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

Conflicts of Interest

• NONE

Trends in US Female Cancer Death RatesTrends in US Female Cancer Death

Ovarian Cancer on the Diaphragm

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

Mortality reduction from cancer

• Therapy• Prevention• Screening and early detection

Natural history of cancer in relation to screening

Hulka, 1988

Preclinical disease

Detection by screening

Disease inception

Symptomonset

UsualDiagnosis

Preclinical disease DiseaseOutcome

Overt disease

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

Length Bias in Cancer Screening

Annual screen

Rapidlyprogressive

cancers

Slowlyprogressive

cancers

Time

Origins of “Ovarian Cancer”

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%

Ovarian Cancer Screening Modalities

• Symptoms• Physical examination• Blood tumor markers• Ultrasound• Multimodality screening

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

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

Pelvic Ultrasound

Ovarian cancer Functional ovarian cysts

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

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

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

Lancet, Dec. 2015

Serial Surveillance of CA-125

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

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

UKCTOCS: Cumulative incidence of Ovarian Cancer

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.

Slide 12

Presented By Usha Menon at 2016 ASCO Annual Meeting

Slide 13

Presented By Usha Menon at 2016 ASCO Annual Meeting

Ovarian Cancer Mortality

15% mortality reduction with MMS (p = 0.15), 11% with US

Ovarian/Peritoneal Cancer Deaths

11% mortality reduction with MMS and 9% with US

Late effect of Screening on Mortality: Breast Cancer Mortality Reduction in Sweden with

Mammography Screening

CA125 Change point Analysis

Prevalent caseIncident case Uncertain case

28% mortality reduction at 14 years

Ovarian Cancer Mortality: MMS vs Control Excluding Prevalent Cases

24% mortality reduction at 14 years

Ovarian/Peritoneal Cancer Mortality: MMS vs Control Excluding Prevalent Cases

Number Needed to Screen to Prevent One Death

NNS = 641

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.

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

EXTRA

Lead time bias

DeathClinicaldiagnosis

Screeningdiagnosis

Time

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

Slide 15

Presented By Usha Menon at 2016 ASCO Annual Meeting

Slide 10

Presented By Usha Menon at 2016 ASCO Annual Meeting

Oral Contraceptive Use and Ovarian Cancer

Analysis of 45 Epidemiological Studies

Slide 16

Presented By Usha Menon at 2016 ASCO Annual Meeting

Slide 14

Presented By Usha Menon at 2016 ASCO Annual Meeting

Stage Shift with MMS

40% diagnosed at an early stage with MMS compared to 26% of controls.No stage shift in the US group

Reduction in Lung Cancer Screening with Low-dose CT

Number Needed to Screen to prevent one death

THE ROCA® TEST –RISK OF OVARIAN CANCER ALGORITHM

Earlier detection of ovarian cancer is now possible

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ROCA TEST:HELPING THE GYN/ONC, PATIENT, AND PROVIDERS

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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

5 MILLION SAMPLE SERUM BIOBANK + ALGORITHM = NOVEL OVARIAN CANCER DX AID

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ROCA TEST:SURPASSES GOLD STANDARDS FOR CANCER SCREENING

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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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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

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ROCA TEST:CLINICAL IMPLEMENTATION / RISK CATEGORIZATION

Normal90% of results

Intermediate8.5% of results

Elevated1.5% of results

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

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ROCA TEST MULTIMODAL SCREENING STRATEGY (MMS)

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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

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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“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

Ovarian Cancer Risk Factors

Increased Risk• Low parity• Infertility• Early menarche/late menopause• BMI - endometrioid, mucinous,

borderline

Decreased Risk• Tubal ligation• Oral contraceptive use

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

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

Tubal origin of ovarian cancer

Walker et al Cancer 2015

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

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

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

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

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

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)

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

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.

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

Population-level risk

• Await UKCTOCS multimodality screening mortality data (late 2015)

• OC use for contraception if appropriate• Consider opportunistic salpingectomy

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

Natural history of cancer in relation to screening

Hulka, 1988

Preclinical disease

Detection by screening

PreclinicalDisease inception

Symptomonset

UsualDiagnosis

Preclinical disease DiseaseOutcome

Overt disease

Ovarian Cancer Screening: Modalities

• Physical examination• Tumor markers• Ultrasound• Multimodality screening

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.

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