am 7.15 shulman
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HEREDITARY BREAST AND OVARIAN CANCER
Lee P. Shulman MDThe Anna Ross Lapham Professor of Obstetrics and Gynecology
and Chief Division of Clinical GeneticsDirector, Northwestern Ovarian Cancer Early Detection and
Prevention ProgramCo-Director, Cancer Genetics Program
The Robert S. Lurie Comprehensive Cancer CenterFeinberg School of Medicine of Northwestern University
Chicago, Illinois
Disclosures Advisory/Consulting
Myriad, Fujireibio, Genzyme (Integrated Genetics), Signature,
Speaking/HonorariaMyriad, Fujireibio, Genzyme
(Integrated Genetics), Signature, Roche, GSK
Research SupportMiraDx
Inherited Cancer
Earlier age of onset Higher rate of bilaterality Associated tumors Not distinguished by pathology,
metastatic pattern or survival characteristics
KNUDSON
Two-step process
First: germinal or somatic mutation
Second: somatic mutation
The Genetics of Cancer
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Normal Cell
Cancerous Cell
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Killed Cell
Intact Tumor Suppressor Gene
Tumor Suppressor Gene Mutation
Comparison of Oncogenes and Tumor-Suppressing Genes
ONCOGENES Gene active
Specific translocations
Translocations somatic
Dominant at cell level
Leukemia/lymphoma
TUMOR-SUPPRESSING Gene inactive
Deletions or mutations
Mutations auto dominant or nonhereditary
Recessive at cell level
Solid tumors
Why do cancer risk assessment and genetic testing 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 interventionsFor non-carriers in families without a
delineated mutations, may not alter risk Offer risk-reducing surgery Information for family members Reproductive decision-making
Genetic Testing in Women’s Health Somatic
HPVGC
GerminalCarrier Screening
Cystic fibrosis, Jewish genetic disease screening Universal genetic screening
Cancer Genetic Testing
Genetic cancer syndromes in women’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
Genetic cancer syndromes in women’s health 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
BRCA1/2
Tumor suppressing genes
Role in cell cycle regulation
Dominant inheritance with relatively high penetrance
BRCA1/2
Tumor suppressing genes
Role in cell cycle regulation
Dominant inheritance with relatively high penetrance
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
Breast & Ovarian Cancer Risks Associated with BRCA1 Alterations
AGE 0 20 40 60 80
90
80
70
60
50
40
30
20
10
0
BRCA 1 - Breast
General Population - Breast
BRCA 1 - Ovarian
General Population - Ovarian
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
Breast & Ovarian Cancer Risks Associated with BRCA2 Alterations
AGE 0 20 40 60 80
90
80
70
60
50
40
30
20
10
0
BRCA 2 - Breast
General Population - Breast
BRCA 2 - Ovarian
General Population - Ovarian
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 1/403 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
Ovarian Cancer Lynch (HNPCC)
ColonEndometrialBreast
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
Lynch syndrome – Genetics
Multistep mismatch repair (MMR) systemGene products are involved in correcting
single base pair mistakes that can occur during DNA replication
○ MLH1 cloned in 1994 (3p21)○ MSH2 cloned in 1993 (2p21-22)○ MSH6 cloned in 1997 (2p15)○ PMS2 cloned in 1994 (7p22)
Shulman LP. Obstet Gynecol Clin N Am 2010
Mismatch Repair Genes
HNPCC is associated with germline mutations in any one of four mismatch repair genes
Chr 2Chr 3
Chr 7
MSH2 MLH1PMS2
MSH6
PMS1?
Lynch Syndrome
· Few adenomas· 80% CRC risk, mean 44
yrs · More proximal colonic· Frequent synchronous and
metachronous CRC· MMR mutations: MLH1,
MSH2, MSH6, PMS2
Burt, J Natl Compr Canc Netw 2010; 8:8-61Jasperson, Burt, Gastroenterol, 2010; 138:2044
Extra-Colonic Cancers
Life-time Risk (%)Life-time Risk (%)
Maul JS et al. Am J Gastroenterol 2006
Other Cancer Predisposition Genes: 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 nonselected OEC cases.
