Lee P. Shulman MDThe Anna Ross Lapham Professor of Obstetrics and Gynecology and Chief                                    ...
Disclosures   Advisory/Consulting     Myriad, Fujireibio, Genzyme (Integrated     Genetics), Signature,   Speaking/Hono...
Inherited Cancer Earlier age of onset Higher rate of bilaterality Associated tumors Not distinguished by pathology, me...
KNUDSON   Two-step process   First: germinal or somatic mutation   Second: somatic mutation
The Genetics of Cancer  Intact Tumor Suppressor Gene                 X                     XX    Killed Cell              ...
Comparison of Oncogenes and Tumor-Suppressing GenesONCOGENES                     TUMOR-SUPPRESSING   Gene active         ...
Why do cancer risk assessment and genetictesting for hereditary cancer syndromes? Our best opportunity to determine risk ...
Genetic Testing in Women’s Health   Somatic     HPV     GC   Germinal     Carrier Screening       Cystic fibrosis, J...
Genetic cancer syndromes inwomen’s health   Hereditary Breast Ovary Cancer Syndrome     BRCA1/BRCA2 (HBOC: 17q21/13q12-1...
Genetic cancer syndromes in women’shealth   Cowden syndrome (10q23.3)     Multiple hamartomas     Thyroid cancer     M...
BRCA1/2   Tumor suppressing genes   Role in cell cycle regulation   Dominant inheritance with relatively    high penetr...
BRCA1/2   Tumor suppressing genes   Role in cell cycle regulation   Dominant inheritance with relatively    high penetr...
BRCA1 17q21 Female mutation carriers     85% lifetime risk of breast CA      ○ 20% develop by age 40      ○ 51% by age ...
Breast & Ovarian Cancer Risks Associated with BRCA1 Alterations9080706050403020100     AGE020406080          BRCA 1 - Brea...
BRCA2 13q12-13 Lifetime breast cancer risk: 80% Lifetime ovarian cancer risk: 12-15% Lifetime male breast cancer risk:...
Breast & Ovarian Cancer Risks Associated with BRCA2 Alterations9080706050403020100     AGE020406080          BRCA 2 - Brea...
BRCA1/2 Founder Mutations   Frequency of BRCA1/2 mutations in general    population approximately 1/500   Frequency of B...
Ovarian Cancer   Lynch (HNPCC)     Colon     Endometrial     Breast   8-10% lifetime risk for developing OEC   Speci...
Lynch syndrome – GeneticsMultistep mismatch repair (MMR) system   Gene products are involved in correcting    single base...
Mismatch Repair Genes          MSH6                          MLH1          MSH2                                         PM...
Lynch        SyndromeFew adenomas80% CRC risk, mean 44 yrsMore proximal colonicFrequent synchronous andmetachronous CRCMMR...
Extra-Colonic Cancers            40            35            30Life-time   25Risk (%)    20            15            10   ...
Other Cancer PredispositionGenes: KRAS?   Ratner et al 2010    ○ Genetic marker for non-small-cell lung cancer    ○ Prese...
Other Putative Genetic Etiologies for OEC   RAD15C germline mutations     Clague et al PLoS ONE 6(9) 2011   Genome-wide...
BRCA1/2 Counseling   Family/personal history is the primary method    to determine risk for cancer predisposition    synd...
Criteria for Further Risk EvaluationAffected individual with one or more of the following:       Early-age-onset breast c...
Assessment   Patient needs and concerns: ·       Knowledge of genetic testing for cancer risk, including benefits, risks...
Hereditary Breast/Ovarian Genetic    Testing Criteria   Individual from a family with a known deleterious BRCA1/BRCA2    ...
Hereditary Breast/Ovarian Genetic    Testing Criteria (cont’d)   Personal history of epithelial ovarian g/fallopian tube/...
BRCA1/2 Testing Bestto first assess affected family members whenever possible (insurance issues, costs), especially in ca...
Variant of Uncertain Significance (VUS) A sequence within a gene not typically  found in the general population and not  ...
Variant of Uncertain Significance (VUS) Clinical response to VUS is based on the  reason for undergoing testing Clinical...
Variant of Uncertain Significance (VUS)   Over time, the status of some VUS will    change based on studies of the    seq...
Genetic predisposition to gynecologiccancer syndromesSummary   Family/personal history-taking remains THE    vital compon...
Breast and Ovarian Cancer                Epidemiology             Estimates for 2012 Breast cancer     226,870 new cases...
Clinical Implications Improved ability to assess risk Limited ability to provide clinically useful  interventions Littl...
Determining risk               Accessed at myriadtests.com
Patients with 5-10% chance of being inHBOC family   Breast cancer ≤40   Bilateral breast cancer (esp. if 1st occurred   ...
Patients with > 25% chance of being inHBOC family   Personal hx of both breast and ovarian cancer   Have ovarian cancer ...
2007 ACS Guidelines for MRI   Women at high risk (> 20% lifetime    risk)     MRI plus mammogram every year   Women at ...
Recommendations for TamoxifenCandidates     Women with 5-year risk of breast cancer >      1.66% should be offered option...
Prophylactic Mastectomy    Total (simple) mastectomy appears more     effective than subcutaneous mastectomy    Shown to...
Typical Intraoperative Appearance of Stage III Epithelial Ovarian CancerAdvanced epithelial ovarian cancer   No “precurso...
Lifetime Family History of Ovarian Cancer             RiskNone                                            1.5%1 first-degr...
Ovarian Cancer: Risk Reduction Birth control pills First full-term pregnancy < age 25;  number of pregnancies Breast-fe...
Chemoprevention of OvarianCancer           Oral ContraceptivesThe risk of ovarian cancer was 60% loweramong women with mut...
Chemoprevention of OvarianCancer    RCGP Oral Contraception Study• 339,000 wy never users compared to   744,000 wy ever us...
Breast Cancer in Women at High-    Risk for Ovarian Cancer Using OCs Comparative study: 1,156 cases of invasive breast  c...
