28 Million £ Down The Drain

28 Million £ Down The Drain
Muhieddine Seoud, MD, FACOG, FACS American University of Beirut Medical Center Department of Obstetrics and Gynecology Kuwait City, Lebanon February

Screening For Ovarian Cancer In Low Risk Women: Re-assessing The UKTOCS After The Latest FDA Warning
Muhieddine Seoud, MD, FACOG, FACS American University of Beirut Medical Center Department of Obstetrics and Gynecology Kuwait City, Lebanon February

Ovarian Cancer screening: Dust in the wind Objectives
Review the latest USA SEER’s data on ovarian cancer Define the different populations to screen: Asymptomatic women with low Genetic Risk for ovarian cancer Asymptomatic women with high Genetic Risk for ovarian cancer Women presenting with a pelvic mass Analyze the available data on the various screening modalities Learn about : UKOPS, OVA1, Ova Check, UKOCSP, ROCA Algorithm, PLCO, UKCTOCS, UKFOCSS, ROMA Algorithm, RMI, OTI, etc.. Present the September 2016 FDA announcement and its repercussions Take home message Five-year survival is over 90 percent for the minority of women with stage I disease. This number drops to about 75 to 80 percent with regional disease, and 25 percent for those with distant metastases. Despite the good prognosis associated with early stage disease, overall five-year survival in women with ovarian cancer is less than 45 percent, in large part because the cancer has spread beyond the ovary at the time of clinical detection in 75 percent of patients. Mortality from ovarian cancer has decreased only slightly in the past 30 years. Little is known about the mechanism or timing of progression from localized to disseminated ovarian cancer. The model of unifocal disease progressing to diffuse disease is plausible; ovarian cancer also may develop from multiple foci within the abdomen since carcinomatosis can develop after the removal of normal ovaries.

Ovarian Cancer: SEER’s Facts, USA
Average age: 63, 10% diagnosed in women < 45 USA 2016 data: ~ new patients, ~ deaths Age Specific Incidence Rate (ASIR): ~ 12.5/100,000 The life time risk: 1.8% 1 in 72 Prevalence: ~ 1/ ~ 20 % are detected at an early stage Stages 1 and 2: < 35% Stages 3 and 4: > 65% Overall 5 YSR 2015: ~ 45% Confined: 90% Metastatic: 25% Five-year survival is over 90 percent for the minority of women with stage I disease. This number drops to about 75 to 80 percent with regional disease, and 25 percent for those with distant metastases. Despite the good prognosis associated with early stage disease, overall five-year survival in women with ovarian cancer is less than 45 percent, in large part because the cancer has spread beyond the ovary at the time of clinical detection in 75 percent of patients. Mortality from ovarian cancer has decreased only slightly in the past 30 years. Little is known about the mechanism or timing of progression from localized to disseminated ovarian cancer. The model of unifocal disease progressing to diffuse disease is plausible; ovarian cancer also may develop from multiple foci within the abdomen since carcinomatosis can develop after the removal of normal ovaries. 1. Ohio Cancer Incidence Surveillance System, Ohio Department of Health, Anderson MR et al. Cancer 2008;113: Myers ER et al. Evidence Report Technology Assessment 2006 full report Cancer Research UK.

Presenting symptoms of ovarian cancer
Lack of specific symptoms- Early stages EOC: Usually portrayed as asymptomatic Only < 11% are truly asymptomatic Mostly vague pain or discomfort Lack of screening for early diagnosis: By the time they reach 3cm, >50 are stage III/ IV Advanced stages EOC: Early satiety and vague GI or GU Abdominal swelling, feeling full (tight closing) Rare vaginal bleeding General cancer symptoms: malaise, anorexia, weight loss and, orthopnea, SOB, dyspnoea Rarely present as pelvic mass Pap smear sensitivity: 10-30% Early ovarian cancer can be asymptomatic but may be associated with mild and non-specific symptoms, such as vague abdominal discomfort, pelvic pressure and pain. A recent study has shown that only 11% of stage I-II patients and 3% of stage III-IV are truly asymptomatic.1 The vast majority of patients are diagnosed with advanced disease, the symptoms of which include abdominal swelling due to either tumour or ascites, urinary and bowel disturbances due to local pressure, and unusual vaginal bleeding. In addition, patients may complain of general cancer symptoms including malaise, anorexia and weight loss, and if metastases are present dyspnoea may occur. 1. Goff BA, et al. Cancer 2000;89: Goff et al Clin Obstet Gynecol Mar;55(1): doi: /GRF.0b013e “Symptoms associated with ovarian cancer.”

