ovarian cancer research and prevention, andrew berchuck, md
TRANSCRIPT
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How has recent research, such as the UK CollaborativeTrial of Ovarian Cancer Screening (UKCTOCS),
helped us better understand early detection in ovarian cancer - and where is the research going?
Andrew Berchuck, MDDirector Duke Gynecologic Oncology
Member, OCRFA Scientific Advisory Committee
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Conflicts of Interest
• NONE
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Trends in US Female Cancer Death RatesTrends in US Female Cancer Death
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Ovarian Cancer on the Diaphragm
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Ovarian Cancer: Scope of Problem
• Estimated ~22,000 new cases of ovarian cancer in the US
• Most present at an advanced stage
• >14,000 deaths annually
• Germline BRCA mutations in 10-15%
• Overall, the 1-, 5-, and 10-yr. survival is 75%, 44%, and 35%, respectively
Huang, Cancer 112:2289, 2008
Gain in life-expectancy
Median survival time
Both
Cure
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Mortality reduction from cancer
• Therapy• Prevention• Screening and early detection
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Natural history of cancer in relation to screening
Hulka, 1988
Preclinical disease
Detection by screening
Disease inception
Symptomonset
UsualDiagnosis
Preclinical disease DiseaseOutcome
Overt disease
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Impediments to Early Detection of Ovarian Cancer
•Ovarian cancer is relatively rare
•Ovaries and tubes are inaccessible
•Preinvasive lesion not easily detectable
•Early cancers produce few symptoms
•Screen detected cancers may be less lethal
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Length Bias in Cancer Screening
Annual screen
Rapidlyprogressive
cancers
Slowlyprogressive
cancers
Time
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Origins of “Ovarian Cancer”
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Histology versus Stage
Cell Type Stage I Stage II-IVSerous 4% 96%
Mucinous 83% 17%
Endometrioid 53% 47%
Clear cell 36% 64%
Brenner 100% 0%
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Ovarian Cancer Screening Modalities
• Symptoms• Physical examination• Blood tumor markers• Ultrasound• Multimodality screening
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Ovarian Cancer Symptoms
•Ovarian cancer symptoms are non-specific
• pelvic ultrasound and CA125 are appropriate tools in the evaluation of these symptoms
•Existing evidence suggests that early recognition of ovarian cancer symptoms does not impact survival
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CA125 Serum Test
•Elevated in 80-85% of advanced ovarian cancers
•Elevated in 50% of Stage I cancers
•Serial levels reflect clinical course of the disease
•Useful in distinguishing between benign and malignant pelvic masses
•Elevated in 3% of healthy menopausal women
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Pelvic Ultrasound
Ovarian cancer Functional ovarian cysts
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Prostate, Lung, Colon and Ovarian (PLCO) screening trial
Randomized 78,215 postmenopausal women to screening or no screening
Screened patients received yearly CA125 (x 6 yrs)yearly TVS (x 4 yrs)
Median follow up 12 yearsBuys et al ASCO 2011
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PLCO Trial Results78,215 subjects
39,111 usual care176 ovarian cancers
77% stage III-IV
100 ovarian cancer deaths
39,105 screening212 ovarian cancers
78% stage III-IV
118 ovarian cancer deaths
Buys et al JAMA 2011
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PLCO Trial ResultsOvarian cancer mortality
Mortality rate ratio 1.18 (95% CI 0.91-1.64)
Morbidity of screening3,285 surgeries resulted from a false positive
screen166 (5%) had at least one serious surgical
complication
Screening did not reduce mortality from ovarian cancer but did cause harm.
