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  • The subject of today’s presentation is the Risk of Ovarian Malignancy Algorithm, or ROMA – and it’s a tool for assessing the risk of ovarian cancer in women scheduled for surgery for pelvic mass.
  • This test can be used to stratify women with pelvic mass into subgroups of high and low risk of harboring ovarian cancer.
    This will provide more useful information to ensure that patients are treated by the right surgeon in the right facility.
    ROMA is not intended to be used as a stand-alone test – it is intended to be used in conjunction with current methods of identifying ovarian cancer risk, such as family history, physical exam and imaging as described in various published guidelines.
  • Today’s presentation will demonstrate that the application of HE4 in combination with CA125 in the ROMA algorithm has the potential to increase the survival of women with ovarian cancer.
    It may also improve treatment for women with non-malignant diseases by assisting in the referral of patients to the optimal specialist for their care.
  • The idea behind developing a multiple marker assay for ovarian cancer risk assessment arose from the fact that many women do not receive optimal care for their disease.
    What is needed is a better way to identify women who are at high risk for having ovarian cancer in order to improve their care and increase survival for this disease.
    But before going over the study results let’s spend some time examining the unmet medical needs that women with pelvic masses and ovarian cancer face that can be addressed by a more accurate risk assessment tool such as the multiple marker assay or ROMA test that we will present today.
  • Ovarian cancer remains one of the deadliest of all cancers.
    GLOBOCAN estimates approximately 205,000 new cases, resulting in 125,000 deaths.
    Ovarian cancer is the number one cause of gynecologic cancer deaths, and the fifth leading cause of all cancer deaths in women.
    Unfortunately, ovarian cancer incident rates are either stable, or in some reports, slowly increasing.
  • The women at highest risk for being diagnosed with ovarian cancer are women that present with a pelvic mass or ovarian cyst.
    In the US it is estimated that 1 in 5 women will be diagnosed with an ovarian cyst or adnexal mass sometime in their lifetime;
    And that up to 200,000 women will undergo surgery for an ovarian neoplasm each year in the US.
    Roughly 13% to 21% of these women will be diagnosed with an invasive epithelial ovarian cancer.
  • We know that women who are diagnosed with early stage disease are fundamentally curable.
    And the 5-year survival rate for Stage 1 ovarian cancer is as high as 93%.
    However, the majority of women – more than 70 % -- will have advanced stage ovarian cancer at the time of their diagnosis and we see the survival rate dramatically decreases to about 40% for these women
    So how can we affect survival for women who will be diagnosed with ovarian cancer?
  • Survival can be increased through prevention, screening, early detection, surgery and chemotherapy.
    Unfortunately, we currently do not have effective prevention, screening or early detection methods readily available to us.
    However, it has been shown that appropriate surgical management can increase survival for women diagnosed with ovarian cancer and this is a tool that should be readily available to all cancer patients.
  • To contrast the impact of advances in chemotherapy and surgery for ovarian cancer patients we see that….
    Over the last 20 years, improved chemotherapy drugs and routes of delivery have resulted in up to a 16 month improvement in survival.
    And that with comprehensive surgery, including optimal tumor debulking and surgical staging, performed by gynecologic oncologist, survival can be increased by at least 12 months.
    With this in mind we have the ability today, this very moment, to impact positively survival rates for thousands of women diagnosed with ovarian cancer just by making sure these patients have optimal ovarian cancer surgery by surgeons experienced in the management of ovarian cancer.
  • Currently, the optimal care for ovarian cancer is cytoreductive surgery, with the goal of complete tumor resection.
    Or, for patients with apparent clinical early stage disease to undergo extensive surgical staging, which helps to:
    define the extent of disease;
    determine the need for adjuvant chemotherapy;
    provide a prognosis for the patient; and outline a plan of care.
  • Studies have also demonstrated that aggressive surgical debulking can improve survival for women with ovarian cancer.
    So what is an optimal surgical debulking?
    Surgical debulking is the removal of all visible tumor to less than 1cm in size and to achieve this, extensive surgical procedures such as bowel resection, diaphragmatic stripping and even splenectomy are performed in order to remove all tumor.