Condition (or Disease)
Screening Basics A screening program for all women > 50 with a sensitivity of 80 % would require Condition (or Disease) True False Test outcome Positive True Positive False Positive  Positive Predictive Value Negative False Negative True Negative  Negative Predictive Value  Sensitivity Specificity Accuracy test with a specificity of at least 99.6 % Predictive values are often used in medical research to evaluate the usefulness of a diagnostic test. Hence the PPV is used to indicate the probability that in case of a positive test, that the patient really has the specified disease. There may be more than one cause for a test to be positive and may not always result in the overt disease seen in a patient. The predictive value of a screening test varies according to the prevalence of disease in the population being screened and the specificity of the screening test. If the prevalence of the disease is very low, the positive predictive value will not be high enough if both the sensitivity and specificity are high. Most experts feel that a screening protocol for ovarian cancer should have a positive predictive value of at least 10 percent. A screening program that targets all women over age 50 would require a test with a specificity of at least 99.6 percent (assuming a sensitivity of 80 percent) to achieve a positive predictive value of 10 percent. to achieve a PPV of 10 %

PPV of a test can differ enormously due to:
The Quest for Ovarian Cancer Screening markers: Are We on the Right Road? PPV of a test can differ enormously due to: Different prevalence even with same SN and SP (Cervical Vs Ovarian Vs Breast ca) Prevalence of pre-invasive disease and early Vs late stages The time it takes to go from normal to pre-invasive to cancer Clinically meaningful OVCA screening tools must meet 2 major conditions: Should recognize cancers with high SN and SP Should recognize these cancers early enough, permitting interventions that can alter the natural history of the disease (especially mortality) Anna E. Lokshin (Int J Gynecol Cancer 2012;22: S35YS Brown PO, Palmer C. PLoS Med. 2009;6:e Mongia SK et. Am J Clin Pathol. 2006;125:921Y927.

Mathematical modeling from the pathology RR prophylactic BSO:
OVCAs spend > 4.3 years as in-situ or stage I-II disease Serous OVCAs have progressed to a late stage ~ 1 year before their discovery Changes in CA 125 are detectable within 3-12 months before clinical diagnosis Early-stage serous OCs have a median diameter of < 0.3 cm Modeling: annual screen needs to detect tumors before they advance to stage III: < 1.3 cm to achieve 50% SN < 0.4 cm to achieve 80% SN No imaging modality could presently detect such small lesions So, current strategies are doomed at best to identify lower-volume HG disease Therefore biomarkers are the only potential tool of early detection Anna E. Lokshin (Int J Gynecol Cancer 2012;22: S35YS Brown PO, Palmer C. PLoS Med. 2009;6:e Mongia SK et. Am J Clin Pathol. 2006;125:921Y927.

The Quest for Ovarian Cancer Screening markers: Available screening modalities
Imaging: Ultrasonography: TV: “extension of the fingers” Trans-abdominal Trans-rectal +/- Doppler 3 D rendering Advanced: MRI?? Biomarkers: CA125 HE4 Lysophosphatidic Acid (LPA) Proteomics OVA1 OVA Check Genomic profiling: the 100 K project (similar to the human genome project)- trying to identify genomic alteration prior to the phenotypic transformation- “Systems Biology” Founder at ASCO Anna E. Lokshin (Int J Gynecol Cancer 2012;22: S35YS Brown PO, Palmer C. PLoS Med. 2009;6:e Mongia SK et. Am J Clin Pathol. 2006;125:921Y927.

Ovarian Cancer Screening: Serum Markers: CA-125
A high MW mucin-type GP surface Ag CA125 > 35 units/ml in: 60% of women with ovarian cancer > 80% of patients with disseminated ovarian cancer 1% of normal healthy women 3% of normal healthy women with benign ovarian diseases 20% of benign ovarian tumors 6% of patients with non-neoplastic conditions Limited SN for early stage disease (high in only 20%) Limited SP: Benign conditions, Other malignancies Uses an antibody directed against MUC 16 (the CA-125 antigen) a cell membrane associated mucin-type glycoprotein with a carbohydrate epitope Thought to provide a protective, lubricating barrier against particles and infectious agents at mucosal surfaces The antibody first used in this test was isolated by Drs. Bass and Knapp in 1981 Limited sensitivity in early stage disease which has better survival Sensitivity for stage I 50%, Sensitivity for stage II 90% Elevated in a variety of benign conditions: Endometriosis, uterine leiomyoma, pelvic inflammatory disease and cirrhosis with or without ascites it also fluctuates with menstrual cycle as well as in patients with other malignancies such as endometrial, breast, lung, and pancreatic cancer so limited specificity

Sonographic Predictors of Ovarian Malignancy
TVUS +/- Doppler: SN: % -Specificity: 94-99% PPV: Limited Poor at Dx early stages 249 women had a TVUS for a pelvic mass at BWH, , and surgery Images reviewed retrospectively by one sonologist blinded to diagnosis & clinical information: 12 U/S features were scored into high, intermediate and low risk Low risk lesions: Invasive tumors: 2/49 (4.0%) Barroilhet, Lisa et al Journal of Clinical Ultrasound. 41(5): , June 2013