Ovarian Cancer   OC use will reduce the risk of developing    ovarian cancer1     5 years of use: 27% reduction     15 ...
Why Tubal Ligation?   Initially thought to be associated with reduced    blood flow to ovaries resulting from tubal    li...
Ovarian Cancer: FallopianTube?   122 BRCA1/2 positive women undergoing    prophylactic BSO     7 early malignancies (5.7...
Ovarian Cancer: Fallopian    Tube?   Serous tubal intraepithelial carcinomas (STICs)     Secretory cells showing signifi...
STIC       Sedhev AS et al. Mod Pathol 2010
Population-Based Screening forOvarian Cancer: NO!   The Prostate, Lung, Colorectal and Ovarian    (PLCO) Cancer Screening...
PLCO  OEC diagnosed  ○ 5.7/10,000 person-years in intervention group  ○ 4.7/10,000 person-years in routine care group  ○ ...
Current ScreeningGuidelines“…annual screening for ovarian cancer,as performed in the PLCO trial…doesnot reduce disease-spe...
Screening for Ovarian Cancer in aHigh-Risk Community: Not Yet!   Increased surveillance   Serum biomarkers   Transvagin...
Screening approaches   Genetic   Imaging   Biochemical   Symptom index   Combination/Multiplex        None have been ...
Increased surveillance   No evidence to support a decrease in    mortality from increased surveillance   Genetic counsel...
Sonography for ovarian neoplasmFishman et al, Am J Obstet Gynecol 2005
NOCEDPPUltrasound Screening in a high-risk population   12,709 scans in 4,526 “high-risk” women   Ultrasound screening a...
University of Kentucky Ovarian CancerScreening Project Update: 2009   31,748 women     22.8% with a positive family hist...
Use of symptom index  Major associated symptoms  Pelvic pain  Abdominal pain  Increased abdominal size  Bloating  Feeling ...
Ovarian cancer biomarkersCA-125 Elevated in about 1% normal  women, 80% of epithelial ovarian  cancers (50% of St I disea...
Lynch syndrome: Screening/Management                                    Annual colonoscopy   Colon                      ...
Women with a Pelvic Mass are at Risk forOEC   20% of women will be diagnosed with an    adnexal mass1     300,000 per an...
Work-up of Adnexal Mass   Must first categorize as functional, benign neoplastic    or potentially malignant   Diagnosti...
ACOG and SGO Referral GuidelinesNewly Diagnosed Pelvic MassPremenopausal                           Postmenopausal(<50 year...
Significantly Higher Survival                         Rates with Oncology                         Specialists             ...
ACOG and SGO Referral GuidelinesNewly Diagnosed Pelvic MassPremenopausal                        Postmenopausal(<50 years o...
Ultrasound Evaluation  of a Pelvic Mass                                  Sensitivity        Specificity        PPV        ...
Non-Malignant Conditions that ElevateCA125     Gynecologic                    Non-gynecologic       Adenomyosis        ...
RMIRisk of Malignancy Index    RMI = USG x [M]eno status x serum CA 125 level             USG = 0 for imaging score of 0  ...
OVA-1™ Multiple Serum Markers•   Approved for presurgical evaluation of women with    ovarian adnexal mass1•   5 biomarker...
ROMATMRisk of Ovarian Malignancy Algorithm• HE4 and CA125 + menopausal status• Estimate the risk of malignancy in women  p...
Pilot Study Cross-validated Estimates of Sensitivity         Benign vs. Ovarian Cancer:    Average from                   ...
ROMA™ vs RMI   Increased Sensitivity with ROMA                                Benign (n = 312) vs EOC (n = 123) All Patien...
OVA-1™ vs. ROMA™          Measure                        OVA-1™                            ROMA™                          ...
Summary The delineation of risk for breast and  ovarian cancer is made primarily by  personal and family history Offerin...
Summary Genomic factors play an important role in  the risk for development of gynecologic  malignancies except for cervi...
Am 7.15 shulman
Am 7.15 shulman
Am 7.15 shulman
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  • Women at highest risk for being diagnosed with ovarian cancer are women that present with a pelvic mass or ovarian cyst. It is estimated that 1 in 5 women will be diagnosed with an ovarian cyst or adnexal mass sometime in their lifetime; and 5-10% of women will have surgery for an ovarian neoplasm each year in the US.Roughly 13% to 21% of these women will be diagnosed with an invasive epithelial ovarian cancer. ReferenceCurtin JP. Management of the adnexal mass. Gynecol Oncol. 1994;55:S42-S46. NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.
  • ACOG and SGO provide joint guidelines for when to refer a women with a pelvic mass to a gynecological oncologists. ReferenceACOG Practice Bulletin, Clinical management Guidelines for Obstetrician-Gynecologists, Number 83, July 2007. Obstet Gynecol. 2007;110:201-14.Im SS, Gordon AN, Buttin BM, et al. Validation of referral guidelines for women with pelvic masses. Obstet Gynecol. 2005;105:35-41.
  • In a study, Paulsen demonstrated a significant survival advantage for patients with ovarian cancer that were operated on by gynecologic oncologists, compared with patients operated on by gynecologists or general surgeons. In addition, patients whose surgery was performed at a tertiary care hospital– versus a community hospital–also had a significant survival advantage.ReferencePaulsen T, Kjaerheim K, Kaern J, et al. Improved short-term survival for advanced ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals. Int J Gynecol Cancer. 2006:16(suppl 1):11-17.
  • ACOG and SGO provide joint guidelines for when to refer a women with a pelvic mass to a gynecological oncologists. ReferenceACOG Practice Bulletin, Clinical management Guidelines for Obstetrician-Gynecologists, Number 83, July 2007. Obstet Gynecol. 2007;110:201-14.Im SS, Gordon AN, Buttin BM, et al. Validation of referral guidelines for women with pelvic masses. Obstet Gynecol. 2005;105:35-41.
  • ReferenceDePriest PD, Shenson D, Fried A, et al. A morphology index based on sonographic findings in ovarian cancer. Gynecol Oncol. 1993 Oct;51(1):7-11.Pavlik EJ, Saunders BA, Doran S, et al. The Search for Meaning—Symptoms and Transvaginal Sonography Screening for Ovarian Cancer. Cancer. 2009;115:3689–98.