    These surgeries can be difficult and highly technical and require surgeons that are specially trained and experienced in ovarian cancer debulking.
  • The surgeons trained in ovarian cancer surgery are Gynecologic Oncologists.
    In the United States, gynecologic oncologists start with a residency and board certification in obstetrics and gynecology, and the complete a fellowship and board certification in gynecologic oncology.
    Outside of the United States, there is no formal fellowship program or board certification for gynecologic oncology, rather it is typically a gynecologist who is experienced ovarian cancer surgery.
    Gynecologic oncologists specialize in the surgical and medical management of ovarian cancer patients. They perform surgery, administer chemotherapy and understand the natural history of ovarian cancer.
  • In 2007, Goff and colleagues, in a multi-state study, reported that gynecologic oncologists more often completed a comprehensive ovarian cancer surgery when compared with gynecologists or general surgeons.
    Gynecologic oncologists performed comprehensive surgery twice as frequently as any other surgeons.
  • Goff also looked at outcomes with high volume surgeons, who are typically gynecologic oncologists.
    They found that high volume surgeons were more likely to perform a comprehensive ovarian cancer surgery when compared to low or medium volume surgeons.
  • When examining the types of hospitals where ovarian cancer patients had their initial surgery, less than 50% of women in the US had their surgery at a high volume hospital, a hospital where the rate of comprehensive ovarian cancer surgery is the highest.
    A third of patients had their surgery at a low volume hospital where about half of these patients had a sub optimal ovarian cancer surgery.
  • In another study, Paulsen demonstrated a significant survival advantage for ovarian cancer patients that were operated on by gynecologic oncologists, compared with patients operated on by gynecologists or general surgeons.
    As well, patients whose surgery was performed at a tertiary care hospital – versus a community hospital – also had a significant survival advantage.
  • In fact, there are many other separate studies with similar findings demonstrating a survival advantage of up to 18 months for ovarian cancer patients operated on by a gynecologic oncologist.
  • In a meta-analysis of 53 studies with over 6,500 patients, it was found that optimal cytoreductive surgery increased survival by up to 1 year or a 50% increase.
    There is no doubt that the type of surgery, the type of surgeon and the institution where a woman with ovarian cancer is treated will improve her survival.
  • Yet, in the US only half of women with ovarian cancer are operated on by high volume surgeons, at high volume centers, even though the data demonstrates their survival rates and outcomes will be improved when they are cared for by multidisciplinary teams and at centers experienced in the care of ovarian cancer patients.
    So how do we get patients to the right surgeons and centers?
    How do we assess a patient’s risk for ovarian cancer?
  • Currently, the tools available to clinicians for assessing risk of malignancy in women presenting with a pelvic mass include: history and physical exam, imaging modalities, and tumor markers, such as CA125.
    The question is, can these tools be improved to ensure that more women get the right treatment by the right surgeon in the right place?
  • We have seen that only 50% of women with ovarian cancer are operated on by high volume surgeons or at high volume centers.
    And that survival rates are improved when ovarian cancer patients have surgery by surgeons and at centers experienced in the management of ovarian cancer patients.
    With more accurate risk assessment tools, we will enable more ovarian cancer patients to have comprehensive surgeries by oncology specialists at multidisciplinary centers that specialize in cancer care.
    If we can get more of the right patients to the right surgeons and the right hospitals, we can improve survival right now.
    We don’t have to wait for improvements in chemotherapy, we don’t have to wait for prevention, screening and early detection. We can take immediate steps today to improve survival rates for women with this deadly disease.
  • Every year, in the U.S., somewhere between 250 and 300 thousand women will undergo surgery for a pelvic mass.
    As has been presented, in order to provide the best possible care for these women, we need more and better tools to assess their risk for having ovarian cancer.
    I will now talk about the Risk of Ovarian Malignancy Algorithm, or ROMA, was validated. ROMA that may be beneficial to patients.
  • A pivotal trial was conducted in the US to validate ROMA.
    This was a multi-center national trial.
  • The objective of this trial was to validate a predictive model utilizing HE4 and CA125 and to assess the risk for epithelial ovarian cancer in women with a pelvic mass.