Sonographic Predictors of Ovarian Malignancy
Intermediate risk lesions: thick wall or thick septa without internal blood flow: Borderline tumors: 5/6 (83.3%) Invasive tumors: one additional patient High risk lesions: all masses with internal vascularity: Benign tumors: 9/82 (11%) Borderline tumors: 1/6 (16.7%) Invasive tumors: 9/12 (75%) Conclusion: In the absence of high or intermediate risk U/S features, the risk of malignancy is low Barroilhet, Lisa et al Journal of Clinical Ultrasound. 41(5): , June 2013

Major Ovarian Cancer Screening Studies in Asymptomatic low risk Women
Screening Trial Type of Study Population Screening Modality Dates Results Japan Screening RCT 82,487 Annual CA 125 and TVUS 1985–2002 No SS # in ovarian cancer incidence UKOCSP Single–arm study 39,337 Annual TVUS 1987–2011 Describes ovarian cancer incidence and FU PLCO Study 78,216 Annual CA 125 for 6 yrs and Annual TVUS for 4 yrs 1993–2010 mortality UKCTOCS 202,638 ROCA- And CA 125–based-algorithms 2001–2014 Ovarian cancer mortality, To be discussed Angela Chan, et al Obstet Gynecol 2012;120:935–40

Ovarian Cancer Screening: Development of the Risk of Ovarian Cancer Algorithm (ROCA)

Development of the Risk of Ovarian Cancer Algorithm (ROCA)
2 screening trials of CA125 for early detection of ovarian cancer were initiated: UK: 22,000 women > 45 yrs had a prevalence screen2: SN: 40% Sweden: 5,550 women > 40 yrs had two annual screens3: SN: 50% Concern: small # of cases and the still low sensitivity Statistical analysis: data from the trials were pulled and analyzed longitudinal features of CA125 A computer algorithm determined ‘‘change-point’’ CA-125 levels 1. Karen H. Lu et al. Cancer 2013;119: Jacobs I et al. BMJ. 1993;306(6884):1030– Einhorn N et al. Obstet Gynecol ;80(1):14–8.

2 statistical models: One estimated from the ovarian cancer cases One from all other women To calculate the risk for a new woman with a series of CA125 values: Average distance between her CA125 profile and the change-point profiles is calculated And compared to the average distance between her CA125 profile and the flat profiles 1. Karen H. Lu et al. Cancer 2013;119: Jacobs I et al. BMJ. 1993;306(6884):1030– Einhorn N et al. Obstet Gynecol ;80(1):14–8.

Ovarian Cancer Screening: Serum Markers CA-125
change-point profiles Studies of CA 125 in screening for ovarian cancer have focused upon postmenopausal women, since menstrual cycle variations and the prevalence of benign gynecologic conditions in premenopausal women would result in a substantially higher likelihood of false-positive tests. Meta-analysis of 3 screening studies from Sweden and England Sensitivity for CA-125 ≥35 IU/mL 70-80% Specificity % Positive predictive value only 3% A PPV of 3% means that in an average-risk population with a low prevalence of disease, would result in >30 false-positive tests for every ovarian cancer detected Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial scheduled for completion in In the ovarian component of PLCO, 78,237 healthy women between 55 and 74 years of age were randomly assigned to screening and control groups; 39,115 women were assigned to screening with annual CA 125 and annual transvaginal ultrasound. Data from the baseline screen in 28,816 women found an abnormal CA 125 in 436 women (1.5 percent); the positive predictive value for invasive cancer was 3.7 percent (16 patients). In one study, the specificity reached 99.9 percent after redefining a positive test as a CA 125 concentration greater than 35 U/mL that doubles within six months. A large prospective study in 9233 postmenopausal women based on one of the UK CA-125 screening studies (SBH study), with measurements of CA 125 at two or more times, used a modeling method to calculate risk. Compared with a specific cutoff value of CA 125, the model improved sensitivity for detection of ovarian cancer from 62 to 86 percent when specificity was fixed at 98 percent. Serial CA-125 levels from six women in the St Bartholomew’s Hospital trial, three subsequently diagnosed with ovarian cancer, and three without disease through Exponential increase from baseline readily identifies cases before clinical detection (1, 2, 5: stages III, IV, III at clinical detection, respectively), whereas stable levels over many years indicate low level of risk. Underscoring one of the problems of screening identifying patients that are affected too late. Flat profiles

The initial OR for having ovarian cancer is: Based on the age as derived from population tumor registries: At 50 yrs her risk is: 1/2,000 At 75 yrs her risk is: 1/1,000 This risk is Xed by 2 yrs (estimated average duration of pre-clinical OVCA) 1. Karen H. Lu et al. Cancer 2013;119: Jacobs I et al. BMJ. 1993;306(6884):1030– Einhorn N et al. Obstet Gynecol ;80(1):14–8.