○ Marker for significant increased risk of developing OC
○ KRAS-variant present in 61% of HBOC patients without BRCA1 or BRCA2 mutations
○ 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
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)
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
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 cancer
An 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
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
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
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
BRCA1/2 Testing
Best to first assess affected family members whenever possible (insurance issues, costs), especially in cases of sporadic disease
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 20082. Miller-Samuel et al. Semin Oncol 2011
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
Variant of Uncertain Significance (VUS) Over time, the status of some VUS
will change based on studies of the sequence in other individuals. Deleterious mutationPolymorphismFavor deleteriousFavor polymorphism
Miller-Samuel et al. Semin Oncol 2011
Genetic predisposition to gynecologic cancer 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 availableEffective surveillance for breast cancerEffective prevention for ovarian cancer
MANAGEMENT OF THE WOMAN WITH IDENTIFIED CANCER RISK
Breast and Ovarian Cancer EpidemiologyEstimates for 2012
Breast cancer226,870 new cases (26% of all cancer)
○ Up from 212,920 (31%) in 200639,920 deaths (15% of all cancer deaths)
○ Down from 40,970 (15%) in 20061975 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 systemData from http://www.cancer.org, 2 February 2012
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
Accessed at myriadtests.com
Determining risk
Patients with 5-10% chance of being in HBOC 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
Patients with > 25% chance of being in HBOC 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
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
Recommendations for Tamoxifen Candidates
Women with 5-year risk of breast cancer > 1.66% should be offered option of tamoxifen
Greatest benefit seen with least side effectsPremenopausal womenWomen without a uterusWomen > 5% 5-year risk
Chlebowski RT, et al. J Clin Oncol. 2002;20(15):3328-43IBIS Investigators. Lancet. 2002;360:817-24
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
Cannistra, S. A. N Engl J Med 2004;351:2519-2529
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
Family History of Ovarian Cancer
Lifetime Risk
None 1.5%
1 first-degree relative 5%
2 first-degree relatives 7%
Hereditary ovarian cancer syndrome
40%
Known BRCA1, BRCA2, Lynch mutation
10-50%
Shulman LP. Obstet Gynecol N Am 2010
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-
oophorectomyReduced risk of primary peritoneal
cancer remains
Shulman LP. Obstet Gynecol N Am 2010
Oral Contraceptives
Chemoprevention of Ovarian Cancer
New Engl J Med 1998; 339:424-8New Engl J Med 2001;345:235-40
The risk of ovarian cancer was 60% lower among women with mutations in BRCA1 and BRCA2 who used oral contraceptives for > 6 years
RCGP Oral Contraception Study
Chemoprevention of Ovarian Cancer
Hannaford et al. BMJ 2007;335:651.
• 339,000 wy never users compared to 744,000 wy ever users
• Relative Risks• Breast 0.98• Uterine Body 0.58*• Ovary 0.54*
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
Ovarian Cancer OC use will reduce the risk of developing
ovarian cancer1
5 years of use: 27% reduction15 years of use: 80% reductionAverage 5% risk reduction per year of OC use2
Protective effect diminishes 10 years after cessationEffects 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 20102. Lurie G et al Epidemiology 20083. Cibula D et al Hum Reprod Update 2011
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 19932. Green A et al. Int J Cancer 19973. Ness RB, et al. Epidemiology 20004. Merritt MA et al. Int J Cancer 20075. Carmona F, et al. AJOB 2003
Ovarian Cancer: Fallopian Tube?
122 BRCA1/2 positive women undergoing prophylactic BSO7 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
Ovarian Cancer: Fallopian Tube?
Serous tubal intraepithelial carcinomas (STICs)Secretory cells showing significant atypiaBy immunohistochemistry, STICs contain p53
mutations and are mostly highlighted by nuclear accumulation of mutated p53 protein
Highly proliferative
p53 signatureBenign secretory outgrowth in fimbria and is a putative
cancer precursor1. Crum CP. Mol Oncol 20092. Chen EY et al. J Pathol 2010
STIC
Sedhev AS et al. Mod Pathol 2010
Population-Based Screening for Ovarian Cancer: NO! The Prostate, Lung, Colorectal and
Ovarian (PLCO) Cancer Screening Randomized Controlled Trial78,216 women 55-74Annual screening vs. usual careAnnual 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
PLCOOEC 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
Current Screening Guidelines“…annual screening for ovarian cancer, as performed in the PLCO trial…does not reduce disease-specific mortality in women at average risk for ovarian cancer but DOES (emphasis added) increase invasive medical procedures and assocaited harms.”
Buys SS, et al. JAMA 2011
Screening for Ovarian Cancer in a High-Risk Community: Not Yet!
Increased surveillance
Serum biomarkers
Transvaginal ultrasound
Screening approaches
Genetic Imaging Biochemical Symptom index Combination/Multiplex
None have been shown to consistently detect early lesions
or reduce mortality
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
Sonography for ovarian neoplasm
Fishman 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 alone ineffective for detecting early stage ovarian cancer
Fishman, Cohen, Blank, Shulman et al. Am J Obstet Gynecol 2005
University of Kentucky Ovarian Cancer Screening 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. CancerVolume 115, Issue 16, pages 3689-3698, 14 JUL 2009 DOI: 10.1002/cncr.24407
Use of symptom index
Major associated symptoms
Pelvic painAbdominal painIncreased abdominal sizeBloatingFeeling full earlyDifficulty eating
Goff et al, Cancer 2007
Screen “positive” if any symptomspresent for < 1yr, but occurred >12 timesper month
Sensitivity: 56.7% early st 79.5% adv st
2-3% of general populationhad positive screen
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
Lynch syndrome: Screening/Management
Colon
Endometrial/Ovarian
Gastric
Upper Epithelial Tract (also with MTS)
Liver
Skin Tumors (MTS)
Annual colonoscopy initiated between 20-25
Annual TVU w/ color Doppler, CA-125 and endometrial aspirate beginning at age 25-35
Annual esophagogastroduodenoscopy (EGD) beginning at age 30
Annual urinanalysis w/ cytology and renal ultrasound beginning at age 30
Annual LFTs beginning at age 30
Annual dermatologic exam
THE ADNEXAL MASS: CURRENT SCREENING ALGORITHMS TO OPTIMIZE CLINICAL OUTCOMES
Women with a Pelvic Mass are at Risk for OEC
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.
