Gynecologic Cancers are many diseases. Speaker Disclosure: Gynecologic Cancer Care in the Age of Precision Medicine. Controversies in Women s Health

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1 Gynecologic Cancer Care in the Age of Precision Medicine Gynecologic Cancers in the Age of Precision Medicine Controversies in Women s Health Lee-may Chen, MD Department of Obstetrics, Gynecology & Reproductive Sciences Speaker Disclosure: I have nothing to disclose December 8, 217 Learning Objectives To describe risk factors and symptoms for the most common gynecologic malignancies Gynecologic Cancers are many diseases To identify appropriate individuals for HPV vaccination To offer genetic counseling and testing to women with ovarian cancer and their immediate family members as appropriate To identify women with endometrial cancer at risk for Lynch Syndrome (And gestational trophoblastic tumors)

2 Causes of Cancer Cancer Statistics, 216 Estimates U.S. Women Est. New Cancer Cases Breast 246,66 Lung 16,47 Colon/Rectum 63,67 Uterus 6,5 Thyroid 49,35 NH Lymphoma 32,41 Melanoma 29,51 Ovary 22,28 Cervix 12,99 Est. Cancer Deaths Lung 72,16 Breast 4,45 Colon/Rectum 23,17 Pancreas 2,33 Ovary 14,24 Uterus 1,47 Leukemia 1,27 NH Lymphoma 8,63 Cervix 4,12 Cancer in a Global View Cervical Cancer Survival Overall: 87% at One Year 69% at Five Years Diagnosis 5-year Survival Stage I Stage II Stage III Stage IV Local Regional Distant Overall

3 Cervical CA--Age Distribution Cervical Cancer Histology % 1-25% Squamous Adeno AdenoSqamous Clear Cell Other >8 3% 3-5% <1% Cervical Cancer Risk Factors HPV infection Early age at 1 st birth Early age at 1 st intercourse Long term oral contraceptive use High parity Low socioeconomic status Smoking?Genetic factors?other sexually transmitted agents (chlamydia) Cervical Cancer--Symptoms Postmenopausal bleeding Irregular menses Postcoital bleeding Vaginal discharge Pain Asymptomatic

4 Cervical CA--Diagnosis HPV types & Cancer risk Pap smear for screening Biopsy for abnormal cervix HPV TYPE CANCER RISK 6,11, Low to nil 31,33,35,39,51-53,58,59,66,68 Intermediate 16,18, 45, 56 High Screening for cervical cancer Primary prevention: HPV vaccines 2 approaches are currently in use in the USA Cytology (Pap test) every 3 years Cytology (Pap test) plus HPV testing every 5 years HPV testing detects the high risk HPV types associated with cervical cancer Bivalent (2vHPV): HPV16 and18 Quadrivalent (4vHPV): HPV 6, 11, 16 and 18 9-valent (9vHPV): HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58

5 CDC Recommendations for HPV vaccination Initiate routine HPV vaccination at age 11 or 12 years. The vaccination series can be started beginning at age 9 years. Vaccination is also recommended for females aged 13 through 26 years and for males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose series Cervical Cancer Take-home Summary Primary prevention of cervical cancer: HPV vaccination before exposure to HPV Secondary prevention of cervical cancer: screening for detection and treatment of cancer precursors Males aged 22 through 26 years may be vaccinated. MMWR March 27, 215 / 64(11);3-34 Ovarian Cancer Survival Ovarian Cancer: pathogenesis Overall: 78% at One Year 46% at Five Years Diagnosis 5-year Survival Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Overall

6 Ovarian Cancer: Risk Factors Germline evaluation of ovarian cancer Increasing age Family history of ovarian, fallopian tube, primary peritoneal cancer, or premenopausal breast cancer Personal history of premenopausal breast cancer Infertility / never becoming pregnant Oral contraceptive pill use is protective 36 consecutive women with primary ovarian, tubal, peritoneal CA at the University of Washington, Screened for 21 germline mutations by genomic sequencing 11% BRCA1 6% BRCA2 6% Other: BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD5, RAD51C, or TP53 31% with no family history of breast/ovarian cancer 63% less than age 6 Walsh et al, Proc Natl Acad Sci USA Personalized Gynecologic Cancer Care through Genetics Helen Diller Family Comprehensive Cancer Center 1/27/15 Causes of Ovarian Cancer Sporadic Hereditary (15-24%) Sporadic Women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of a family history. SGO Clinical Practice Guideline Genetic Screening for Ovarian Cancer October 214 Walsh et al, Proc Natl Acad Sci USA Personalized Gynecologic Cancer Care through Genetics Helen Diller Family Comprehensive Cancer Center 1/27/15 24 Personalized Gynecologic Cancer Care through Genetics Helen Diller Family Comprehensive Cancer Center 1/27/15 3

7 BRCA1 / BRCA2 & Survival Outcome Homologous Recombination Pooled analysis of 26 observational studies, 99 BRCA1 mutation carriers, 34 BRCA2 mutation carriers, 2666 noncarriers, from Differences remained after adjustment for age, stage, histology Bolton et al, JAMA BRCA Mutation & Homologous Recombination Deficiency as a Target Ovarian Cancer: Know the symptoms Pelvic or abdominal pain Difficulty eating or feeling full quickly Bloating Urinary symptoms (urgency & frequency) 27