The final OR is: The initial OR Xed OR calculated from her serial CA125 (converted to a risk of having a change-point, interpreted as the risk of having undetected ovarian cancer) If a 50 yrs has a sequence of CA X as close to a change-point profile as to a flat profile: Initial OR: 1/2000 Final OR: 10 times 1/2,000 = 1 in 200 ROCA was intended for average-risk patients 1. Karen H. Lu et al. Cancer 2013;119: Jacobs I et al. BMJ. 1993;306(6884):1030– Einhorn N et al. Obstet Gynecol ;80(1):14–8.

The clinical recommendations for FU are based on the ROCA risk score
Development of the Risk of Ovarian Cancer Algorithm (ROCA) The clinical recommendations for FU are based on the ROCA risk score Annual CA 125 screening ROCA Calculation Low Risk: < 1/2000 Intermediate Risk: 1/ /500 High Risk: 1/500 ROCA uses data culled from previous trials, and a computer algorithm determined ‘‘change-point’’ CA-125 levels, which might indicate that postmenopausal women were at risk for development of ovarian cancer. ROCA was originally developed using data from prospective screening trials for postmenopausal women that included more than 22,000 women in the United Kingdom and more than 5000 women in Sweden. Statistical analysis of these data indicated most women without ovarian cancer had a flat CA125 profile, namely, a baseline level individual to each woman around which her CA125 levels fluctuated. In contrast, women with incident cases of ovarian cancer had a baseline level followed by a sharp increase in CA125 values significantly above her baseline, called a change-point CA125 profile, which could not be explained by background CA125 fluctuations. These thousands of profiles form the basis for the ROCA calculation that determines a woman's risk of having ovarian cancer at that time.[4, 5] For each new woman in the study, the probability calculation of ovarian cancer begins with incidence based on her age, and increases the closer her profile is to the change-point profiles compared with the flat profiles. ROCA is recalculated after every additional CA125 value. This systematic method is more efficient than using a single cut-point (eg, 35 U/mL) or an ad hoc rule of thumb, because it incorporates all sources of signal (baseline CA125 level, doubling time) and noise (variation of CA125 baseline levels, variation of baseline levels between women, variation between cases of doubling times) to obtain the most efficient signal/noise ratio, maximizing sensitivity for any level of specificity. The clinical recommendations for follow-up are based on the ROCA risk score. If a patient's ROCA risk of ovarian cancer score is less than 1 in 2000 (called “normal risk”), the recommendation is for the woman to return for a repeat CA125 in 1 year. For a ROCA risk between 1 in 2000 to 1 in 500 (“intermediate risk”), the recommendation is to return for a repeat CA125 in 3 months. For a ROCA risk of greater than 1 in 500 (“elevated risk”), the recommendation is for a TVS and referral to a gynecologic oncologist. After each additional CA125 value, ROCA is recalculated and a new recommendation is made. Resume Annual CA125 Screening Repeat CA 125 In 3 months Repeat CA 125 And do TVUS After each additional CA125 , ROCA is recalculated and a new recommendation is made Lu et al Cancer 2013“A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value”

This was the state of the art
Risks and Benefits of Screening Asymptomatic Women for OVCA Systematic Review and Meta-Analysis 2013: In 8/10 trials: FP results in 10.6% of the controls led to additional testing, including surgery 9 surgeries (95% CI, ) were performed to diagnose one case of OVCA: TVUS: 38 surgeries per OVCA detected (95% CI, ) CA-125: 4 surgeries per OVCA detected (95% CI, ) Unnecessary surgeries increase morbidity (surgical complications, pain and recovery time, and increased anxiety) Conclusions: Screening asymptomatic women for ovarian cancer => Does not reduce mortality => Results in unnecessary surgery => Does not result in diagnosis at an earlier stage This was the state of the art prior to the UKCTOCS Resulted in unnecessary surgery for false positves Gynecologic Oncology 2013;130: , PMID:

Ovarian cancer screening and mortality in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)- Lancet December Jacobs IJ, Menon U, Ryan A, et al. The Lancet: December 17, 2015 DOI: /S (15) Jacobs I et al, Lancet Dec S (15)

28 million pounds funding
1ry endpoint: To establish the impact of ovarian cancer screening on ovarian cancer mortality 7 yrs after randomization (by December 2014) 2ry endpoints: Morbidity of ovarian cancer screening Resource implications of screening Feasibility of population screening as reflected by: Uptake of invitations Compliance rates with annual screening Compare the performance of two screening strategies 3ry endpoint: Establish a serum bank for future novel tumor markers Jacobs I et al, Lancet Dec S (15)

Size of study population: 1 243 282 women invited
202,638 recruited over 4 years ( June 2001 and October 2005)- FU till Dec 2014 13 regional centers in the NHS Inclusion criteria Age years Postmenopausal: > 12 months amenorrhea following a natural menopause or hysterectomy OR > 12 months of HRT commenced for menopausal symptoms Exclusion criteria: Bilateral oophorectomy or ovarian cancer Currently active non-ovarian malignancy (excluding skin cancer) Women who have had an ovarian malignancy in the past Women at high risk of ovarian cancer due to a familial predisposition Woman participating in other ovarian ca Jacobs I et al, Lancet Dec S (15)