  • ReferenceCopeland LJ. In Philip J. DiSaia &amp; William T. Creasmann. Clinical Gynecology, 7th edition. Chapter 11 Epithelial Ovarian Cancer. Page 321.
  • Let’s examine how ROMA performs compared with risk assessment tools currently used in clinical practice.An algorithm that is used either formally or informally by clinicians to assess risk in a patient with a pelvic mass is the Risk of Malignancy Index or RMI developed by Ian Jacobs.The RMI employs an imaging score along with CA125 values and menopausal status to calculate a risk for malignancy. This is an algorithm that employs clinical findings on imaging and uses quantitative data to derive a patient’s risk for malignancy.ROMA was comparied to the RMI, which uses clinicopathologic variables to demonstrate that the performance of ROMA as a stand-alone test is superior to a currently used clinical algorithm.
  • OVA-1 is a risk-stratification tool intended for the presurgical evaluation of women with ovarian adnexal mass.1{PI, Exec Summary, p.1, para 2}OVA-1 utilizes the results of five biomarkers-- 2-microgobulin, apolipoprotein A1, CA125, transferrin, and transthyretin (prealbumin) to generate a numerical score between 0 and 10 that reflects the likelihood of ovarian malignancy.2{OVA1 test Summary, p.2, Method} The derived single score that separates low probability from high probability of malignancy is slightly different in premenopausal and postmenopausal women.1{PI, Exec Summary, p.2, last para}Low probability of malignancy in premenopausal women: &lt; 5.0Low probability of malignancy in postmenopausal women: &lt; 4.4References1. OVA-1 package insert: executive summary; Vermillion, Inc. (Accessed February 8, 2011, at http://www.ova-1.com/physicians/package-insert.)2. OVA-1 Test summary; Quest Diagnostics. (Accessed February 8, 2011, at http://www.questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=HematOnc/Ovary/TS_OVA1.htm.)
  • The Risk of Ovarian Malignancy Algorithm, or ROMA, represents a risk assessment tool for ovarian cancer that combines HE4 and CA125 estimates, in conjunction with menopausal status. ROMA is intended to aid in estimating the risk of malignancy in premenopausal and postmenopausal women presenting with an adnexal mass who will undergo surgical intervention. ROMA findings must be interpreted in combination with independent clinical assessments.This tool will provide more useful information to physicians to ensure that patients are treated by the right physician in the right facility, and to better plan for and implement the most appropriate treatment and postoperative care.ReferenceROMA package insert {p.1, para 1}
  • We were able to calculate an RMI for 80% of the study patients. We compared these results to the ROMA for those individual patients. We found at a specificity of 75%, the RMI had a sensitivity of 85%, compared to the ROMA, which achieved a sensitivity of 94%. ReferenceMoore RG, Jabre-Raughley M, Brown AK, et al. Comparison of a novel multiple marker assay vs the Risk of Malignacy Index for the prediction of epithelial ovarian cancer in patients with a pelvic mass. Am J Obstet Gynecol. 2010;203(3):228.e1-6.
  • OVA-1 was evaluated in a multicenter, prospective, double-blind clinical study in a total of 516 women, 54.5% of whom were postmenopausal.1 {PI Exec Summary, p 2, para 1} For subjects evaluated by a nongynecological oncologist, the sensitivity for ovarian malignancy increased from 72% to 92% with the dual use of a presurgical assessment and OVA-1 versus a single presurgical assessment alone. Specificity for ovarian malignancy declined however from 83% with the single presurgical assessment to 42% with the dual assessment that included OVA-1.1{PI Exec Summary, p.3, Table 2, para 3}With the use of the dual assessment, positive predictive value also declined; however, negative predictive value increased from 89.1% 93.2%.For nongynecological oncologists and oncological oncologists, the dual assessment using OVA-1 and a presurgical assessment, detected 82.5% of the cases missed by the clinical assessment alone.1 {PI ExecSummary, p.3, para 3}ROMA—combination of pre and post menopausal women.Cost of OVA-1: $650.00 retail; $516.25 Medicare (As per Vermillion’s Director of Marketing, Scott Henderson, May 18, 2011)ReferenceOVA-1 package insert: executive summary; Vermillion, Inc. (Accessed February 8, 2011, at http://www.ova-1.com/physicians/package-insert.)Moore RM, et al. Obstet Gynecol. 2001, In press.ROMA CSR, page 60Vermillion, Inc Press Release? Cost of test
  • Am 7.15 shulman

    1. 1. Lee P. Shulman MDThe Anna Ross Lapham Professor of Obstetrics and Gynecology and Chief Division of Clinical Genetics Director, Northwestern Ovarian Cancer Early Detection and Prevention Program Co-Director, Cancer Genetics Program The Robert S. Lurie Comprehensive Cancer Center Feinberg School of Medicine of Northwestern University Chicago, Illinois
    2. 2. Disclosures Advisory/Consulting  Myriad, Fujireibio, Genzyme (Integrated Genetics), Signature, Speaking/Honoraria  Myriad, Fujireibio, Genzyme (Integrated Genetics), Signature, Roche, GSK Research Support  MiraDx
    3. 3. Inherited Cancer Earlier age of onset Higher rate of bilaterality Associated tumors Not distinguished by pathology, metastatic pattern or survival characteristics
    4. 4. KNUDSON Two-step process First: germinal or somatic mutation Second: somatic mutation
    5. 5. The Genetics of Cancer Intact Tumor Suppressor Gene X XX Killed Cell XXX Normal CellTumor Suppressor Gene Mutation X XXX XX XXX XX XX Cancerous Cell
    6. 6. Comparison of Oncogenes and Tumor-Suppressing GenesONCOGENES TUMOR-SUPPRESSING Gene active  Gene inactive Specific translocations  Deletions or mutations Translocations somatic  Mutations auto dominant or nonhereditary Dominant at cell level  Recessive at cell level Leukemia/lymphoma  Solid tumors