Buys et al JAMA 2011
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Lancet, Dec. 2015
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Serial Surveillance of CA-125
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UKCTOCS Study
• Trial overview– 2001-2005: enrollment of women > age 50 in the UK– 2011: screening ended– 2015: mortality analysis
• Control arm 100,000: no screening
• Ultrasound arm 50,000: annual ultrasound exam, clinical evaluation if concerning
• Multimodal arm 50,000: annual CA125 with reflex ultrasound, and clinical evaluation if concerning
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UKCTOCS Multimodal Screening
• Annual CA125 for ROCA– ROCA based on age, menopausal status, FH of
breast/ovarian cancer, BRCA1/2 and other mutations
• Normal ROCA (90%) repeat in one year• Intermediate ROCA (8.5%): repeat in a few weeks• Elevated ROCA (1.5%): Ultrasound
– If ultrasound or clinical findings concerning refer for surgery
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UKCTOCS: Cumulative incidence of Ovarian Cancer
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UKCTOCS Study: Detection of primary invasive ovarian and tubal cancers
Sensitivity Specificity Operations per cancerMMS 86% 99.8% 4US 63% 98.2% 17
• Conclusion: Multimodal screening is more sensitive than Ultrasound and leads to fewer unnecessary surgeries.
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Slide 12
Presented By Usha Menon at 2016 ASCO Annual Meeting
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Slide 13
Presented By Usha Menon at 2016 ASCO Annual Meeting
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Ovarian Cancer Mortality
15% mortality reduction with MMS (p = 0.15), 11% with US
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Ovarian/Peritoneal Cancer Deaths
11% mortality reduction with MMS and 9% with US
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Late effect of Screening on Mortality: Breast Cancer Mortality Reduction in Sweden with
Mammography Screening
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CA125 Change point Analysis
Prevalent caseIncident case Uncertain case
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28% mortality reduction at 14 years
Ovarian Cancer Mortality: MMS vs Control Excluding Prevalent Cases
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24% mortality reduction at 14 years
Ovarian/Peritoneal Cancer Mortality: MMS vs Control Excluding Prevalent Cases
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Number Needed to Screen to Prevent One Death
NNS = 641
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OCRFA Banbury Consensus Conference - Feb 2016
• Wide range of stakeholders attended.• “Further follow up is needed before firm conclusions can be
reached on the efficacy and cost effectiveness of ovarian cancer screening.”
• It is premature to recommend multimodal screening for the early detection of ovarian cancer.
• Reanalysis of the data in 3 years may allow firmer conclusions.• The ROCA test is commercially available, so health care
professionals should be prepared to advise women regarding the potential benefits and risks as we see them now.
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Future Directions• Reanalysis of mortality data from UKCTOCS in 3 yrs.
• Establish utility of Multimodal screening– Number needed to screen, for how long, and at what cost to prevent one
ovarian cancer death– Patient preferences and acceptance of MMS (anxiety etc)
• Cost effectiveness– Rarity of ovarian cancer may represent a barrier to population screening– Focusing screening of high risk women based on genetic and
epidemiological risk factors may be more cost effective.
• Search for other ovarian cancer biomarkers using UKCTOCS
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EXTRA
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Lead time bias
DeathClinicaldiagnosis
Screeningdiagnosis
Time
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Stage I Ovarian Cancer:Target for Screening
• Complete surgical resection of disease– No adjuvant therapy for selected stage IA disease– Chemotherapy: most patients
• Platinum/Taxane• Stage IA-IB disease has good prognosis
– IA – 92% five year survival– IB – 85% five year survival
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Slide 15
Presented By Usha Menon at 2016 ASCO Annual Meeting
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Slide 10
Presented By Usha Menon at 2016 ASCO Annual Meeting
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Oral Contraceptive Use and Ovarian Cancer
Analysis of 45 Epidemiological Studies
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Slide 16
Presented By Usha Menon at 2016 ASCO Annual Meeting
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Slide 14
Presented By Usha Menon at 2016 ASCO Annual Meeting
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Stage Shift with MMS
40% diagnosed at an early stage with MMS compared to 26% of controls.No stage shift in the US group
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Reduction in Lung Cancer Screening with Low-dose CT
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Number Needed to Screen to prevent one death
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THE ROCA® TEST –RISK OF OVARIAN CANCER ALGORITHM
Earlier detection of ovarian cancer is now possible
05/01/2023DRAFT. © COPYRIGHT 2016. COMPANY PROPRIETARY AND CONFIDENTIAL.