202 638 out of 1243 282 PM women PM women: randomized 1:1:2
Multimodal group: Annual CA 125: TVUS group: Annual: Control group: Normal Abnormal Normal Level II Screen Normal Abnormal Normal Level II screen: Detail TVUS in both groups + repeat CA 125 in multimodal group Refer to Gyn Oncol All women FU in NHS cancer registry and by postal questionnaire Jacobs I et al, Lancet Dec S (15)

Repeat CA 125 in 6 weeks and Level II Screen
: randomized 1:1:2 Multimodal group: Annual CA 125: TVUS group: Annual: Control group: Normal Intermediate Abnormal Repeat CA 125 in 3 months Repeat CA 125 in 6 weeks and Level II Screen Normal Abnormal Refer to Gyn Oncol Jacobs I et al, Lancet Dec S (15)

Level II Screen-TVUS in 6-8 wks
Complex morphology Simple cyst Normal morphology Volume > 60 ml Volume < 60 ml Level II Screen-TVUS in 6-8 wks Complex morphology OR Simple cyst > 60 ml Normal morphology Refer to Gyn Oncol Normal Jacobs I et al, Lancet Dec S (15)

Average FU duration 11 years
Average age is 60 yrs Average FU duration 11 years Parity ~ 2, OCP 5 years, 59% ever used OCP 6% family hx of OVCA Take into consideration: lead time for ovarian cancer between prevalent Vs. developing case in the intervention Vs. the no screen groups Jacobs I et al, Lancet Dec S (15)

A screening program for all women > 50
Screening Basics A screening program for all women > 50 with a sensitivity of 80 % would require test with a specificity of at least 99.6 % Predictive values are often used in medical research to evaluate the usefulness of a diagnostic test. Hence the PPV is used to indicate the probability that in case of a positive test, that the patient really has the specified disease. There may be more than one cause for a test to be positive and may not always result in the overt disease seen in a patient. The predictive value of a screening test varies according to the prevalence of disease in the population being screened and the specificity of the screening test. If the prevalence of the disease is very low, the positive predictive value will not be high enough if both the sensitivity and specificity are high. Most experts feel that a screening protocol for ovarian cancer should have a positive predictive value of at least 10 percent. A screening program that targets all women over age 50 would require a test with a specificity of at least 99.6 percent (assuming a sensitivity of 80 percent) to achieve a positive predictive value of 10 percent. to achieve a PPV of 10 %

The overall SN for detection of OVCA (within a year of a screening):
MMS: 84% (95% CI 79–88; 199 of 237) USS: 73% (95% CI 66–79; 161 of 221) Proportion of “ early stages OVCA: I, II, and IIIa”: MMS: 40% (119 of 299; p<0·0001) USS: 24% (62 of 259; p=0·57) No screening: 26% (149 of 574) The mortality reduction over years 0–14 with the Cox model: MMS: 15% (95% CI: –3 to 30 ; p=0·10) USS: 11% (95% CI: –7 to 27 ; p=0·21) Not SS Jacobs I et al, Lancet Dec S (15)

UKCTOCS: the Kaplan-Meier cumulative death rates
The no screening group HR continues to rise The MMS HR starts levelling off, becoming substantially lower than that of the no screening group at about 7 years The USS HR levelling off at about 9 years Potential delayed effect of screening Jacobs I et al, Lancet Dec S (15)

The Kaplan-Meier cumulative death rates
The mortality: HRs was lower in the MMS Vs. no screening (20% [95% CI: –2 to 40],p=0·021) SS higher for: years 0–7: (8% [95% CI: –27 to 43]) years 7–14: (28% [95% CI: –3 to 49]) For each OCA or PPC detected by screening additional FP surgeries in: MMS: 2 (< 0.1%) (211 annual screens) USS: 10 (< 0.1%) (164 annual screens) Complication rate MMS: 3.1% or 15/488 (95% CI 1·7–5·0) USS: 3.5% or 57/1634 (95% CI 2·7–4.7) Jacobs I et al, Lancet Dec S (15)

Screen positive surgery and Histological finding
Performance characteristics of Invasive EOC/FT/PPC Screen positive surgery and Histological finding Slide 6 True Positives : MSS USS 105 Presented By Usha Menon at 2016 ASCO Annual Meeting

Screen positive surgery and Histological finding
Performance characteristics of Invasive EOC/FT/PPC Screen positive surgery and Histological finding Slide 7 False Positives: MSS USS 1719 Presented By Usha Menon at 2016 ASCO Annual Meeting

Presented By Usha Menon at 2016 ASCO Annual Meeting
Performance characteristics of Invasive EOC/FT/Peritoneal cancer diagnosed within one year of diagnosis Slide 8 Presented By Usha Menon at 2016 ASCO Annual Meeting

