Am 7.15 shulman

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

XX

XX

X

X

XX

XXX

Normal Cell

Cancerous Cell

XXX

XXXXX

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 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


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


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


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)


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

http://www.cancer.org/

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

http://onlinelibrary.wiley.com/doi/10.1002/cncr.v115:16/issuetoc

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)


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)


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

Am 7.15 shulman

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