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ROCA TEST:HELPING THE GYN/ONC, PATIENT, AND PROVIDERS
DRAFT. © COPYRIGHT 2016. COMPANY PROPRIETARY AND CONFIDENTIAL. 5205/01/2023
ROCA Finds More Ovarian Cancers, and Sooner Stage I; Stage II; Stage IIIa (low volume)
when survival rates are highest Significantly lower false positive rate than other
tests
ROCA’s Multimodal Screening Strategy (MMS) Triages earlier referrals to GYN/ONC from OB/GYN GYN/ONC now has the option to perform all
surgeries Triage flow can be modified to support
each institution’s referral preferences
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5 MILLION SAMPLE SERUM BIOBANK + ALGORITHM = NOVEL OVARIAN CANCER DX AID
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ROCA TEST:SURPASSES GOLD STANDARDS FOR CANCER SCREENING
DRAFT. © COPYRIGHT 2016. COMPANY PROPRIETARY AND
CONFIDENTIAL.54
Performance of the ROCA Test compared to PLCO*, Breast, and Colorectal Cancer Screening Tests
Screening Methodology Clinical Trial
Sensitivity
Specificity PPV
/ MMS UKCTOCS 85.8% 99.8% 20.8%CA-125 and TVU◊ PLCO 26.0% 98.8% 23.8%
CA-125 or TVU† PLCO 81.0% 89.0% 1.8%TVU UKCTOCS 75.0% 98.2% 2.8%
Mammography for Breast Cancer 85.6% 90.5%Fecal Immunochemical Test (FIT) for
Colorectal Cancer 73.8% 86.8%
Multi-target Stool DNA Test (Exact Sciences) for CRC 92.3% 94.9%
* PLCO REFERS TO THE PROSTATE LUNG COLORECTAL AND OVARIAN SCREENING TRIAL CONDUCTED IN THE US BETWEEN 1993 AND 2011. THE PLCO RESULTS ARE FROM THE FIRST FOUR ROUNDS OF SCREENING AS DESCRIBED IN PUBLICATION 5 BELOW WITH FIGURES IN THIS TABLE AS A PERSONAL COMMUNICATION FROM THE AUTHOR. † WOMEN WERE SCREENED WITH CA-125 AND TVU, AND A POSITIVE RESULT WAS DEFINED AS CA-125 GREATER THAN 35U/ML, OR SUSPICIOUS IMAGE ON TVU. IF EITHER ONE OF THESE TESTS WAS ELEVATED, IT WOULD BE INTERPRETED AS A SIGNAL FOR FURTHER CLINICAL EVALUATION FOR POSSIBLE SURGERY. ◊ A POST-HOC ANALYSIS WHERE BOTH CA-125 {>35U/ML) AND A POSITIVE TVU WERE EVIDENCE AHEAD OF SURGERY TO CONFIRM OVARIAN CANCER.
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05/01/2023
Two Business Days forActionable Results Results accompanied
with Triage Guide to helppractitioners implement actionable clinical follow up
TVUS is required second line test
Clinical follow up protocol was validated in the15-year UKCTOCS trial
DRAFT. © COPYRIGHT 2016. COMPANY PROPRIETARY AND CONFIDENTIAL. 55
ROCA TEST:CLINICAL IMPLEMENTATION / RISK CATEGORIZATION
Normal90% of results
Intermediate8.5% of results
Elevated1.5% of results
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Stage I/II Stage I/II/IIIa
23.9%26.0%
36.1%40.1%
ROCA TEST MORTALITY REDUCTION 7-14 YEARS BEYOND DIAGNOSIS; STAGE SHIFT AT DIAGNOSIS
DRAFT. © COPYRIGHT 2016. COMPANY PROPRIETARY AND
CONFIDENTIAL.56LANCET. 2016 MAR 5; 387(10022): 945–956.