Invasive EOC/FT/Peritoneal ca diagnosed after randomization: 2001-2005
Screening till Dec FU till Dec Mean FU 11.1 years Proportion of all invasive Ca that were screen detected: MSS 60.2% USS 40.5% Presented By Usha Menon at 2016 ASCO Annual Meeting

P=0.002 as SS due to multiple comparisons
Stage Distribution of invasive EOC/FT/Peritoneal cancers ITT population Slide 10 SS higher % of earlier stages ca Vs control arm SS lower % of stages I/II/IIIA Vs. control arm P=0.002 as SS due to multiple comparisons Presented By Usha Menon at 2016 ASCO Annual Meeting

All are likely to be HGSOC Most are probably HGSOC
Invasive EOC/FT/Peritoneal cancers: Histological types All are likely to be HGSOC Most are probably HGSOC Presented By Usha Menon at 2016 ASCO Annual Meeting

No Stage shift in type I cancer in MMS Vs. Controls, USS Vs. Controls
Stage Distribution of Type I cancers Slide 12 No Stage shift in type I cancer in MMS Vs. Controls, USS Vs. Controls Presented By Usha Menon at 2016 ASCO Annual Meeting

Stage Distribution of Type II HGSOC cancers
Slide 13 SS Stage shift in type II cancer in MMS Vs. Controls P=0.002 as SS due to multiple comparisons Presented By Usha Menon at 2016 ASCO Annual Meeting

Invasive EOC/FT/Peritoneal ca Summary
MMS: SN of 86%, SP of 99.8% PPV of 24.5% with 4 surgeries/Invasive ca USS: SN of was 63% with 17 surgeries/Invasive ca Screen detected ca: SS stage shift for MMS: 44% and USS: 43% Vs control 26% All Cancers (ITT): SS Stage shift only with MMS 40% Vs control 26% Type I detected ca: No SS stage shift for MMS or USS% Vs control 83% Type II detected ca: SS stage shift for MMS both screen detected (37%) and ITT 33% Vs control (17%) Overall SS stage shift in MMS arm is a reflection of both higher sensitivity and better ability to detect Type II cancers earlier Presented By Usha Menon at 2016 ASCO Annual Meeting

The FDA recommends against using screening tests for ovarian cancer screening:
September 7, 2016 Based on currently available information, the FDA recommends against using currently offered tests to screen for ovarian cancer (false-positives and false-negatives) For women: (including those at increased risk) Currently, there is no safe and effective screening test Do not rely on screening test results to make health or treatment decisions Talk to your doctor about ways to reduce your risk (esp. with a family history) or are BRCA1 or BRCA2 muted For physicians: Do not recommend or use tests that claim to screen for ovarian cancer in the general population. Testing higher risk asymptomatic patients has no proven benefit and is not a substitute for preventive actions that may reduce their risk.

28 Million £ Down The Drain
Abcodia Statement on the ROCA® Test for Ovarian Cancer Screening October 2016 Abcodia acknowledges the recent statement issued by the U.S. FDA regarding the use of blood tests for ovarian cancer screening. Notwithstanding our confidence in the clinical utility of the ROCA® Test, we are voluntarily choosing to temporarily suspend its commercial availability in the US and the UK.

If you look like some of them: I am in trouble

Part II Screening for Ovarian Cancer in Women with High Genetic Risk for Ovarian Cancer

Screening for Ovarian Cancer U. S
Screening for Ovarian Cancer U.S. Preventive Services Task Force Recommendation (USPSTF): September 2012 Population Asymptomatic women with known genetic mutations that increase risk for ovarian cancer Risk Assessment Women are at increased risk if they have: BRCA1 and BRCA2 genetic mutations Lynch syndrome Family history of OVCA Women with an increased-risk family history should be considered for genetic counseling: Having > 2 1rst- or 2nd-degree relatives with a history of OVCA or a combination of BCA and OVCA Of Ashkenazi Jewish descent: having a 1rst-degree relative (or 2 2nd-degree relatives on the same side of the family) with BCA & OVCA Screening Tests TVUS and CA–125 testing are the suggested screening modalities. Relevant USPSTF Recommendations

Ovarian Cancer Screening in High Risk women 3 Pending Trials
ROCA trial in High Risk women (NCI’s Cancer Genetics Network, the Early Detection Research Network, Ovarian Specialized Program on Research Excellence): Single-arm trial of 2400 High Risk women > 30 yrs, initiated in 2001 CA125 tests are scheduled every 3 months (results pending) GOC 0199: 2-arm prospective study begun in 2003 of women at High Risk women Chose between RR-BSO and screening with ROCA ~ 1600 women chose ROCA During the course of the study, ~ 400 screening patients switched to RR BSO Data pending UKFOCSS in 2 phases: Steven J. Skates. Int J Gynecol Cancer 2012;22: S24YS26

Adam N. Rosenthal et al ESGO 2013
United Kingdome Familial Ovarian Cancer Screening Study (UKFOCSS)- 42 centers Adam N. Rosenthal et al ESGO 2013

