Surgical Prophylaxis in Ovarian Cancer

Surgical Prophylaxis in Ovarian Cancer Mark H. Greene, M.D. Clinical Genetics Branch National Cancer Institute ?? Need for a More Precise Terminology ?? • “Current data suggest that BPM may significantly reduce the risk [of breast cancer], although it may not be completely prophylactic. Thus, we advocate labeling this surgery: RISK-REDUCING MASTECTOMY” • I suggest using this terminology across the board when it comes to surgical prophylaxis M Stefanek et al: J Natl Cancer Inst 2001; 93:1297-1306 BRCA1/2 Disease Spectrum Fallopian Tube Carcinoma Fallopian Tube Cancers in Hereditary Breast/Ovarian Cancer Syndrome • Evidence: – Case reports of FTC in mutation positive patients from BRCA mutation positive families – Detection of germline mutations in BRCA1/2 in women with FTC – Data from Breast Cancer Linkage Consortium 7 cases of FTC in their cohort of families: RR = 50 (95% CI: 22-111) – 7/44 (16%) pop-based FTC case series BRCA positive • 5/18 (28%) of women dx age <55 were mutation positive • “FTC should be considered to be a clinical component of HBOC syndrome” DJ Thompson: Am J Hum Genet 2001; 69:387 S Aziz Gynecol Oncol 2001; 80:1-5 Fallopian Tube Cancer in Hereditary Breast/Ovarian Cancer Syndrome • Since FTC appears to be one of the cancers which occurs at increased frequency in women with BRCA mutations, the risk-reducing surgical procedure should include complete removal of the fallopian tubes as well as the ovaries, i.e.: Risk-Reducing Salpingo-Oophorectomy (RRSO) Prevention of Sporadic Ovarian Cancer: Incidental Oophorectomy Prevention of Sporadic Ovarian Cancer: Incidental Oophorectomy • 1970 –1990: 5263 hysterectomies done • Ovarian cancer subsequently diagnosed in 520 (9.9%) of women • Mean interval TAH to OC: 7.2 years • “If incidental prophylactic oophorectomy had been routinely practiced in women above the age of 40, 9.4% of cases would have been prevented.” A Kontorvadis et al: Int J Obstet Gynecol 1996; 54:257-262 Prevention of Sporadic Ovarian Cancer: Incidental Oophorectomy • Population-based series of women with new ovarian cancer studied for the incidence of prior abdominal surgery • 270 abdominal operations had been done prior to the diagnosis of OC • Surgical procedures subdivided into those in which the pelvis was explored and those in which it was not Prevention of Sporadic Ovarian Cancer: Incidental Oophorectomy Cases of Ovarian Cancer that Might have been Prevented had Prophylactic Oophorectomy been Done SURGERY > 40 10.9% 26.9% > 45 6.7% 20.0% > 50 4.0% 16.6% PELVIC UPPER ABDOMEN D Rozario et al: Am J Surg 1997; 173:495-498 The “Residual Ovary” Syndrome • Term coined by RH Grogan Obstet Gynecol 1958; 12:329-332 • “Pelvic pain, dyspareunia or asymptomatic pelvic mass post-TAH” • 1963-1972: 8445 hysterectomies at Houston Methodist Hospital; in 6188, one or both ovaries were retained • 202 women were operated on for residual ovarian disease or symptoms: – 77%: chronic pelvic pain – 67%: dyspareunia – 14%: asymptomatic pelvic mass • 6 (3%) had ovarian carcinoma • Significant morbidity associated with retained ovaries JE Christ et al: Obstet Gynecol 1975; 46:551-556 Prevention of Sporadic Ovarian Cancer: Incidental Oophorectomy • Survey of 90 consultant gynecologists in Ireland: 75% response rate • Would remove normal ovaries at TAH: <40: 0% 40-44: 6% 45-49: 43% >49: 68% Postmenopausal: 88% • 82% routinely discussed PSO preoperatively with their patients scheduled for TAH M Geary et al: Ir Med J 1997; 90:186-187 Prevention of Sporadic Ovarian Cancer: Incidental Oophorectomy • Postmenopausal women undergoing major abdominal surgery should be informed of the potential risks & benefits of performing an incidental oophorectomy, within the context of their individual risk of OC Hereditary Ovarian Cancer Risk-Reducing Salpingo-Oophorectomy (“RRSO”) Primary Prevention of Ovarian Cancer: Risk-Reducing Salpingo-Oophorectomy • Potential benefits associated with RRSO in genetically at-risk women: – Presumed reduction in the risk of OC (not well studied, quantified) – Reduced worry, anxiety and apprehension on the part of the patient – Probable reduction in the risk of subsequent breast cancer [ ~ 50% ] Primary Prevention of Ovarian Cancer: Risk-Reducing Oophorectomy • Potential risks associated with PO: – It is not 100% effective: primary peritoneal carcinomatosis! – It renders the premenopausal patient immediately