    7. 7. Why do cancer risk assessment and genetictesting for hereditary cancer syndromes? Our best opportunity to determine risk for cancer development For carriers, positive status will impact surveillance/prevention recommendations For non-carriers in families with mutation, avoids unnecessary interventions  For non-carriers in families without a delineated mutations, may not alter risk Offer risk-reducing surgery Information for family members Reproductive decision-making
    8. 8. Genetic Testing in Women’s Health Somatic  HPV  GC Germinal  Carrier Screening  Cystic fibrosis, Jewish genetic disease screening  Universal genetic screening  Cancer Genetic Testing
    9. 9. Genetic cancer syndromes inwomen’s health Hereditary Breast Ovary Cancer Syndrome  BRCA1/BRCA2 (HBOC: 17q21/13q12-13)  Breast  Ovarian Epithelial (OEC) Lynch Syndrome (HNPCC)  Multiplex mismatch repair (MMR) genes  Colorectal  Endometrial  OEC
    10. 10. Genetic cancer syndromes in women’shealth Cowden syndrome (10q23.3)  Multiple hamartomas  Thyroid cancer  Male and female breast cancer  Endometrial cancer Li-Fraumeni syndrome (TP53)  Early onset breast cancer  Childhood malignancies: brain, stomach, lung, pancreas, ovary, melanoma  50% risk fo cancer by age 40, 90% by age 60
    11. 11. BRCA1/2 Tumor suppressing genes Role in cell cycle regulation Dominant inheritance with relatively high penetrance
    12. 12. BRCA1/2 Tumor suppressing genes Role in cell cycle regulation Dominant inheritance with relatively high penetrance
    13. 13. BRCA1 17q21 Female mutation carriers  85% lifetime risk of breast CA ○ 20% develop by age 40 ○ 51% by age 50 ○ 85% by age 70  10% of women with breast CA under the age of 35 are mutation carriers 40-60% lifetime risk of ovarian CA Shulman LP. Obstet Gynecol Clin N Am 2010
    14. 14. Breast & Ovarian Cancer Risks Associated with BRCA1 Alterations9080706050403020100 AGE020406080 BRCA 1 - Breast General Population - Breast BRCA 1 - Ovarian General Population - Ovarian
    15. 15. BRCA2 13q12-13 Lifetime breast cancer risk: 80% Lifetime ovarian cancer risk: 12-15% Lifetime male breast cancer risk: 6%  100-fold increase in male breast cancer risk compared to general population Shulman LP. Obstet Gynecol Clin N Am 2010
    16. 16. Breast & Ovarian Cancer Risks Associated with BRCA2 Alterations9080706050403020100 AGE020406080 BRCA 2 - Breast General Population - Breast BRCA 2 - Ovarian General Population - Ovarian
    17. 17. BRCA1/2 Founder Mutations Frequency of BRCA1/2 mutations in general population approximately 1/500 Frequency of BRCA1/2 mutations in Ashkenazi Jewish community approximately 1/40  3 mutations comprise 98% of mutations detected in AJ community ○ BRCA1: 185delAG, 5382insC ○ BRCA2: 6174delT Icelandic founder mutation in BRCA2: 999delG accounts for 7% of all EOC cases in Iceland Shulman LP. Obstet Gynecol Clin N Am 2010
    18. 18. Ovarian Cancer Lynch (HNPCC)  Colon  Endometrial  Breast 8-10% lifetime risk for developing OEC Specific criteria for genetic screening: microsatellite instability (MSI genes) per Bethesda criteria Colonoscopy and endometrial surveillance remain the main screening modalities Shulman LP. Obstet Gynecol Clin N Am 2010
    19. 19. Lynch syndrome – GeneticsMultistep mismatch repair (MMR) system  Gene products are involved in correcting single base pair mistakes that can occur during DNA replication ○ MLH1cloned in 1994 (3p21) ○ MSH2cloned in 1993 (2p21-22) ○ MSH6cloned in 1997 (2p15) ○ PMS2cloned in 1994 (7p22) Shulman LP. Obstet Gynecol Clin N Am 2010
    20. 20. Mismatch Repair Genes MSH6 MLH1 MSH2 PMS2 PMS1? Chr 7 Chr 3 Chr 2 HNPCC is associated with germline mutations in any one of four mismatch repair genes
    21. 21. Lynch SyndromeFew adenomas80% CRC risk, mean 44 yrsMore proximal colonicFrequent synchronous andmetachronous CRCMMR mutations:MLH1, MSH2, MSH6, PMS2 Burt, J Natl Compr Canc Netw 2010; 8:8-61 Jasperson, Burt, Gastroenterol, 2010; 138:2044
    22. 22. Extra-Colonic Cancers 40 35 30Life-time 25Risk (%) 20 15 10 5 0 Renal cell Urinary Biliary CNS Ovarian Edometrial Bowel Gastric Small tract Maul JS et al. Am J Gastroenterol 2006
    23. 23. Other Cancer PredispositionGenes: KRAS?  Ratner et al 2010 ○ Genetic marker for non-small-cell lung cancer ○ Present in fewer than 18% of other solid tumors ○ KRAS-variant associated with more than 25% of nonselectedOEC cases. ○ Marker for significant increased risk of developing OC ○ KRAS-variant present in 61% of HBOC patients without BRCA1 or BRCA2mutations ○ KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities. Ratner et al. Cancer Res 2010
    24. 24. Other Putative Genetic Etiologies for OEC RAD15C germline mutations  Clague et al PLoS ONE 6(9) 2011 Genome-wide Association Studies  19p13 (Bolton et al, Nat Genet 2010)  2q31 (Goode et al, Nat Genet 2010)  8q24 (Goode et al, Nat Genet 2010) Telomeres  Structures at end of chromosomes that contribute to genomic stability  Shortening with repeated cell divisions may lead to genomic instability and carcinogenesis  Women with serous OEC had shorter telomeres than age-matched controls (Mirabello et al Cancer Causes Control 2010)
    25. 25. BRCA1/2 Counseling Family/personal history is the primary method to determine risk for cancer predisposition syndrome, likelihood of mutation and risk for cancer development Advise of current limitations of screening Negative results IN NO WAY guarantee protection Positive results do not guarantee malignancy Implications of negative/positive results with regard to screening/diagnostic and therapeutic options