28% Average MortalityReduction Years 7-14
20% Overall Average Mortality ReductionUKCTOCS Trial Cumulative OC Deaths
NoScreening
ROCAMMS
UKCTOCS Trial Stage Shift
Years
No Screening
No Screening
Invasive epithelial, ovarian, fallopiantube + peritoneal cancer
P=0.00013
P<0.0001
05/01/2023
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ROCA TEST MULTIMODAL SCREENING STRATEGY (MMS)
DRAFT. © COPYRIGHT 2016. COMPANY PROPRIETARY AND CONFIDENTIAL. 5705/01/2023
GYN/ONC
Normal
Intermediate
90% of results
8.5% of results
Risk ScoreClassifications
OB/GYN
BloodDraw
ROCAAlgorithm
Triage Guides General High Risk
2-3Months
ClinicalAssessment
Initial Surgery
6Weeks
High Risk
GeneralPopulation
4 -12 Months
Elevated1.5% of results
Referralfor TVU
Numerical
Risk Score
SEE TRIAGE GUIDES WITH FULL DETAILS FOR TRIAGING HIGH RISK PATIENTS OR GENERAL POPULATION
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ROCA® TEST – RISK OF OVARIAN CANCER ALGORITHM▪ Highly Accurate ▪ Earliest Detection ▪ Stage shift1. Highest Performing Test
for Early Detection of Ovarian Cancer Evidence of mortality
reduction Proven through large-scale
clinical trials2. Multi-Modal Screening
(MMS) Early intervention with at-risk
patients Lifetime screening and
management3. Improving quality of life
Earlier treatments Minimizing surgical harm
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20.8%PositivePredictiveValue*
99.8%Specificity
85.8%Sensitivity
*WHEN COMBINED WITH TVUS AS A SECOND LINE TEST.
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DRAFT. © COPYRIGHT 2016. COMPANY PROPRIETARY AND CONFIDENTIAL. 61
“These results from UKCTOCS provide estimates of the mortality reduction attributable to ovarian cancer screening which range from 15% to 28%. Further follow up in UKCTOCS will provide greater confidence about the precise reduction in mortality which is achievable. It is possible thatthe mortality reduction afterfollow up for an additional2-3 years will be greater orless than these initial estimates.”
Professor Ian Jacobs President & Vice-
Chancellor of UNSW Australia
Honorary Professor at University College London
Co-principal investigator
Co-inventor of ROCA
ROCA® – RISK OF OVARIAN CANCER ALGORITHMFirst-of-its kind, most accurate test for detecting ovarian cancer earlier
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Ovarian Cancer Risk Factors
Increased Risk• Low parity• Infertility• Early menarche/late menopause• BMI - endometrioid, mucinous,
borderline
Decreased Risk• Tubal ligation• Oral contraceptive use
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Oral contraceptivesCollaborative Group on Epidemiological Studies of Ovarian Cancer
• Pooled case control study of 110,000 women in 45 studies
• Relative risk 0.73 (95% CI 0.70-0.76)
• 20% risk reduction per 5 years OC use
• Risk reduction correlates to duration of use
Beral et al Lancet 2008
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Tubal origin of ovarian cancer? Evidence
• No precursor lesion in ovary for “ovarian cancer”• Molecular markers are “Mullerian”• Matching p53 mutations/genetic profiles between ovarian
cancer and FT • STIC lesions and small invasive cancers seen in 5-9%
BRCA carriers at RRSO• >70% of “Ovarian” cancers have tubal involvement
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Tubal origin of ovarian cancer
Walker et al Cancer 2015
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Hereditary cancer genes• 24% of unselected ovarian, fallopian
tube cancers
• 1/3 had no family history of breast or ovarian cancer
• Genetic referral now indicated for all women with EOC
• We may soon be identifying more women at high genetic risk of ovarian cancer
Walsh et al 2011, PNAS
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Tubal Ligation
General Population:
• 34% overall risk reduction (Cibula meta-analysis 2011)– Endometrioid– Serous
BRCA carriers:
• BTL: 71% risk reduction• BTL+OC: 82% risk reduction
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Risk Reducing SurgeryBRCA 1 / 2 carriers
• RRSO– 70-85% reduction ovarian cancer– 37-54% reduction breast cancer– Complications