  • The study was conducted in 14 geographically dispersed centers across the US.
    Most of the sites had divisions of gynecologic oncology, within departments of obstetrics and gynecology.
    This allowed us to enrich the study population with patients with ovarian cancer, to achieve statistical power.
    Also, by using sites with gynecologic oncologists, all patients diagnosed with an ovarian cancer were able to have surgical staging as required by the protocol.
  • This was a prospective, double-blind, multicenter trial.
    All patients were required to be 18 years of age or older;
    They all had a documented ovarian cyst or mass on imaging, with a planned surgical intervention.
    Patients that were diagnosed with an ovarian malignancy were to be surgically staged as part of the protocol.
    All blood samples were obtained preoperatively.
    We used a central pathology review to confirm pathology.
  • 566 patients were enrolled into the study, of which 530 or 94% were evaluable.
    There were 246 premenopausal patients and 284 post menopausal patients.
    Now let’s look at the pathology distribution of all the cases……
  • When the disease distribution was examined, it was found that 66% of the patients had benign disease, 24% of the patients were diagnosed with invasive EOC and that 4% had LMP tumors and 6% had other types of malignancies.
  • Similarly, when examining the patients with benign disease in the study cohort, you see that the spectrum of pathology is what we would typically find in patients with a benign pelvic mass or ovarian cyst.
    For instance, you see a higher incidence of endometriosis in the premenopausal group, and a higher incidence of serous cystadenomas in the postmenopausal group.
  • Similarly, the stage distribution for all the invasive ovarian cancers in the cohort was similar to what you would expect to find in a population of women diagnosed with invasive EOC.
    13% of patients were diagnosed with Stage I disease, 14% with Stage II, 65% with Stage III and 5% with Stage IV disease. Only 3% of patients were unstaged.
    Now let’s look at the results of the ROMA risk stratification of patients into high and low risk groups.
  • When examining all pre and postmenopausal women with either benign disease, invasive EOC or LMP tumors,
    You see that 262 patients with benign disease were classified to the low risk group, and that 89 patients with benign disease were classified to the high risk group representing a false positive test.
    When examining women diagnosed with an invasive EOC or LMP tumor, you find that ROMA classified 134 patients into the high risk group and only 17 patients with an invasive EOC or LMP tumor were classified to the low risk group representing a false negative test.
    This provided a sensitivity of 89% at a set specificity of 75% and a PPV of 60% with a NPV of 94%.
    Now lets look at a breakdown of the patients with invasive EOC and LMP tumors that had false negative tests….
  • You see that in the postmenopausal group, 3 out of the 9 patients had LMP tumors, and that only 6 EOC had a false negative test and therefore 95% of postmenopausal patients with an invasive EOC were correctly identified.
    In the premenopausal group, 6 out of the 8 patients had LMP tumors and only 2 patients with EOC had a false negative test and therefore 89% of the premenopausal patients with an invasive EOC were correctly identified.
    When examining all patients together, only 8 of 129 patients with an invasive EOC had a false negative test -- and therefore 94% of all EOCs in the trial -- were correctly identified.
    This is an important finding because over half of the patients with a false negative test had LMP tumors, where the clinical effect of a false negative test is minimal compared with that for an invasive epithelial ovarian cancer.
  • When you examine stratification by stage of invasive epithelial ovarian cancer, we see that ROMA correctly classified 86% of all early stage I & II invasive epithelial ovarian cancer and nearly all the late stage III and IV ovarian cancers.
    This is in stark contrast to the historical rate for CA125, where only half of early stage EOC have elevated CA125 and where only 80% of all EOC have an elevated CA125.
  • Let’s examine how ROMA performs compared with risk assessment tools currently used in clinical practice.
    An algorithm that is used either formally or informally by clinicians to assess risk in a patient with a pelvic mass is the Risk of Malignancy Index or RMI developed by Ian Jacobs.
    The RMI employs an imaging score along with CA125 values and menopausal status to calculate a risk for malignancy. This is an algorithm that employs clinical findings on imaging and uses quantitative data to derive a patient’s risk for malignancy.