8 Ovarian Cancer: Routine Screening is NOT recommended Screening test must be noninvasive Screening test must be inexpensive Detection of tumors at an early stage to allow more successful treatment CA125 Elevated in 8% of epithelial ovarian cancers but only 25 5% of Stage I. May be elevated in benign conditions: fibroids, adenomyosis, endometriosis, pelvic inflammatory disease, pregnancy, menstruation Ovarian Cancer: Prevention Oral contraceptive pills decrease ovarian cancer risk by up to 5% Even 6 months is beneficial Benefits last for 15 years Even in BRCA1/BRCA2 mutation carriers, any use of OCPs yields odds ratio of.5. CASH Study, N Eng J Med 1987 Narod et al, N Engl J Med 1998 Narod et al, N Engl J Med, 1998 Incremental Risk of Ovarian Cancer Risk-reducing Salpingo-oophorectomy Prospective multicenter cohort study of 2482 women with BRCA1 & BRCA2 mutations, PROSE consortium Decrease in breast cancer risk Lower all-cause mortality HR.4 ( ) Lower breast cancer-specific mortality HR.44 ( ) Lower ovarian cancer-specific mortality HR.21(.6-.8) Antoniou et al, Am J Hum Genet 23 Domchek et al, JAMA Personalized Gynecologic Cancer Care through Genetics Helen Diller Family Comprehensive Cancer Center 1/27/15

9 Ovarian Cancer Take-home Summary Endometrial Cancer Survival Prevention of ovarian cancer: Genetic testing and risk-reducing surgery for high risk individuals. Oral contraceptive pills & salpingectomy as appropriate Overall: Diagnosis 88% at 5 year 5-year Survival Treatment of ovarian cancer: Considering the paradigm of ovarian cancer as a heterogenous disease that can be better managed through molecular stratification Stage I Stage II Stage III Stage IV Stage I Stage II Stage III Stage IV Uterine Cancer Histology Uterine Cancer: Risk Factors Taking estrogen alone without progesterone 75-8% Obesity Later menopause Endometrioid Mucinous Serous Clear cell Sarcomas Diabetes Never becoming pregnant Hypertension Family history of endometrial or colon cancer 3% 4% 1% 5% Use of tamoxifen

10 Endometrial Carcinoma Presentation Abnormal uterine bleeding Post-menopausal bleeding Irregular vaginal bleeding Uterine enlargement: variable Average age at diagnosis: 58 years Endometrial Cancer: Routine Screening is NOT recommended Screening test must be noninvasive Screening test must be inexpensive Detection of tumors at an early stage to allow more successful treatment 9% of women with endometrial cancer present with postmenopausal bleeding No satisfactory or cost-effective screening for endometrial cancer Consider ultrasound or biopsy for Lynch Syndrome family members Endometrial Cancer: Prevention Endometrial Cancer: Types I & II Obesity increases endometrial cancer risk by as much as 1-fold. Obesity may affect how cancer is treated (surgery, chemotherapy, radiation) and how well these treatments may work Diet, exercise, and weight loss may decrease risk of cancer, diabetes, heart disease, death 373 endometrial cancers: 37 endometrioid, 66 serous Tumor samples & corresponding germline DNA Median follow-up: 32 months (range 1-195) 21% patients with recurrence, 11% died Microsatellite instability in 4% of endometrioid tumors, 2% of serous tumors Narod et al, N Engl J Med, 1998 Nature 213

11 TCGA Endometrial Cancer Mutation Spectra across endometrial carcinomas POLE-mutant tumors have better progression-free survival All women with endometrial cancer should be evaluated for the possibility of Lynch Syndrome Tumor testing after clinical screening including personal & family medical history Tumor testing on all cases diagnosed before age 6 Tumor testing on all cases of endometrial cancer Lynch Syndrome Evaluation Prevalence of Lynch 543 endometrial cancer patients underwent microsatellite instability testing 118 (21.7%) MSI positive all underwent mutation testing 1 (1.8%) patients with deleterious germline mutation 9 of 118 MSI positive pts--mlh1, 3 MLH2, 5 MSH6 1 MSI stable tumor had absence of MSH6 on IHC confirmed on germline mutation Hampel et al, Cancer Res 26

12 Identification of Women at Risk N=117 women from Lynch families with dual gynecologic and colorectal cancers from 5 Lynch registries 14% patients with synchronous cancers 51% with gynecologic cancer first Median age 44, time to second cancer 11 yrs 49% with colon cancer first Median age 4, time to second cancer 8 yrs Lu et al, Obstet Gynecol 25 Colorectal Cancer Screening in Lynch Surveillance colonoscopy reduces mortality N=133, from 22 HNPCC families Compared to 119 controls who declined surveillance or could not be contacted Screening every 3 years: colonoscopy or flex sig + BE over 15 years Colorectal cancers incidence: 8/133 vs 19/119, p=.14 Relative risk of death:.344 (95% CI ) Jarvinen et al, Gastroenterology 2 Lynch Syndrome & Risk-reducing Surgery N=38 women with MLH1, MSH2, and MSH6 mutations from 3 HNPCC registries, Median age 41 years at prophylactic surgery 46 at endometrial cancer diagnosis 42 at ovarian cancer diagnosis Incidence of endometrial CA % after prophylactic hysterectomy (13 year follow-up) 33% controls (7 year follow-up) Incidence of ovarian CA % after prophylactic oophorectomy (11 yr follow-up) Endometrial Cancer Take-home Summary Prevention of endometrial cancer: Endometrial cancer is associated with unopposed estrogen, exogenous or endogenous Prevention of of endometrial & other cancers: Identification of women with Lynch syndrome may allow screening and prevention of colorectal and endometrial cancer 5.4% controls (11 yr follow-up Schmeler et al, N Engl J Med, 26