    26. 26. Criteria for Further Risk EvaluationAffected individual with one or more of the following:  Early-age-onset breast cancer  Triple negative (ER-, PR-, HER2-) breast cancer ·  Two breast cancer primaries  Breast cancer at any age, with ○ > 1 close blood relative with breast cancer < 50 y ○ > 1 close blood relative with OEC/FT cancer at any age ○ >2 close blood relatives with breast cancer/pancreatic cancer at any age  A combination of breast cancer with one or more of the following: thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, pancreatic cancer, brain tumors, diffuse gastric cancer,dermatologic manifestations or leukemia/lymphoma on the same side of family  Ovarian/fallopian tube/primary peritoneal cancer  Male breast cancerAn unaffected individual with a family history of one or more of the following: ○ > 2 breast primaries from the same side of family (maternal or paternal) ○ >1 ovarian primary from the same side of family (maternal or paternal) ○ A combination of breast cancer with one or more of the following: thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer, pancreatic cancer, brain tumors, diffuse gastric cancer, dermatologic manifestations or leukemia/lymphoma on the same side of family  A known mutation in a breast cancer susceptibility gene ·  From a population at risk  Male breast cancer NCCN Guidelines, Version 1.2011
    27. 27. Assessment Patient needs and concerns: ·  Knowledge of genetic testing for cancer risk, including benefits, risks, and limitations  Goals for cancer family risk assessment Detailed family history  Expanded pedigree to include first-, second-, and third- degree relatives (parents, children, siblings, aunts, uncles, nieces, nephews, grandparents, grandchildren, half-siblings, great- grandparents, great-aunts, great-uncles, great-grandchildren, first-cousins  Types of cancer  Bilaterality  Age at diagnosis  History of chemoprevention and/or risk-reducing surgery  Medical record documentation, particularly pathology reports of primary cancers Detailed medical and surgical history  Any personal cancer history  Carcinogen exposure (eg, history of radiation therapy)  Reproductive history  Hormone use  Previous breast biopsies Focused physical exam (refer to specific syndrome)  Breast/ovarian  Dermatologic,f including oral mucosa  Head circumference  Thyroid NCCN Guidelines, Version 1.2011
    28. 28. Hereditary Breast/Ovarian Genetic Testing Criteria Individual from a family with a known deleterious BRCA1/BRCA2 mutation Personal history of breast cancer + one or more of the following:  Diagnosed age <45 y  Diagnosed age <50 y with >1 close blood relative with breast cancer <50 y and/or >1 close blood relative with epithelial ovarian/fallopian tube/primary peritoneal cancer at any age  Two breast primaries when first breast cancer diagnosis occurred prior to age 50 y  Diagnosed age < 60 y with a triple negative breast cancer  Diagnosed age < 50 y with a limited family history (e.g., adoption)  Diagnosed at any age, with >2 close blood relatives with breast and/or epithelial ovarian/ fallopian tube/ primary peritoneal cancer at any age  Close male blood relative with breast cancer  Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer  For an individual of ethnicity associated with higher mutation frequency (e.g., Ashkenazi Jewish, Icelandic), no additional family history may be required. NCCN Guidelines, Version 1.2011
    29. 29. Hereditary Breast/Ovarian Genetic Testing Criteria (cont’d) Personal history of epithelial ovarian g/fallopian tube/ primary peritoneal cancer Personal history of male breast cancer Personal history of breast and/or ovarian cancer at any age with >2 close blood relatives with pancreatic cancer at any age Personal history of pancreatic cancer at any age with >2 close blood relatives with breast and/or ovarian and/or pancreatic cancer at any age Family history only:  First- or second-degree blood relative meeting any of the above criteria  Third-degree blood relative with breast cancer and/or ovarian/fallopian tube/ primary peritoneal cancer with >2 close blood relatives with breast cancer (at least one with breast cancer <50 y) and/or ovarian cancer NCCN Guidelines, Version 1.2011
    30. 30. BRCA1/2 Testing Bestto first assess affected family members whenever possible (insurance issues, costs), especially in cases of sporadic disease
    31. 31. Variant of Uncertain Significance (VUS) A sequence within a gene not typically found in the general population and not consistently associated with disease VUS found in approximately 12% of women tested for BRCA1/2 status1 VUS should be discussed in all genetic counseling sessions for individuals considering genetic testing2 1. Domchek et al. J Clin Oncol 2008 2. Miller-Samuel et al. Semin Oncol 2011
    32. 32. Variant of Uncertain Significance (VUS) Clinical response to VUS is based on the reason for undergoing testing Clinical response also based on ethnic/racial background if gene mutations are found in certain ethnic/racial groups More detailed family history (e.g., medical records) will help to better delineate risk if VUS is found Testing of other family members, especially those with cancer, is invaluable to determine the clinical implication of VUS Miller-Samuel et al. Semin Oncol 2011
    33. 33. Variant of Uncertain Significance (VUS) Over time, the status of some VUS will change based on studies of the sequence in other individuals.  Deleterious mutation  Polymorphism  Favor deleterious  Favor polymorphism Miller-Samuel et al. Semin Oncol 2011