Ovarian Cancer Screening in the High-Risk Population United Kingdome Familial Ovarian Cancer Screening Study (UKFOCSS) UKFOCSS in 2 phases: 1rst : initiated in 2002 on 4,531 high-risk women, screened with an annual CA125 >35 U/mL 2nd: 4531 women at an estimated ≥10% lifetime risk of OC/FTC begun in 2007: At baseline, their mean age was 44.6 years All women were counseled that RR BSO was recommended UKFOCSS Phase II Study design High Risk women > 35 yrs Assess menopausal status CA 125 every 4 months 15% every 4 months ROCA Return to Annual screening if ROCA OK Refer to Gynecologic Oncologist if TVUS abnormal or ROCA is high Adam N. Rosenthal et al ESGO 2013

Adam N. Rosenthal et al ESGO 2013
Ovarian Cancer Screening in the High-Risk Population United Kingdome Familial Ovarian Cancer Screening Study (UKFOCSS) 18 incident OVCA/FTCA: 6/18 were occult discovered at RR BSO No symptomatic cancers Sensitivity: 100% ( %) if occult cancers are counted as TP 67% (41%-87%) if classified as FN PPV: 13% (7-22%) NPV: 100% (99-100%) Cancers detected: 26% incident screen-detected OC/FTC were stage IIIC vs. 85.7% on annual screening (UK FOCSS Phase 1) (p=0.009) 92% were completely cyto-reduced on Phase 2 vs. 62% on Phase 1 (p=0.16) Adam N. Rosenthal et al ESGO 2013

Ovarian Cancer Screening in the High-Risk Population United Kingdome Familial Ovarian Cancer Screening Study (UKFOCSS) Conclusions: 4-monthly ROCA-based screening: had high sensitivity for OC/FTC was associated with high complete cytoreduction rates failed to detect the majority of OC/FTC at early stage These results are encouraging but screening cannot currently be considered a safe alternative to RRSO Adam N. Rosenthal et al. 18th ESGO Oct 2013

Part III Estimating the Risk of epithelial ovarian cancer in women presenting with a pelvic mass

Diagnostic Value of Serum Human Epididymis Protein 4 (HE4) in OVCA A Systematic Review and Meta-Analysis (HE4), a precursor of human epididymis protein. Recently identified as a new promising serum biomarker for ovarian carcinoma. A systematic review of a total of 9 studies involving 1807 women When the control group was composed of healthy women for diagnosing ovarian cancer: pooled sensitivity: 83% (95% CI, 77%Y88%) specificity : 90% (95% CI, 87%Y92%) . The area under the SROC curve was When the control group was composed of women with benign disease pooled sensitivity: 74% (95% CI, 69%Y78%) Specificity: 90% (95% CI, 87%Y92%). The area under the SROC curve was Conclusions: HE4 may be a valuable marker in the diagnosis of ovarian carcinoma: useful preoperative test for predicting the benign or malignant nature of pelvic masses Has a potential to be used as an initial step in ovarian cancer screening strategy Li Wu et al Int J Gynecol Cancer 2012;22: 1106Y1112

Risk of Ovarian Malignancy Algorithm (ROMA) Classifies patients as being low or high risk for malignant disease Uses the ratio of CA125 and HE4 to calculate the ROMA depending on the menopausal status Premenopausal Postmenopausal ≥ 7.4% High risk of finding EOC ≥ 25.3% High risk of finding EOC < 7.4% Low risk of finding EOC < 25.3% Low risk of finding EOC Menopausal Status Disease Sensitivity Specificity PPV NPV Combined Benign + Cancer Total 87.3% 75.3% 60.6% 93.2% Premenopausal 79.4% 75.4% 36.0% 95.5% Postmenopausal 89.7% 75.2% 73.8% 90.3% Li Wu et al Int J Gynecol Cancer 2012;22: 1106Y1112

Risk of Malignancy Index (RMI) Classifies patients as being low or high risk for malignant disease
RMI is a product of U/S score (U), menopausal status (M) and CA125 level (IU/ml): RMI = U x M x CA125 The U/S is scored 1 point for each of the following characteristics: multilocular cysts, solid areas metastases, ascites bilateral lesions U = 0 (for U/S score of 0), U = 1 (for U/S score of 1), U = 3 (for U/S score of 2–5) The menopausal status is scored as: 1 = pre-menopausal and 3 = post-menopausal (no period for more than 1 year or a woman over 50 who has had a hysterectomy) Serum CA125 is measured in IU/ml

Ovarian Tumor Index (OTI) Classifies patients as being low or high risk for malignant disease
Combines Patient’s age Specific TVUS markers Doppler velocimetry Color-flow mapping Continuous US variables included: Ovarian volume Sassone morphology scale Doppler determination of angle-corrected systole, diastole, and time-averaged velocity Patient’s age The Doppler pulsatility index (PI), vessel location, presence of a diastolic notch, and echogenic predominance of the lesion, suggestive of dermoid, also were assessed

