age % % % small 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

19 HBOCS: Facts Cowden syndrome Germline mutations in the PTEN gene 19 28% risk of endometrial cancer by age 70 True risk higher with an intact uterus 50% risk of breast cancer 3 10% risk of thyroid cancer 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

20 HBOCS: Facts Li Fraumeni syndrome P 53 mutation carriers 60% lifetime risk of breast cancer Sarcomas, brain, and adrenocortical carcinomas, etc.. 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

21 HBOCS: Facts Peutz Jeghers syndrome Less common Mutations in STK11/LKB1 gene 10% risk of cervical (adenoma malignum) 21% risk of ovarian (sex cord stromal tumors) 50% risk of breast cancers Other cancers: colon, pancreas, endometrium, gastric.. 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

22 HBOCS: Facts: Other genes BRIP1, RAD51D, and RAD51C: a lifetime risk of 10 15% PALB2 mutations: a clear increased RR has not been established DICER1: Sertoli Leydig tumors SMARCA4: ovarian small cell carcinoma List of genes associated with BCA and OCA will continue to increase 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

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24 More Than BRCA1/2? The concept of BRCA ness Breast cancer : Basal phenotype Triple negative as an imperfect surrogate Ovarian cancer Particularly high grade serous Many of these patients may have dysregulation of BRCA1/2 The Cancer Genome Atlas (CGA) defect in the HR pathway in 50% of 489 tumors The Cancer Genome Atlas Network. Nature. 2011;474(7353):

25 The Cancer Genome Atlas (CGA) Network: 50% of Serous OVC have Germline or somatic HR defects

26 BRCA function BRCA RAD51C Normal DNA Double Strand DNA breaks Loss of BRCA function P 53 P 53 Cell Cycle arrest: Apoptosis Proliferation

27 Tumor selective Synthetic Lethality Endogenous DNA Damage (SS breaks: SSBs) PARP inhibition DNA DSbs accumulate with normal DNA replication HR Functional HR pathway (ie, BRCA wild type in normal cell) HR mediated DNA repair Cell survival NHEJ HR deficciency tumor cell (ie, BRCA mutated) Apoptosis: cell death Impaired HR mediated DNA repair Lord CJ et al. Ann Rev Med 2015;66: Iglehart JD et al NEJM 2009;361:189 91

28 BRCA 1 and BRCA 2 BRCA1 and BRCA2 mutations: 1. AD, highly penetrant, germline mutations on chromosomes 13, and 17 Lifetime risk varies among different populations: 1. Penetrance 2. Risk modifiers Different types of cancer and age of onset depending on: 1. gene gene interactions: Position of the mutation in the BRCA1 or BRCA2 gene Genetic variation in other genes 2. gene environment interactions: Age/Hormonal or reproductive factors/lifestyle factors The prevalence in the general population of European ancestry is ~ 0.25 % Increased prevalence in individuals of Norwegian, Dutch, and Icelandic ancestry Founder effect : The prevalence varies among ethnic groups and geographic area

29 Ovarian Cancer: Risk Factors Relative Risk Lifetime Probability No risk factors % (~ 1/72) Familial ovarian cancer 30 to 50% 2 or 3 relatives with ovarian cancer % (15% if 1 ) 1 relative with ovarian cancer % (5% if 1 ) Infertility 2.8 Nulligravity 1.6 HRT 1.27 Past pregnancy % Tubal ligation 0.59 Past oral contraceptive use % Past breast feeding 0.81

30 BRCA 1 and BRCA 2 mutations in ethnic lebanese Arab women with high risk hereditary breast cancer: Saghir N, Zgheib N, Seoud M et al.. Oncologist Lebanese women with breast cancer ( ) High risk of carrying BRCA1 or BRCA2 mutations young age positive family history (FH) of breast or ovarian cancer Despite high percentage of breast cancer in young women of Lebanese and Arab descent Prevalence of deleterious BRCA is lower than expected Doesn t support the hypothesis that BRCA mutations alone as a cause Oncologist 2015;20:357 64