    34. 34. Genetic predisposition to gynecologiccancer syndromesSummary Family/personal history-taking remains THE vital component of cancer risk assessment At-risk women should be offered genetic testing when appropriate “If you have a hammer, everything is a nail”  Not every woman at increased for OEC is at risk for BRCA1/2; consider associated malignancies in family Surveillance and conservative prevention strategies available  Effective surveillance for breast cancer  Effective prevention for ovarian cancer
    35. 35. Breast and Ovarian Cancer Epidemiology Estimates for 2012 Breast cancer  226,870 new cases (26% of all cancer) ○ Up from 212,920 (31%) in 2006  39,920 deaths (15% of all cancer deaths) ○ Down from 40,970 (15%) in 2006  1975 to 2002 – survival improved 75 to 89%  Second behind lung cancer as a cause of cancer death in women Ovarian cancer  22,280 new cases (3% of all cancers) ○ Up from 20,180 in 2006  15,500 deaths (6% of all cancer deaths) ○ Up from 15,310 in 2006  Causes most deaths from cancers of the female reproductive system Data from http://www.cancer.org, 2 February 2012
    36. 36. Clinical Implications Improved ability to assess risk Limited ability to provide clinically useful interventions Little information regarding interaction of multiple risk factors Few options for women at increased risk for breast cancer – increased surveillance but few conservative preventative options
    37. 37. Determining risk Accessed at myriadtests.com
    38. 38. Patients with 5-10% chance of being inHBOC family Breast cancer ≤40 Bilateral breast cancer (esp. if 1st occurred <50) Breast cancer ≤50 and close relative with breast cancer ≤50 Jewish women with breast cancer ≤50 2 or more close relatives with any of these criteria SGO Committee Statement, 2007
    39. 39. Patients with > 25% chance of being inHBOC family Personal hx of both breast and ovarian cancer Have ovarian cancer AND close relative with ovarian cancer (any age) or breast cancer (<50) Jewish women with ovarian cancer (any age) or breast cancer (<40) Have breast cancer (<50) and close relative with ovarian cancer (any age) or male with breast ca 1° or 2° relative with known BRCA1 or BRCA2 mutation SGO Committee Statement, 2007
    40. 40. 2007 ACS Guidelines for MRI Women at high risk (> 20% lifetime risk)  MRI plus mammogram every year Women at moderately increased risk (15-20%)  Consult with their doctors about benefits and limitations of adding MRI to yearly mammograms Women with lifetime risk < 15%  Yearly MRI screening is not recommended
    41. 41. Recommendations for TamoxifenCandidates  Women with 5-year risk of breast cancer > 1.66% should be offered option of tamoxifen  Greatest benefit seen with least side effects  Premenopausal women  Women without a uterus  Women > 5% 5-year riskChlebowski RT, et al. J Clin Oncol. 2002;20(15):3328-43IBIS Investigators. Lancet. 2002;360:817-24
    42. 42. Prophylactic Mastectomy  Total (simple) mastectomy appears more effective than subcutaneous mastectomy  Shown to reduce risk of breast cancer in women with BRCA mutations by 90-94% New Engl J Med 2001;345:159-64
    43. 43. Typical Intraoperative Appearance of Stage III Epithelial Ovarian CancerAdvanced epithelial ovarian cancer No “precursor lesion” Most diagnosed in Stage 3 or 4 Mortality rates directly correlated with stage at diagnosis Cannistra, S. A. N Engl J Med 2004;351:2519-2529
    44. 44. Lifetime Family History of Ovarian Cancer RiskNone 1.5%1 first-degree relative 5%2 first-degree relatives 7%Hereditary ovarian cancer 40%syndromeKnown BRCA1, BRCA2, Lynch 10-50%mutation Shulman LP. Obstet Gynecol N Am 2010
    45. 45. Ovarian Cancer: Risk Reduction Birth control pills First full-term pregnancy < age 25; number of pregnancies Breast-feeding BTL/hysterectomy RR 0.33/0.67 Prophylactic salpingo-oophorectomy  Reduced risk of primary peritoneal cancer remains Shulman LP. Obstet Gynecol N Am 2010
    46. 46. Chemoprevention of OvarianCancer Oral ContraceptivesThe risk of ovarian cancer was 60% loweramong women with mutations in BRCA1 andBRCA2 who used oral contraceptives for > 6years New Engl J Med 1998; 339:424-8 New Engl J Med 2001;345:235-40
    47. 47. Chemoprevention of OvarianCancer RCGP Oral Contraception Study• 339,000 wy never users compared to 744,000 wy ever users• Relative Risks • Breast 0.98 • Uterine Body 0.58* • Ovary 0.54* Hannaford et al. BMJ 2007;335:651.
    48. 48. Breast Cancer in Women at High- Risk for Ovarian Cancer Using OCs Comparative study: 1,156 cases of invasive breast cancer (47 BRCA1 and 36 BRCA2) and 815 controls using low dose oral contraceptives OC use for at least 12 months reduced risk of breast cancer for BRCA1 (OR 0.22) and no change for BRCA 2 (1.02) or noncarriers (0.93) OC use in women who are BRCA mutation carriers will not increase the risk for breast cancer and will likely reduce the risk for ovarian cancer Milne et al 2005
    49. 49. Ovarian Cancer OC use will reduce the risk of developing ovarian cancer1  5 years of use: 27% reduction  15 years of use: 80% reduction  Average 5% risk reduction per year of OC use2  Protective effect diminishes 10 years after cessation  Effects are associated with all combination OCs Tubal ligation will reduce the risk of developing ovarian cancer by 50%3 1. Cibula D et al Hum Reprod Update 2010 2. Lurie G et al Epidemiology 2008 3. Cibula D et al Hum Reprod Update 2011
    50. 50. Why Tubal Ligation? Initially thought to be associated with reduced blood flow to ovaries resulting from tubal ligation1 Theories as to tubal ligation causing a separation of the ovaries from the rest of the genital tract to reduce ovarian inflammation2,3 Studies of inflammation and decreases in estrogen levels and follicle numbers and activity have failed to support the aforementioned theories4,5 1. Hankinson SE et al. JAMA 1993 2. Green A et al. Int J Cancer 1997 3. Ness RB, et al. Epidemiology 2000 4. Merritt MA et al. Int J Cancer 2007 5. Carmona F, et al. AJOB 2003