• 1% intraoperative• 3% postoperative
• Bilateral mastectomy– 90-95% reduction breast cancer
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The RISKS of reducing cancer risk• Nurses’ Health Study - 28 year follow up• Deaths from all causes in women who had
undergone hysterectomy plus bilateral oophorectomy
• HR 1.12 (95% CI, 1.02-1.21) compared to hysterectomy with ovarian conservation
• No age at which oophorectomy improved survival• Hormone loss, osteoporosis, cardiac issues
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Rationale for risk-reducing salpingectomy
• Majority of HGSC have precursor lesions in FT• Salpingectomy should have a benefit >= BTL• 2 types of salpingectomy
– Opportunistic– Prophylactic
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Opportunistic salpingectomy
• Removal of fallopian tubes at the time of another surgery such as hysterectomy or BTL
• No known benefit to retaining FT at time of hysterectomy
• May prevent re-operation for hydrosalpinx (up to 12% re-operation for adnexal masses)
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Uptake of opportunistic salpingectomy
• 43,931 women in British Columbia
• Hysterectomy +/- BSO• BS adds 16 minutes to hyst, 10
min to BTL• No differences in readmission or
blood transfusion
McAlpine et al, Am J Ob Gyn 2014
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Prophylactic salpingectomy• Not recommended outside high genetic risk group to
delay loss of hormones
• SGO: “although salpingectomy followed by oophorectomy is intriguing, there are no actual data on risk reduction for ovarian cancer by salpingectomy, and there are clear data that RRSO reduces the risk of both breast and ovarian cancer and improves survival in women with BRCA1 and BRCA2 mutations.”
• Women who refuse premenopausal oophorectomy will not get the associated reduction in breast cancer risk.
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ACOG Committee Opinion
• Surgeon and patient should discuss the potential benefits of the removal of the fallopian tubes during a hysterectomy.
• When counseling women about sterilization, clinicians can communicate that bilateral salpingectomy provides effective contraception.
• Prophylactic salpingectomy may offer clinicians the opportunity to prevent ovarian cancer in their patients.
• Randomized controlled trials are needed to support this.
ACOG 620; Jan 2015
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Population-level risk
• Await UKCTOCS multimodality screening mortality data (late 2015)
• OC use for contraception if appropriate• Consider opportunistic salpingectomy
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High genetic risk (deleterious mutation has been identified)
• Await UKCTOCS multimodality screening mortality data (late 2015)
• OC use for contraception if appropriate (consider breast cancer history)
• RRSO by age 35-40 • Consider prophylactic salpingectomy in clinical
trials or for patients who decline RRSO
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Natural history of cancer in relation to screening
Hulka, 1988
Preclinical disease
Detection by screening
PreclinicalDisease inception
Symptomonset
UsualDiagnosis
Preclinical disease DiseaseOutcome
Overt disease
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Ovarian Cancer Screening: Modalities
• Physical examination• Tumor markers• Ultrasound• Multimodality screening
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Welch HG et al. N Engl J Med 2015;373:1685-1687.
Incidence of Cancer That Was Metastatic at First Presentation, United States, 1975–2012.
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Overview of “Ovarian Cancer”
5th most common cause of cancer deaths in women, but relatively rare compared to colon, lung and breast cancers
Most start in the fallopian tube and present at an advanced stage
Early stage cases are highly curable, but most of these are not high grade cancers
Overall cure rate is about 40%
Treated by Gynecologic Oncologists surgical staging/debulking, platin/taxane chemo
No approved screening test