31 HBOC: BRCA 1 and 2 carriers and the Lifetime risk of subsequent cancers Depends on the data base and ethnic background Cancer By age 70 Lifetime Risk BRCA 1 BRCA 2 Wild type Breast 65 85% 45 85% 1/7 8 (12%) OVC/FT/PC 39 46% 10 27% 1/72 (1.8%) 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

32 HBOC: BRCA 1 and 2 carriers and the Lifetime risk of subsequent cancers Depends on the data base and ethnic background Syndrome/Gene Clinical Mutation positivity rate Life time OC risk Other Features BRCA % % OC at earlier age (50) BRCA 2 1 6% % Lynch Syndrome 2,3 < 1% 3 14 % OC at same age as general population (60) OC at earlier age (43 50) Endometrial and colon cancer risks are higher RAD51C 4,7 1.3 % (RR 6 8) % RAD51D % (RR 6 9) % BRIP % (RR 8) %

33 Mutations Dramatically increase the risk of developing cancer Data From Myriad Genetic R

34 HBOCS: Genetic Testing Debate Changing Landscape Understanding of genetic predisposition for cancers is changing : from individual genes and syndromes to multiplex testing for a number of cancer susceptibility genes Expression profiling/ IHC Evolving use of BRCA1/2 testing vs. panel tests with expanded number of genes Such multiplex panels can be chosen based upon: Particular cancer patterns in families Ethnicity: Norwegian, Dutch, Icelandic, French Canadians, Hispanic, etc. Multiple genomic platforms Sequencing Clinical correlations is not always validated/ Could be used to identify appropriate clinical trials 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

35 HBOCS: Genetic Testing Debate Changing Landscape Single gene testing Traditional Sanger Multigene panel Massive parallel sequencing Sequencing approach High throughput Low throughput Lower cost for multiple genes High cost for multiple genes Misses structural rearrangements Better assessment of rearrangements Large number of VUS VUS, variants of uncertain significance

36 HBOCS: Genetic testing Things to consider 1. Increase in complexity of testing technology 1. Uncertainty in the interpretation of the results 2. Range of potentially identifiable cancer risk 3. Need for evaluating the likelihood of of a hereditary cancer syndrome Choosing the appropriate test/panel, and interpreting the result, all clearly argue that the first step in patient assessment should be genetic counseling 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

37 HBOCS: Genetic counseling Assessment for the presence of an inherited cancer syndrome Education Counseling Evaluation of available tumor by IHC and MSI (somatic mutations) Genetic counselor or others with expertise in cancer genetics Germline genetic testing 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK. year

38 Ovarian cancer STIC in BRCA mutated and non mutated patients ~ 60% of patients with BRCA mutation undergoing RR-BSO had HG STIC Although STIC is capable of metastasizing (i.e. cannot be considered CIS), compelling evidence for a tubal origin of BRCA+ HGSC has accumulated over the past decade [2,3] HG STIC is not only reported in BRCA+ pats but also in: 1. Advanced-stage sporadic HGSCs associated with ovarian tumor masses 2. Rare cases of 1ry tubal or peritoneal HGSCs without obvious ovarian involvement 1. Piek JM, et al. J Pathol 2001;195(4): Callahan MJ, et al. J Clin Oncol 2007;25(25): Kindelberger DW, et al. Am J Surg Pathol 2007;31(2):161 9.

39 Early tumor progression within the fallopian tube and the resultant genetic profile of HG SOC.

40 Risk reducing interventions/procedures Procedure Risk Reduction of ovarian cancer Salpingo oophorectomy 71 96% Tubal ligation 18% Salpingectomy 70% Cortesi, L., A. Toss, and E. De Matteis. "Preventive Strategies for Ovarian Cancer." (2013), Rice, Megan S. et al, International Journal of Cancer(2013), Aderson et al. Int J Gynecol Cancer 2013