    ROMA was comparied to the RMI, which uses clinicopathologic variables to demonstrate that the performance of ROMA as a stand-alone test is superior to a currently used clinical algorithm.
  • An RMI calculation was made using a combination of US, CT scan and MRI for 80% of the study patients.
    The RMI values obtained were compared to the ROMA results for those individual patients.
    When Benign and invasive EOC was examined……
  • At a specificity of 75%, the ROMA had a sensitivity of 94%, compared to the RMI, which achieved a sensitivity of 85%.
    This difference was found to be statistically significant.
  • When you look at early stage I & II invasive EOC patients, the ROMA achieved a sensitivity of 86%, compared with a sensitivity of only 66% for the RMI.
    This difference approached statistical significance with a p value of 0.05.
  • So, we’ve seen that ROMA correctly identifies 94% of all patients with epithelial ovarian cancer;
    And, that ROMA alone performs better than the RMI.
    In addition, the ROMA is a simple, easy to use quantitative test without the use of subjective data.
    ROMA provides a risk assessment tool that is easy to interpret and we believe will be helpful to physicians in evaluating their patients and beneficial to patients by addressing the unmet medical need we discussed earlier.
    ROMA will be a valuable addition to the tools we currently use to assess risk.
  • Persistent abdominal pain or bloating, urinary symptoms, change in bowel habits may herald onset.
  • BG32
  • BG35
    The stats are 25 years old. Should we find a more up-to-date reference?
  • BG36
  • ACOG has recommended that patients with a pelvic mass and considered to be at increased risk for ovarian cancer be referred to a gynecologic oncologist.
    In their referral guidelines, a patient with an adnexal mass and one or more of the following risk factors, should be referred.
  • Transcript

    • 1. C- 1 A New Test for Assessing the Risk of Ovarian Cancer in Women with Adnexal Mass Presenter Place Date
    • 2. C- 2 Ovarian Cancer is a Major Women's Health Problem • High morbidity and mortality • Appropriate treatment improves survival1 – Oncology specialists – High volume centers • Need better risk assessment tools 1 ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
    • 3. C- 3 ROMA™: A Novel Ovarian Cancer Risk Assessment Tool • Evaluated 15 biomarkers including HE4, which is: – Putative protease inhibitor – CE-Marked and available for clinical use • Assess Risk of ovarian cancer in patients with Pelvic Mass • Monitor patients with ovarian cancer – Expressed in reproductive, respiratory tissues – Complementary to CA 125 • Developed ROMA™ – 89% sensitive1 – 75% specific1 1 FDI-03 Clinical Study Report.
    • 4. C- 4 ROMA™: A Novel Ovarian Cancer Risk Assessment Tool • Stratify risk of ovarian cancer • Ensure treatment by right surgeon/right facility • Used in conjunction with other Dx methods • Not intended for detection or screening
    • 5. C- 5 ROMA™ Will Improve Treatment of Women with Adnexal Mass
    • 6. C- 6 Agenda • Ovarian Cancer Risk Assessment • ROMA™ Development • Multicenter Validation Trial • Conclusion and Summary
    • 7. C- 7 Ovarian Cancer Risk Assessment
    • 8. C- 8 Need New Tools to Better Assess Ovarian Cancer Risk
    • 9. C- 9 Ovarian Cancer is a Deadly Disease • 204,499 new cases in 2008 • 124,860 deaths • Leading cause of gynecologic cancer deaths • 5th leading cause of cancer deaths in women International Agency for Research on Cancer. Globocan 2002. http://www-dep.iarc.fr/
    • 10. C- 10 1 in 5 Women will have a Pelvic Mass • 20% of women will be diagnosed with an adnexal mass1 • 5 - 10% of women will have surgery for an ovarian neoplasm (100,000 to 200,000)2 • 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.
    • 11. C- 11 Survival Rates for Ovarian Cancer Need to be Improved Ovarian Cancer 5-yr Survival Rate by Stage Stage Distribution at Diagnosis Survival Rate Stage I 20-27% 73-93% Stage II 5-10% 45-70% Stage III 52-58% 21-37% Stage IV 11-17% 11-25% Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 :107-138. Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10.
