1. Lee P. Shulman MD
The 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. Disclosures
 Advisory/Consulting
 Myriad, Fujireibio, Genzyme (Integrated
Genetics), Signature,
 Speaking/Honoraria
 Myriad, Fujireibio, Genzyme (Integrated
Genetics), Signature, Roche, GSK
 Research Support
 MiraDx

3. Inherited Cancer
 Earlier age of onset
 Higher rate of bilaterality
 Associated tumors
 Not distinguished by pathology, metastatic
pattern or survival characteristics

4. KNUDSON
 Two-step process
 First: germinal or somatic mutation
 Second: somatic mutation

5. The Genetics of Cancer
Intact Tumor Suppressor Gene X
XX Killed Cell
XXX
Normal Cell
Tumor Suppressor Gene Mutation
X
XXX
XX
XXX
XX
XX
Cancerous Cell

6. Comparison of Oncogenes and Tumor-
Suppressing Genes
ONCOGENES 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. 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 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. 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. 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

10. 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

11. BRCA1/2
 Tumor suppressing genes
 Role in cell cycle regulation
 Dominant inheritance with relatively
high penetrance

12. BRCA1/2
 Tumor suppressing genes
 Role in cell cycle regulation
 Dominant inheritance with relatively
high penetrance

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. Breast & Ovarian Cancer Risks Associated with BRCA1 Alterations
90
80
70
60
50
40
30
20
10
0
AGE020406080
BRCA 1 - Breast
General Population - Breast
BRCA 1 - Ovarian
General Population - Ovarian

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. Breast & Ovarian Cancer Risks Associated with BRCA2 Alterations
90
80
70
60
50
40
30
20
10
0
AGE020406080
BRCA 2 - Breast
General Population - Breast
BRCA 2 - Ovarian
General Population - Ovarian

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. 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. Lynch syndrome – Genetics
Multistep 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. 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. 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; 8:8-61
Jasperson, Burt, Gastroenterol, 2010; 138:2044

22. Extra-Colonic Cancers
40
35
30
Life-time 25
Risk (%) 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. 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 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. 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. 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. Criteria for Further Risk Evaluation
Affected 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

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. 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. 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. BRCA1/2 Testing
 Bestto first assess affected
family members whenever
possible (insurance
issues, costs), especially in cases
of sporadic disease

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. 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. 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. Genetic predisposition to gynecologic
cancer syndromes
Summary
 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

36. 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

37. 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

38. Determining risk
Accessed at myriadtests.com

39. 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

40. 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

41. 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

42. 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 risk
Chlebowski RT, et al. J Clin Oncol. 2002;20(15):3328-43
IBIS Investigators. Lancet. 2002;360:817-24

43. 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

44. Typical Intraoperative Appearance of Stage III Epithelial Ovarian Cancer
Advanced 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

45. Lifetime
Family History of Ovarian Cancer Risk
None 1.5%
1 first-degree relative 5%
2 first-degree relatives 7%
Hereditary ovarian cancer
40%
syndrome
Known BRCA1, BRCA2, Lynch
10-50%
mutation
Shulman LP. Obstet Gynecol N Am 2010

46. 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

47. Chemoprevention of Ovarian
Cancer
Oral Contraceptives
The risk of ovarian cancer was 60% lower
among women with mutations in BRCA1 and
BRCA2 who used oral contraceptives for > 6
years
New Engl J Med 1998; 339:424-8
New Engl J Med 2001;345:235-40

48. Chemoprevention of Ovarian
Cancer
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.

49. 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

50. 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

51. 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

52. Ovarian Cancer: Fallopian
Tube?
 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

53. 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

54. STIC
Sedhev AS et al. Mod Pathol 2010

55. Population-Based Screening for
Ovarian 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

56. 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

57. 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

58. Screening for Ovarian Cancer in a
High-Risk Community: Not Yet!
 Increased surveillance
 Serum biomarkers
 Transvaginal ultrasound

59. Screening approaches
 Genetic
 Imaging
 Biochemical
 Symptom index
 Combination/Multiplex
None have been shown to
consistently detect early lesions or
reduce mortality

60. 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

61. Sonography for ovarian neoplasm
Fishman et al, Am J Obstet Gynecol 2005

62. NOCEDPP
Ultrasound 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

63. 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. Cancer
Volume 115, Issue 16, pages 3689-3698, 14 JUL 2009 DOI: 10.1002/cncr.24407

64. Use of symptom index
Major associated symptoms
Pelvic pain
Abdominal pain
Increased abdominal size
Bloating
Feeling full early
Difficulty eating
Sensitivity: 56.7% early st
Screen “positive” if any symptoms
79.5% adv st
present for < 1yr, but occurred >12 times
2-3% of general population
per month
had positive screen
Goff et al, Cancer 2007

65. Ovarian cancer biomarkers
CA-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

67. 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

69. 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.

70. 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

71. ACOG and SGO Referral Guidelines
Newly Diagnosed Pelvic Mass
Premenopausal 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.

72. 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 0.8
Cumulative 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.

73. ACOG and SGO Referral Guidelines
Newly Diagnosed Pelvic Mass
Premenopausal 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.

74. 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 95.7
PPV = positive predictive value
DePriest PD, et al. Gynecol Oncol. 1993;51:7-11.
NPV = negative predictive value
NA = not available Pavlik EJ, et al. Cancer. 2009;115:3689-98.

75. Non-Malignant Conditions that Elevate
CA125
 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.

76. RMI
Risk 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

77. 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.

78. 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

79. Pilot Study
Cross-validated Estimates of
Sensitivity Benign vs. Ovarian Cancer:
Average from Sensitivity at
Leave-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.

80. 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.

81. 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 - 276.00
ICA = Initial clinical risk assessment
PPV = positive predictive value OVA-1 package insert: executive summary; Vermillion, Inc.
NPV = negative predictive value Moore RM, et al. Obstet Gynecol 2011

82. 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

83. 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