Ovarian Tumor Index (OTI) Classifies patients as being low or high risk for malignant disease
Of 244 women 214 had nonmalignant findings (85 of which were benign neoplasm) 30 had malignant neoplasms Age and all U/S continuous variables except systole were found to be statistically significant (P < 0.05) between: Malignant (N = 30) Vs nonmalignant masses (N = 214) Malignant (N = 30) Vs benign neoplasms( N = 85) A ROC (area under the curve = 0.91) : was generated by adding the continuous measures (age [in years], ovarian volume [mL], and Sassone morphology scale [1–15]) and weighting other variables ([−10] × PI, central or septal location [+10], peripheral location [−10], and echogenic [−10]) was found to be discriminating, predictive, and able to replicate the more complex logistic regression model Prediction of malignancy was generated from the population-based data of the current study.

Comparison of ROMA, RMI, & OTI in patients with adnexal mass
Objectives: To compare of ROMA, RMI, OTI indexes in patients with adnexal mass Methods: 51 patients with adnexal mass: surgery done when suspicious for malignancy Demographic and clinical characteristics of the patients were identified Morphological scores calculated via gray-scale and Doppler ultrasonography Pre-operatively blood samples were taken to assess CA 125 and HE4 levels Scores of ROMA, RMI and OTI were calculated of all the cases Compared each other to SN, SP, PPV and NPV to detect the malignancy Results: 43 of the adnexal mass were benign, 2 were borderline and 6 were malignant The mean of age of patients with: Benign mass: ±14,9 yrs Malignant mass: ±17,16 yrs (p=0,029) Tevfik Guvenal et al. ESGO 2013

Comparison of ROMA, RMI, & OTI in patients with adnexal mass
Pre-menopausal patients Post-menopausal patients SN SP PPV NPV ROMA score 50% 100% 96.5 92.8% 85.7% 96.5% sensitivity specificity PPV NPV RMI score 87.5% 100% 97.6% OTI Score 79% 57.1% Conclusions: ROMA index was more sensitive and specific in postmenopausal patient group rather than other tests ROMA index is better on detecting malignant masses at postmenopausal patients and benign masses on premenopausal patients OTI is also has a remarkable sensitivity though the specificity is not enough at all Tevfik Guvenal et al. ESGO 2013

Ovarian Cancer: To Screen or not to screen? Conclusions
Need to identify specific symptoms for OVCa Need to control for systemic therapy and type of surgery CA 125 and ROCA: high specificity and PPV decreasing unnecessary procedures Early stage detection is cost effective Waiting on UKCTOCS for its main outcome (UKOPS) (PLCO) (ROCA) (UKCTOCS)

Ovarian Malignancy Risk Stratification of the Adnexal Mass Using a Multivariate Index Assay
Several prediction models and referral guidelines have been investigated to assist in the diagnostic triage of women with an adnexal mass and determine the need for gynecologic oncology referral, but none has received widespread acceptance. a diagnostic multiple biomarker test, the multivariate index assay (OVA1) marketed by Vermillion, was developed to assist in the diagnostic triage of women with an adnexal mass In 2011, a pivotal trial examined the predictive value of OVA1 for ovarian malignancy; it contained a mix of subjects enrolled by both gynecologists and gynecologic-oncologists the overall prevalence of ovarian malignancy was 29%. Robert E. Bristow et al Gynecol Oncol 2013;128:252Y259

Ovarian Malignancy Risk Stratification of the Adnexal Mass Using a Multivariate Index Assay
A multi-institutional trial was to investigate the effectiveness of OVA1 for identifying ovarian malignancy among an intended-use cohort of women undergoing surgery for an adnexal mass after enrollment by non-gyn oncologists The predictive performance of OVA1 was compared with that of clinical assessment and serum CA125-II. The comparative sensitivity of each method for detecting malignancy was stratified according to histology, stage of disease, and menopausal status. 494 patients were evaluable for OVA1 and CA125-II and clinical impression A pelvic malignancy was found in 92 (18.6%): Ovarian cancer in 65 (13.2%), with 43.1% having stage I Combined with clinical impression, the sensitivity of OVA1 in detecting OVCA was 95.7% (95% CI, 89.3%Y98.3%) OVA1 had higher sensitivity than CA125-II in detecting OVCA among women with early-stage disease 91.4% [95% CI, 77.6%Y97.0%] vs CA125-II, 65.7% [95% CI, 49.2%Y79.2%] OVA1 correctly identified 83.3% of malignancies missed by clinical impression and 70.8% of cases missed by CA125-II Both clinical impression and CA125-II were more accurate than OVA1 for identifying benign disease: When combined with clinical impression, OVA1 correctly identified benign pathology in 204 of 402 patients (specificity, 50.7%; 95% CI, 45.9%Y55.6%) Robert E. Bristow et al Gynecol Oncol 2013;128:252Y259

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