postmenopausal, with attendant QOL issues (mood, sleep, sexual function) – Irreversible infertility – Must confront the issue of estrogen replacement in women at high genetic risk of breast cancer – Surgical morbidity and mortality – Adverse psychosexual consequences • No prospective follow-up available RRSO in BRCA1/2 Mutation Carriers • Retrospective study of OC risk in 259 RRSO subjects, 292 controls, all mutation carriers, f/u = 8 yrs • RRSO: 6 OC at surgery (all Stage I), and 2 primary peritoneal cancers @ 3.8, 8.6 years after risk-reducing surgery • Controls: 56 ovarian cancers! • Hazard ratio = 0.04…i.e., a 96% reduction in the risk of ovarian cancer T Rebbeck et al: N Engl J Med 2002, in press Prospectively Diagnosed Ovarian Cancer in High-Risk Women from Norway • Survey of 845 women from hereditary breast/ovarian families: – 754 unaffected women – 49 women with breast cancer • 9 and 7 ovarian cancers detected in these two groups respectively: – 15/16 cases were > age 40 – 4/16 borderline neoplasms • If RRSO had been done routinely at age 45, 75% of these cancers would have been prevented A Dorum et al: Acta Obstet Gynecol Scand 1999; 78:906-911 RRSO: What is the Correct Operation? • Salpingo-Oophorectomy • Talk to your gyn surgeon before hand • The fallopian tubes should be transected as close to the uterine wall as possible; avoid removing just the fimbriated end of the tube • Can be done laparascopically • If TAH done, examine the interstitial portion of the fallopian tube • Examine gross morphology of the ovaries very carefully: cancers may be small • 2-3 mm thick sections; 1 cut per block Decision-making About RRSO Among High-Risk Women • Review of literature in the context of a cognitive-social framework • Women are more likely to choose RRSO if they – feel more vulnerable to cancer – believe that surgery will prevent cancer – are worried about developing cancer • Decision influenced by coping style: – “monitors:” scan for & amplify threatening cues – “blunters:” distract from threatening cues SM Miller et al: Gynecol Oncol 1999; 75:406-412 Occult Ovarian Tumors in Women Undergoing P.O. • 50 women underwent P.O., 2/3 of whom had a prior probability of BRCA mutation > 25% • 4/33 (12%) high risk women had incidental ovarian tumors detected: – 1 noted at the time of surgery – 3 found only at pathology review • All 4 were BRCA mutation carriers KH Lu et al: J Clin Oncol 2000; 18:2728-2732 Occult Ovarian Tumors in Women Undergoing P.O. • 60 carefully studied, consecutive, prospective PSO cases from 2 Toronto hospitals • All were from women judged at increased genetic risk; 39/49 (80%) tested carried a BRCA mutation • Entire ovaries & tubes were submitted • 5 mutation carriers (8%) had occult carcinoma; only 1 was seen grossly – 1 ovarian carcinoma – 2 fallopian tube carcinomas – 2 carcinoma involving both organs TJ Colgan et al: Am J Surg Pathol 2001; 25:1283-1289 Occult Tumors in PSO: Literature Reports AUTHOR YEAR CANCERS/PSO Menczer Salazar 1991 1996 1/5 2/20 Deligdisch Eltabbakh 1999 1999 1/21 0/62 Morice Stratton Lu Colgan Leeper 1999 1999 2000 2001 2002 1/27 1/11 4/50 5/60 5/30 TOTAL 20/286 (7.0%) Etiology of Primary Peritoneal Carcinoma • One consequence of recognizing that, at least in some instances, disseminated ovarian cancer occurs in the presence of a microscopic, clinically occult primary ovarian cancer: some cases of what appears to be PPC might, in fact, represent the unrecognized presence of such an occult ovarian primary • A subset might also represent occult carcinomas of the fallopian tubes Primary Prevention of Ovarian Cancer: Risk-Reducing Salpingo-Oophorectomy • Decision analysis of effect of PO on life expectancy among cancer-free women with BRCA1/2 mutations: – 30 year old: gain 0.3 - 1.7 years – gains diminish as age at RRSO rises – 10 year delay in RRSO for 30 year old is not associated with adverse impact – assumes that RRSO reduces the risk of OC by only 50% D Schrag et al: N Engl J Med 1997; 336:1465-1471 A Pervasive Error in Need of Correction The “Struewing Estimate” of Ovarian Cancer Risk Reduction Following Bilateral SalpingoOophorectomy J Struewing et al: Risk-Reducing Oophorectomy in Hereditary Breast/Ovarian Cancer Families • Prospective analysis of 14 families with breast/ovarian cancer • 8 ovarian cancers in 346 at-risk first-degree relatives (1600 WYO): RR=24 • 2 “ovarian cancers” in 44 women post RRSO (460 