Work-up of Adnexal Mass
Age Size of mass Unilateral vs. bilateral CA-125 levels
Ultrasound configuration Color-flow Doppler flow Presence of symptoms
Must first categorize as functional, benign neoplastic or potentially malignant
Diagnostic approach depends on:
Premenopausal (<50 years of age)
CA 125 >200U/ml) Ascites Evidence of abdominal
or distant metastasis (by exam or imaging study)
Family history of breast or OC(in a first-degree relative)
Postmenopausal(≥50 years of age)
CA 125 >35U/ml Ascites Nodular or fixed pelvis mass Evidence of abdominal or
distant metastasis (by exam or imaging study)
Family history of breast or OC(in a first-degree relative)
ACOG and SGO Referral GuidelinesNewly Diagnosed Pelvic Mass
ACOG Practice Bulletin No. 83. Obstet Gynecol. 2007;110:201-14.Im SS, et al. Obstet Gynecol. 2005;105:35-41.
Significantly Higher Survival Rates with Oncology SpecialistsType of Surgeon Impacts
Survival RatesType of Hospital Impacts
Survival Rates
Paulsen T et al. Int J Gynecol Cancer. 2006:16(suppl 1):11-17.
TH: Teaching hospitalNTH: Nonteaching hospital
Premenopausal (<50 years of age)
CA 125 >200 U/ml) Ascites Evidence of abdominal
or distant metastasis (by exam or imaging study)
Family history of breast or OC(in a first-degree relative)
Postmenopausal(≥50 years of age)
CA 125 >35 U/ml Ascites Nodular or fixed pelvis mass Evidence of abdominal or
distant metastasis (by exam or imaging study)
Family history of breast or OC (in a first-degree relative)
ACOG and SGO Referral GuidelinesNewly Diagnosed Pelvic Mass
ACOG Practice Bulletin No. 83. Obstet Gynecol. 2007;110:201-14.Im SS, et al. Obstet Gynecol. 2005;105:35-41.
Ultrasound Evaluation of a Pelvic Mass
Study Sensitivity(%)
Specificity(%)
PPV(%)
NPV(%)
DePriest et al. (1993)
88 40 28 93
Pavlik et al. (2009) 73.3 74.4 26.2 95.7
DePriest PD, et al. Gynecol Oncol. 1993;51:7-11.Pavlik EJ, et al. Cancer. 2009;115:3689-98.
PPV = positive predictive valueNPV = negative predictive valueNA = not available
Non-Malignant Conditions that Elevate CA125
GynecologicAdenomyosisEndometriosisAcute PIDBenign ovarian
neoplasmFunctional ovarian
cystMenstruationUnexplained
infertility
Non-gynecologicAcute hepatitis/pancreatitisChronic liver disease/cirrhosisColitis/DiverticulitisCongestive Heart FailureDiabetes (poorly controlled)PericarditisPeeumoniaRenal diseaseLupus
Copeland LJ. In DiSaia PJ, et al Clinical Gynecology, 7th ed.
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
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.
ROMATM
Risk 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 internet
Determine if patient should be referred to an advanced cancer center
Average from Leave-One-Out Analysis
Marker Combination
Benign vs. Ovarian Cancer: Sensitivity at
90%Specificity
95%Specificity
98%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.
Pilot StudyCross-validated Estimates of Sensitivity
ROMA™ vs RMIIncreased Sensitivity with ROMA
All Patients
Benign (n = 312) vs EOC (n = 123)
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.
OVA-1™ vs. ROMA™ Measure OVA-1™
(Presurgical assessment + OVA-1™)
ROMA™(ICA + ROMA™)
Sensitivity (95% Cl); %
91.7 (83.0-96.1) 90.9 (81.3-96.6)
Specificity (95% Cl); %
41.6 (35.0-48.6) 67.2 (62.2-71.9)
PPV(95% Cl); %
36.5 (29.8-43.7) 32.8 (26.0-40.1)
NPV (95% Cl); %
93.2 (85.9-96.8) 97.7 (95.0-99.1)
Cost $516.25-650.00 $65.00 - 276.00ICA = Initial clinical risk assessmentPPV = positive predictive valueNPV = negative predictive value
OVA-1 package insert: executive summary; Vermillion, Inc.Moore RM, et al. Obstet Gynecol 2011
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
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