41 Take Home Messages Consider taking a comprehensive personal and family history Consider using a risk model to estimate the cancer risk (e.g. Claus model) Consider a medical oncology genetic counseling when it looks too complicated Consider testing when risk estimates are appropriate Discuss risk reducing surgeries Discuss implications on the patient herself and her family members

42 Conclusions 1. The science is rapidly developing: we are too slow 2. We all have to keep up

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47 Do Salpingectomy.. Avoid Debulking?! Mohamad Kanso MED III

48 Serous epithelial cancer of the Ovary Most serious gynecological cancer Too late Diagnosis almost always 2013 The Clearity Foundation. All Rights R Pathogenesis is still unclear due to the lack of clearly identified carcinogenic sequence

49 New Studies Ovarian Cancer and Origins in the Fallopian Tubes, Linda Perrett, 20 Fallopian Tube Probable starting point for most serous ovarian

50 Two theories about EOC origin

51 1. Ovulation Theory:

52 Ovulation Scarring Deep Epithelial Invaginations Inclusion Cysts Mullerian Metaplasia Malignant transformation Due to stromal hormones and pro inflammatory cells

53 Epidemiological and Experimental arguments supporting this theory:

54 Protective Role of Oral Contraception Pregnancy Breast Feeding

55 Ovulation for > 35 years significantly higher RR of ovarian cancer

56 Forced to High ovulate prevale nce of Ovarian carcino ma Exponential relationship Number of between: ovulations & Malignant transformation

57 However As ovulation is a natural and physiological process Incriminating ovulation in the carcinogenesis of ovarian cancer Remains surprising, despite the facts described earlier.

58 Shifting the paradigm

59 2. Tubal Origin Theory

60 There is Convincing evidence that the distal Fallopian may be the commonest site of origin for HGSOC Herrington et al. The Journal of pathology (2010)

61 So the Tubal Theory is

62 Dysplastic tubal abnormalities TP53 mutations Genotoxic stress on secretory cells STIC (Serous Tubal Intraepithelial Carcinoma) Clonal expansion Progressive loss of control of cell control cycle Extension by anatomical proximity to ovary by endosalpingiosis

63 Supporting the tubal theory 1) Malignant tumors: found in the oviduct Fathalla Experimental data 2) STICs in prophylactic salpingo oophorectomies in BRCA patients Quick, Charles M., et al Modern Pathology (2011)

64 3) Overexpression of RSF 1, Cyclin E, p16, FASN and Stathmin 1 in both HGSOC and STICs 2011 Karst AM, Levanon K, Duraisamy S, et al. Gynecologic Oncology

65 4) STICs present in 61% in a series of HGSC of ovarian origin Przybycin et al. American Journal of Surgical Pathology (2010)

66 5)Other series of sporadic serous ovarian cancer were analyzed: STICs: 30 50%

67 6) Ovarian and Fallopian mucosal Carcinoma Shows similar copy number changes (FISH analysis) Possible Monoclonal Origin

68 Still Research could not yet confirm that the tube is the origin of Ovarian cancer

69 But what really matters is How could we reduce the risk of EOC?

70 Sudden decrease In estrogen PREMATURE MENOPAUSE night sweats, sleep disturbance, hot flashes, vaginal dryness, dyspareunia, and loss of sex drive.

71 2 Tubal Ligation? Risk reduction: 18% Strongest effects: in endometrioid tumors women who underwent the procedure after the last childbirth Rice, Megan S. et al, International Journal of Cancer(2013)

72 3 Salpingectomy? Estimated risk reduction: 70 % BS: greater protection than ligation Completely eliminating communication between the uterus and ovary Prevent ascending cancer cells or carcinogens Aderson et al. Int J Gynecol Cancer 2013

73 Bilateral Salpingectomy + TLH : Preservation of Ovarian function No perioperative complication May be used as a method for sterilization Morelli, Michele, et al. Gynecologic oncology(2013).

74 Conclusion The idea of tubal origin is still growing Clinicians and scientists prepared to take action But.. how to proceed? Trial may not be feasible An International prospective observational study might be the only hope