WYO): RR=13 • These differences were NOT statistically significant • Yet this became the basis for the assertion by other investigators that PSO led to a 50% reduction in the risk of ovarian cancer. NO!! JP Struewing et al: JNCI Monogr 1995; 17:33-35 Decision Analysis in BRCA Mutation Carriers • Markov model assessing life expectancy (LE) and quality-adjusted life expectancy (QALE) • Compared four strategies: – – – – PMPO PMOS BSPO BSOS • Computed estimates for a hypothetical 30 year old subject for two different scenarios: – high risk: 85%/63% – medium risk 56%/16% MS van Roosmalen et al: J Clin Oncol 2002; 20:2092-2100 Decision Analysis in BRCA Mutation Carriers • Model more refined than prior analyses by taking into account: • Impact of RRSO on breast cancer risk • More accurate estimate of the protective effect of RRSO on the risk of ovarian cancer • Impact of RRSO on the risk of breast cancer recurrence Decision Analysis in BRCA Mutation Carriers Strategy PMPO BSPO High Risk 11.7 years 9.5 years Medium Risk 6.6 years 5.3 years PMOS 4.9 years 4.4 years •IF QUALITY OF LIFE TAKEN INTO ACCOUNT •For high-risk women: PMPO the preferred option • For intermediate risk: BSPO the preferred option GOG 0199 Prospective National Cohort Study of Risk-Reducing Oophorectomy and Ovarian Cancer Screening in Women at Increased Genetic Risk of Ovarian Cancer Collaborating Organizations Clinical Genetics Branch DCEG, NCI Gynecologic Oncology Group Cancer Genetics Network Project Design • Collaboration between intramural NCI, GOG and the Cancer Genetics Network • Enroll women at increased genetic risk of ovarian cancer who have chosen either prophylactic surgery or screening (not randomized) • Projected accrual: – 1000 women who undergo surgery – 2400 women who elect ovarian cancer screening Project Design • Participants followed quarterly for 5 years • Powered with the goal of accruing: – 400 BRCA1/2 mutation carriers who elect surgery, and – 400 mutation carriers who elect screening • Accrual anticipated to begin by July 2002 Women at Increased Risk of Ovarian Cancer Risk Assessment Ineligible Enroll in Study [Informed Consent] Decline Participation BASELINE DATA Questionnaires Blood Samples TVUS CA-125 SURGERY BSO Tissue q 3 months: CA-125 ROCA w/u Q 6 months: Q.O.L. Cancer Events Health Status SCREENING q 3 months: CA-125 ROCA w/u Q 6 months: Q.O.L. Cancer Events Health Status Yearly: TVUS Project Goals • To analyze the natural history of the postprophylactic oophorectomy state: – Prevalence of clinically occult cancer at PSO – Search for ovarian cancer precursor lesions – Prospective incidence of: • “Ovarian Cancer” (Primary Peritoneal Cancer) • Breast Cancer • All Cancer – Assemble repository of ovarian tissue, sera, DNA from women at high risk – Quality of Life Assessment GOG 0199: Quality of Life • MOS SF-36 Health Survey • Impact of Events Scale (IES) • Center for Epidemiologic Studies Depression Scale (CES-D) • Speilberger State-Trait Anxiety Scale (STAI) • Sexual Activity Questionnaire (SAQ) • Multidimensional Impact of Cancer Risk Assessment (MICRA) • Endocrine Subscale of the FACT (FACTES) GOG 0199: Laboratory Studies • Diagnostic Cytology • Computerized Image Analysis • Cells for Ovarian Cancer Targeted Protein Expression Array • RNA Extraction for cDNA Expression Array • Biospecimen Repository: – Serum – Plasma – Normal ovarian stroma – Tumor Tissue: • Ovary • Fallopian Tube • Primary Peritoneal Carcinoma Project Goals • Evaluate longitudinal CA-125 as a novel mode of screening for ovarian cancer in women at increased genetic risk: – “ROCA” (Risk of Ovarian Cancer) Algorithm S Skates et al: • Cancer 1995; 76:2004-2010 • J Am Stat Assoc 2001; 96:429-439 Summary: Surgical Prophylaxis in Ovarian Cancer • Fallopian tube carcinoma IS part of the BRCA syndrome disease spectrum • RRSO is the desired surgical procedure • Better studies needed to assess the potential utility of incidental RRSO in the general population • Surgical material must be meticulously evaluated to detect occult cancers • RRSO is a valid option for women at increased genetic risk: BUT we need to know more about the natural history of the postRRSO state Clinical Genetics Branch Research Mandate To translate recent discoveries in the molecular biology of cancer susceptibility into evidence-based improvements in the quality of life and overall survival for persons at increased genetic risk of malignancy.