    • 12. C- 12 How can we Affect Ovarian Cancer Survival? • Prevention • Screening • Early detection • Surgery • Chemotherapeutic agents
    • 13. C- 13 Surgery can Impact Survival • Cytoxan to Paclitaxel – 14 month survival advantage1 • Intravenous to Intraperitoneal – 16 month survival advantage2 • Surgery by gynecologic oncologist – 12 month survival advantage3,4 1 McGuire WP et al. NEJM. 1996;334(1):1-6. 2 Armstrong DK et al. NEJM. 2006;354(1):34-43. 3 Engelen MJA et al. Cancer. 2006;106(3):589-598. 4 Bristow RE et al. J Clin Oncol. 2002;20(5):1248-1259
    • 14. C- 14 The Optimal Care for Ovarian Cancer • Cytoreductive surgery with complete surgical staging • Rationale for surgical staging: – Define the extent of disease – Determine the need for adjuvant treatment – Provide prognosis – Outline a plan of care
    • 15. C- 15 Surgical Debulking Increases Survival for Ovarian Cancer Optimal surgical debulking can include: • Hysterectomy • Removal of ovaries • Bowel resection • Peritoneal stripping • Diaphragmatic stripping • Lymph node debulking
    • 16. C- 16 Gynecologic Oncologists are Ovarian Cancer Specialists • Gynecologic oncologist – Recognized sub-specialty in US • Residency in Obstetrics and Gynecology (4 yrs) • Fellowship in Gynecologic Oncology (3-4 yrs) – Outside US Gynecologists with high oncology surgical volume • Experienced in: – Surgical care – Medical management – Chemotherapy – Natural history
    • 17. C- 17 Oncology Specialist Most Likely to Perform Comprehensive Surgery *Ovarian Cancer Surgery by: Surgeon Surgeon Specialty Rate of Comprehensive Surgery Gynecologic oncologist 75.7% Obstetrician gynecologist 37.3% General surgeon 38.5% Goff BA et al. Cancer. 2007;109(10):2031-2042. * South Carolina admissions
    • 18. C- 18 High Volume Surgeons Most Likely to Perform Comprehensive Surgery Ovarian Cancer Surgery by: Surgeon Surgery Volume Percentage of Cases Rate of Comprehensive Surgery Very Low 1 case/year 25.2% 55.2% Low / Medium 2-9 cases/year 22.7% 65.1% High ≥ 10 cases/year 52.1% 75.2% Goff BA et al. Cancer. 2007;109(10):2031-2042.
    • 19. C- 19 Less than Half of Ovarian Cancer Surgery is at High Volume Hospital Ovarian Cancer Surgery by: Hospital Surgery Volume Percentage of Cases Rate of Comprehensive Surgery Low 1-9 cases/year 33.3% 57.4% Medium 10-19 cases/year 18.1% 69.5% High ≥ 20 cases/year 48.6% 73.7% Goff BA et al. Cancer. 2007;109(10):2031-2042.
    • 20. C- 20 Significantly Higher Survival Rates with Oncology Specialists 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 Survival in days CumulativeSurvival 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 Survival in days CumulativeSurvival Type of Surgeon Impacts Survival Rates Type of Hospital Impacts Survival Rates Paulsen T et al. Int J Gynecol Cancer. 2006;16(Suppl 1):11-17. TH: Teaching hospital NTH: Nonteaching hospital
    • 21. C- 21 Significantly Higher Survival Rates with Oncology Specialists Study Gynecologic Oncologists Gynecologists/ General Surgeons p value Eisenkop 1992 35 months 17 months <0.001 Junor 1999 18 months 13 months <0.005 Carney 2002 26 months 15 months <0.01 Tingulstad 2003 21 months 12 months 0.01 Eisenkop SM et al. Gynecol Oncol. 1992;47(2):203-209. Junor EJ et al. Br J Obstet Gynaecol. 1999;106(11):1130-1136. Carney ME et al. Gynecol Oncol. 2002;84:36-42. Tingulstad S et al. Obstet Gynecol. 2003;102(3):499-505.