    51. 51. Ovarian Cancer: FallopianTube? 122 BRCA1/2 positive women undergoing prophylactic BSO  7 early malignancies (5.7%)  All 7 originated in the fimbrial and ampullary regions of the fallopian tubes ○ 2 with surface implants on the ovarian surface ○ 2 cases required more detailed sectioning of the FT to detect malignancy Callahan et al. J Clin Oncol 2007
    52. 52. Ovarian Cancer: Fallopian Tube? Serous tubal intraepithelial carcinomas (STICs)  Secretory cells showing significant atypia  By immunohistochemistry, STICs contain p53 mutations and are mostly highlighted by nuclear accumulation of mutated p53 protein  Highly proliferative p53 signature  Benign secretory outgrowth in fimbria and is a putative cancer precursor 1. Crum CP. Mol Oncol 2009 2. Chen EY et al. J Pathol 2010
    53. 53. STIC Sedhev AS et al. Mod Pathol 2010
    54. 54. Population-Based Screening forOvarian Cancer: NO! The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial  78,216 women 55-74  Annual screening vs. usual care  Annual screening: CA-125 for 6 years and TV- USG for 4 years. ○ CA-125 > 35U/ml ○ Ovarian volume greater than 10 cm3 ○ Cyst volume greater than 10 cm3 ○ Any solid area or papillary projection extening into the cavity of a cystic ovarian tumor of any size ○ Any mixed (solid and cystic) component Buys SS et al. JAMA 2011
    55. 55. PLCO  OEC diagnosed ○ 5.7/10,000 person-years in intervention group ○ 4.7/10,000 person-years in routine care group ○ Rate ratio 1.21 (95% CI: 0.99-1.48)  Deaths ○ 3.1/10,000 person-years in intervention group ○ 2.6/10,000 person-years in routine care group ○ Rate ratio 1.18 (95% CI: 0.82-1.71) Buys SS et al. JAMA 2011
    56. 56. Current ScreeningGuidelines“…annual screening for ovarian cancer,as performed in the PLCO trial…doesnot reduce disease-specific mortality inwomen at average risk for ovariancancer but DOES (emphasis added)increase invasive medical proceduresand assocaited harms.” Buys SS, et al. JAMA 2011
    57. 57. Screening for Ovarian Cancer in aHigh-Risk Community: Not Yet! Increased surveillance Serum biomarkers Transvaginal ultrasound
    58. 58. Screening approaches Genetic Imaging Biochemical Symptom index Combination/Multiplex None have been shown to consistently detect early lesions or reduce mortality
    59. 59. Increased surveillance No evidence to support a decrease in mortality from increased surveillance Genetic counseling and testing increased surveillance and led to risk-reducing surgeries that resulted in the prevention of OEC and the detection of early-stage tumors in women with BRCA1 and BRCA2 mutations Scheuer L et al. J Clin Oncol 2002
    60. 60. Sonography for ovarian neoplasmFishman et al, Am J Obstet Gynecol 2005
    61. 61. NOCEDPPUltrasound Screening in a high-risk population 12,709 scans in 4,526 “high-risk” women Ultrasound screening alone ineffective for detecting early stage ovarian cancer Fishman, Cohen, Blank, Shulman et al. Am J Obstet Gynecol 2005
    62. 62. University of Kentucky Ovarian CancerScreening Project Update: 2009 31,748 women  22.8% with a positive family history TVS better than Symptom Index (SI) for the detection of malignancies  DR: 73.3% v. 20% SI better than TVS for delineating benign lesions  91.3% v. 74.4% Use of TVS and SI resulted in poor identification of malignancies (16.7%) but improved distinguishing of benign lesions (97.9%) Pavlik EJ, et al. Cancer Volume 115, Issue 16, pages 3689-3698, 14 JUL 2009 DOI: 10.1002/cncr.24407
    63. 63. Use of symptom index Major associated symptoms Pelvic pain Abdominal pain Increased abdominal size Bloating Feeling full early Difficulty eating Sensitivity: 56.7% early stScreen “positive” if any symptoms 79.5% adv stpresent for < 1yr, but occurred >12 times 2-3% of general populationper month had positive screen Goff et al, Cancer 2007
    64. 64. Ovarian cancer biomarkersCA-125 Elevated in about 1% normal women, 80% of epithelial ovarian cancers (50% of St I disease) PPV alone <10%, around 20% in combo with sonography May perform better as serial assay
    65. 65. Lynch syndrome: Screening/Management  Annual colonoscopy Colon initiated between 20-25 Endometrial/Ovarian  Annual TVU w/ color Doppler, CA-125 and endometrial aspirate beginning at age 25-35  Annual Gastric esophagogastroduodenosc opy (EGD) beginning at age 30 Upper Epithelial Tract (also  Annual urinanalysis w/ with MTS) cytology and renal ultrasound beginning at age 30 Liver  Annual LFTs beginning at age 30 Skin Tumors (MTS)  Annual dermatologic exam
    66. 66. Women with a Pelvic Mass are at Risk forOEC 20% of women will be diagnosed with an adnexal mass1  300,000 per annum in U.S. 5-10% of women will have surgery for an ovarian neoplasm2 13-21% of these masses will be malignant2 1.Curtin JP. Gynecol Oncol. 1994;55:S42-S46. 2. NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.
    67. 67. Work-up of Adnexal Mass Must first categorize as functional, benign neoplastic or potentially malignant Diagnostic approach depends on: Age  Ultrasound configuration Size of mass  Color-flow Doppler flow Unilateral vs. bilateral  Presence of symptoms CA-125 levels
    68. 68. ACOG and SGO Referral GuidelinesNewly Diagnosed Pelvic MassPremenopausal Postmenopausal(<50 years of age) (≥50 years of age) CA 125 >200U/ml)  CA 125 >35U/ml Ascites  Ascites  Nodular or fixed pelvis mass Evidence of abdominal or  Evidence of abdominal or distant metastasis (by distant metastasis (by exam or exam or imaging study) imaging study) Family history of breast or  Family history of breast or OC(in a first-degree OC(in a first-degree relative) relative) ACOG Practice Bulletin No. 83. Obstet Gynecol. 2007;110:201-14. Im SS, et al. Obstet Gynecol. 2005;105:35-41.