    • 22. C- 22 Cytoreductive Surgery Increases Survival for Ovarian Cancer Patients Multiple studies and large meta-analyses have shown residual disease following surgery is the most significant prognostic factor: 53 studies, 6,885 patients Optimal cytoreduction ↑ survival from 22.7 to 33.9 months (50% ↑) Bristow RE et al. J Clin Oncol. 2002;20(5):1248-1259.
    • 23. C- 23 Current Practice is Sub-Optimal for Ovarian Cancer Patients • In the US only 50% of women with ovarian cancer are operated on by high volume surgeons or at high volume centers1 • Studies around the world show that survival rates are improved when patients have surgery by surgeons and at centers experienced in the management of ovarian cancer2 1 Goff BA et al. Cancer. 2007;109(10):2031-2042. 2 ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
    • 24. C- 24 Current Clinical Tools to Assess Risk of Ovarian Cancer • History • Physical exam • Imaging (US, CT and MRI) • Tumor markers (CA 125)
    • 25. C- 25 We can Improve the Care for Ovarian Cancer Patients • Better risk assessment • Improved patient care and management
    • 26. C- 26 Validation of ROMA™ as a Risk Assessment Tool and Patient Benefit
    • 27. C- 27 Development and Validation of ROMA™ • Two pilot studies combined to generate ROMA™ – Patients enrolled from: • Women and Infants’ Hospital, Providence RI • Massachusetts General Hospital, Boston MA • Pivotal trial (FDI-03) to validate ROMA™ – National trial – New patient cohort for validation
    • 28. C- 28 Primary Objective of Pivotal Trial • To validate a predictive model utilizing a dual marker assay of HE4 and CA 125 to assess the risk for epithelial ovarian cancer including borderline/low malignant potential tumors in women with a pelvic mass FDI-03 Clinical Study Report.
    • 29. C- 29 Pivotal Trial Study Sites Chosen to Enrich Ovarian Cancer Population • 14 geographically dispersed sites across the US • Divisions of Gynecologic Oncology, within Departments of Obstetrics and Gynecology • Sites chosen to enrich study population FDI-03 Clinical Study Report.
    • 30. C- 30 Pivotal Trial Methods • Prospective double-blind multicenter trial • Eligibility criteria: – ≥18 years of age – Ovarian cyst or a pelvic mass – Planned surgical intervention • All EOC patients to be surgically staged • All blood samples obtained preoperatively • Central pathology review FDI-03 Clinical Study Report.
    • 31. C- 31 Pivotal Trial Enrollment • 566 patients enrolled • 530 evaluable patients – 246 premenopausal – 284 postmenopausal • 94% of patients were evaluable FDI-03 Clinical Study Report.
    • 32. C- 32 Study Cohort Disease Distribution: Enriched for EOC Pivotal Trial: Pathology Distribution for All Cases Pathology Premenopausal (N) Postmenopausal (N) All Patients (N) Benign 200 151 351 (66%) Invasive EOC 18 111 129 (24%) LMP Tumors 16 6 22 (4%) Non EOC 6 0 6 (1%) Metastatic 5 9 14 (3%) Other Gyn 1 7 8 (2%) Total 246 284 530 FDI-03 Clinical Study Report.
    • 33. C- 33 Spectrum of Benign Disease as Expected Pathology Pre Post All % Serous cystadenoma/Cystadenoma 25 53 78 22.2 Endometriosis 42 2 44 12.5 Simple/Paratubal 34 21 55 15.7 Teratoma 18 11 29 8.3 Adenofibroma/Cystadenofibroma 6 16 22 6.3 Mucinous Cystadenoma 9 13 22 6.3 Leiomyoma 16 3 19 5.4 Fibroma/Fibrothecoma 3 15 18 5.1 Tubo-ovarian abscess/Hydrosalpinx 8 6 14 4.0 Functional cyst/Hemorrhagic cyst 14 0 14 4.0 Normal 3 2 5 1.4 Other 22 9 31 8.8 Total 200 151 351 100 Data on file, FDI.
    • 34. C- 34 Stage Distribution for EOC as Expected Invasive EOC Premenopausal (N) Postmenopausal (N) All Patients (N) Stage I 4 13 17 (13%) Stage II 3 15 18 (14%) Stage III 8 76 84 (65%) Stage IV 1 5 6 (5%) Unstaged 2 2 4 (3%) Total 18 111 129 Data on file, FDI.
    • 35. C- 35 Most Ovarian Cancers Correctly Classified All Patients: Distribution of Benign vs EOC + LMP Tumors Disease Low Risk (N) High Risk (N) All (N) Sensitivity Specificity PPV NPV Benign 262 89 351 89% 75% 60% 94% EOC + LMP 17 134 151 Total 279 223 502 FDI-03 Clinical Study Report.
    • 36. C- 36 Age Groups LMP EOC Stage % EOC incorrectly classified % EOC correctly classified I II III & IV Not Staged Postmenopausal (n=111) 3 1 3 1 1 5% 95% Premenopausal (n=18) 6 1 - - 1 11% 89% All Ages (n=129) 9 2 3 1 2 6% 94% Most Ovarian Cancers Correctly Classified FDI-03 Clinical Study Report.
    • 37. C- 37 Most Early Stage EOC Correctly Classified Correctly Identified Total Cases Percentage correctly Identified Stage I & II 30 35 86% Stage III & IV 89 90 99% All Invasive EOC* 121 129 94% *All EOC including unstaged EOC FDI-03 Clinical Study Report.
    • 38. C- 38 ROMA™ vs RMI Risk of Malignancy Index (RMI) RMI = U x M x serum CA 125 level U = 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 Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929.
    • 39. C- 39 Secondary Analysis of ROMA™ vs RMI • Able to calculate an RMI for 80% of patients • Utilized US, CT scans and MRI results for RMI imaging scores
    • 40. C- 40 ROMA™ has Increased Sensitivity Compared with RMI Pre & Post Menopausal Benign (n=315) vs EOC (n=124) Sensitivity* (95% CI) Specificity (95% CI) RMI 85% (77% to 90%) 75% (70% to 80%) ROMA™ 94% (89% to 98%) 75% (70% to 80%) Benign and EOC: All Stages *Two Sample Test of Equality of Proportions p=0.0129 CI: Confidence Interval Data on file, FDI.
    • 41. C- 41 ROMA™ has Increased Sensitivity vs RMI for Early Stage Cancer Pre & Post Menopausal Benign (n=315) vs Stage I-II EOC (n=35) Sensitivity* (95% CI) Specificity (95% CI) RMI 66% (48% to 81%) 75% (70% to 80%) ROMA™ 86% (70% to 95%) 75% (70% to 80%) Benign and EOC: Stage I & II *Two Sample Test of Equality of Proportions p=0.0510 CI: Confidence Interval Data on file, FDI.
    • 42. C- 42 ROMA™ Demonstrates Superior Performance • Correctly identifies 94% of EOC1 • Performs better than RMI • Simple and easy to use • Quantitative test • No subjective data • Assigns a risk for malignancy Data on file, FDI.
    • 43. C- 43 Additional Slides
    • 44. C- 44 Ovarian Cancer Epidemiology • Age adjusted incidence is 2 to 15 cases per 100,000 women • Incidence rates are stable or slowly increasing
    • 45. C- 45 Surgical Staging • The current standard of care for ovarian cancer is cytoreductive surgery with complete surgical staging. • Complete surgical staging includes: – Laparotomy – Hysterectomy – Bilateral salpingo-oophorectomy – Careful evaluation of all peritoneal surfaces – Multiple washings for cytology – Multiple peritoneal biopsies – Hepatic and diaphragmatic cytology – Omentectomy – Pelvic and periaortic lymphadenectomy • Less than 50% of women undergoing surgery for an ovarian cancer will have an adequate staging or cytoreductive surgery1,2 . Gynecologic Oncologists are trained in staging of ovarian cancer. 1 Carney ME et al. Gynecol Oncol. 2002;84:36-42. 2 McGowan L et al. Obstet Gynecol. 1985;65(4):568-572.