    69. 69. Significantly Higher Survival Rates with Oncology Specialists Type of Surgeon Impacts Type of Hospital Impacts Survival Rates Survival Rates 1.0 1.0 0.8 0.8Cumulative Survival Cumulative Survival 0.6 0.6 TH: Teaching hospital 0.4 0.4 NTH: Nonteaching hospital 0.2 0.2 0.0 0.0 0 200 400 600 800 1000 0 200 400 600 800 1000 Survival in days Survival in days Paulsen T et al. Int J Gynecol Cancer. 2006:16(suppl 1):11-17.
    70. 70. ACOG and SGO Referral GuidelinesNewly Diagnosed Pelvic MassPremenopausal Postmenopausal(<50 years of age) (≥50 years of age) CA 125 >200 U/ml)  CA 125 >35 U/ml Ascites  Ascites Evidence of abdominal or  Nodular or fixed pelvis mass distant metastasis (by  Evidence of abdominal or exam or imaging study) distant metastasis (by exam or imaging study) Family history of breast or  Family history of breast or OC OC(in a first-degree (in a first-degree relative) relative) ACOG Practice Bulletin No. 83. Obstet Gynecol. 2007;110:201-14. Im SS, et al. Obstet Gynecol. 2005;105:35-41.
    71. 71. Ultrasound Evaluation of a Pelvic Mass Sensitivity Specificity PPV NPV Study (%) (%) (%) (%)DePriest et al. 88 40 28 93(1993)Pavlik et al. (2009) 73.3 74.4 26.2 95.7PPV = positive predictive value DePriest PD, et al. Gynecol Oncol. 1993;51:7-11.NPV = negative predictive valueNA = not available Pavlik EJ, et al. Cancer. 2009;115:3689-98.
    72. 72. Non-Malignant Conditions that ElevateCA125  Gynecologic  Non-gynecologic  Adenomyosis  Acute hepatitis/pancreatitis  Endometriosis  Chronic liver disease/cirrhosis  Colitis/Diverticulitis  Acute PID  Congestive Heart Failure  Benign ovarian  Diabetes (poorly controlled) neoplasm  Pericarditis  Functional ovarian cyst  Peeumonia  Menstruation  Renal disease  Unexplained infertility  Lupus Copeland LJ. In DiSaia PJ, et al Clinical Gynecology, 7th ed.
    73. 73. RMIRisk of Malignancy Index RMI = USG x [M]eno status x serum CA 125 level USG = 0 for imaging score of 0 = 1 for imaging score of 1 = 3 for imaging score of 2-5 M = 1 if premenopausal = 3 if postmenopausal• (1990) 85% sensitivity/97% specificity1• (2012) 80% sensitivity/92% specificity/PPV 83%2 1. Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929. 2. Hakansson et al Acta Obstet Gynecol Scand 2012
    74. 74. OVA-1™ Multiple Serum Markers• Approved for presurgical evaluation of women with ovarian adnexal mass1• 5 biomarkers2 – 2-microgobulin – Apolipoprotein A1 – CA125 – Transferrin – Transthyretin (prealbumin)• Single numerical score (0-10) that indicates the likelihood of malignancy1 1. OVA-1 package insert: Executive summary; Vermillion, Inc.2011. 2. OVA-1 test summary; Quest Diagnostics.2011.
    75. 75. ROMATMRisk of Ovarian Malignancy Algorithm• HE4 and CA125 + menopausal status• Estimate the risk of malignancy in women presenting with adnexal mass who will undergo surgical intervention• Calculation is performed on internetDetermine if patient should be referred to an advanced cancer center
    76. 76. Pilot Study Cross-validated Estimates of Sensitivity Benign vs. Ovarian Cancer: Average from Sensitivity atLeave-One-Out Analysis 90% 95% 98% Marker Combination Specificity Specificity Specificity CA125 61.2% 43.3% 23.9% HE4 77.6% 72.9% 64.2% CA125 + HE4 80.7% 76.4% 71.6% CA125 + HE4 + SMRP 80.6% 74.7% 71.7%CA125 + HE4 + CA72-4 82.1% 78.8% 71.5% Moore RG et al. Gynecol Oncol 2008;108:402-8.
    77. 77. ROMA™ vs RMI Increased Sensitivity with ROMA Benign (n = 312) vs EOC (n = 123) All Patients Sensitivity* (95% CI) Specificity(95% CI) RMI 83.7% (76.0% - 89.8%) 75%(69.8% - 79.7%) ROMA™ 94.3% (88.6% - 97.7%) 75%(69.8% - 79.7%)*Two Sample Test of Equality of Proportions p=0.0129 CI: Confidence Interval Moore et al, Am J Obstet Gynecol. 2010;203(3):228.e1-6.
    78. 78. OVA-1™ vs. ROMA™ Measure OVA-1™ ROMA™ (Presurgical assessment (ICA + ROMA™) + OVA-1™) Sensitivity 91.7 (83.0-96.1) 90.9 (81.3-96.6) (95% Cl); % Specificity 41.6 (35.0-48.6) 67.2 (62.2-71.9) (95% Cl); % PPV 36.5 (29.8-43.7) 32.8 (26.0-40.1) (95% Cl); % NPV 93.2 (85.9-96.8) 97.7 (95.0-99.1) (95% Cl); % Cost $516.25-650.00 $65.00 - 276.00ICA = Initial clinical risk assessmentPPV = positive predictive value OVA-1 package insert: executive summary; Vermillion, Inc.NPV = negative predictive value Moore RM, et al. Obstet Gynecol 2011
    79. 79. Summary The delineation of risk for breast and ovarian cancer is made primarily by personal and family history Offering genetic testing should be only to those at increased risk – genetic testing is not yet appropriate for the general population Breast cancer is amenable to effective screening protocols while OEC is amenable to effective prevention protocols
    80. 80. Summary Genomic factors play an important role in the risk for development of gynecologic malignancies except for cervical cancer Most gynecologic malignancies occur in women with little or no family history of the malignancy Detection of gene(s) that increase the likelihood of cancer development will likely improve screening, diagnosis and prognosis assessment

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