    • 46. C- 46 Ovarian Cancer • Age at presentation is bimodal with peaks at age 40 and 60 years old • Symptoms often are nonspecific: – Abdominal bloating – Pelvic pressure – GI symptoms – Respiratory – Constitutional
    • 47. C- 47 EDRN “Top Ten” Biomarkers for Detection of Ovarian Cancer • CA 125 • HE4 • CA 15-3 • CA 72-4 • B7-H4 (Ov- 110) • Transthyretin • IGFBP-2 • SMRP (Mesomark™) • HK6 • Cytokeratin 19 (CYFRA 21-1)
    • 48. C- 48 CA 125 • “Gold Standard” biomarker in ovarian cancer • Elevated CA 125 in 50% of Stage I disease and 80% of epithelial ovarian cancers1 • Elevated in the pre-clinical asymptomatic phase of the disease Limitations – Elevated levels in benign gynecological disease1,2 – Low sensitivity in Stage I ovarian cancer – CA 125 alone is not a sensitive marker HE4 • A commonly up-regulated biomarker in ovarian cancer • Serum HE4 is a useful biomarker in the early diagnosis of ovarian cancer Biomarkers for Ovarian Cancer 1 NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14. 2 ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
    • 49. C- 50 Genetic Risk Factors for Ovarian Cancer • BRCA 1 (17q21) • BRCA 2 (13q12) • P53 (17q13) • PTEN (10q24) • HNPCC – MLH 1 (3p21) – MSH 2 (2p16) – PMS 1 (2q31) – PMS 2 (7p22) Only 10% of ovarian cancers are inherited
    • 50. C- 51 Ultrasound Assessment of Pelvic Mass • Limitations of Ultrasound – Not all morphologic variables are commonly reported or measured – User variability (tertiary care vs community) – Ultrasound reporting is not standardized – Quality and complexity of machine (e.g. Doppler) – Complex algorithms Moore RG et al. J Clin Oncol. 2007;25:4159-4161.
    • 51. C- 52 Preoperative Differentiation of Benign and Malignant Pelvic Masses • To evaluate the risk of a malignancy • To determine the need for surgery • To triage patients • To Improve the quality of care for patients – Allow patients to stay in their community – Appropriate patients referred to specialists • Medical-legal implications
    • 52. C- 53 Epidemiologic Risk Factors for Ovarian Cancer • Age • Early age at menarche • Late age at menopause • Nulliparity • Infertility • Caucasian race • History of endometriosis ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
    • 53. C- 54 Surgical Staging Surgical Staging by Specialty Study Gynecologic Oncologist Gynecologist General surgeon Earle 2006 60% (nodes) 118/198 36% (nodes) 146/409 16% (nodes) 23/144 Engelen 2006 61% (nodes) 40/65 30% (nodes) 41/135 - Grossi 2002 47% (ext staging) 15% (ext staging) 0% (ext staging) Earle CC et al. J Ntl Cancer Inst. 2006;25:172-180. Engelen MJA et al. Cancer. 2006;106:589-598. Grossi M et al. MJA..2002;177:11-16.
    • 54. C- 55 Ultrasound and CA125 RMI Score Sensitivity (%) Specificity (%) Likelihood ratio for malignancy if result is: Positive Negative 25 100 62.2 2.7 0.00 50 95.1 76.5 4.1 0.06 75 92.7 84.7 6.1 0.09 100 85.4 87.8 7.0 0.17 150 85.4 93.9 14.0 0.16 200 85.4 96.9 42.1 0.15 250 78.0 99.0 76.9 0.22 Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929.
    • 55. C- 56 Adequacy of Surgical Staging Results of repeat staging in apparent early stage ovarian cancers Initial Stage # of Patients % Upstaged IA 37 16 IB 10 30 IC 2 0 IIA 4 100 IIB 38 39 IIC 9 33 Total 100 31 Young RC et al. JAMA.1983;250(22):3072-3076.
    • 56. C- 57 Ultrasound Evaluation of a Pelvic MassUltrasound Evaluation of a Pelvic Mass Study Score Sensitivity (%) Specificity (%) PPV (%) NPV (%) Ferrazzi 1997 9 87 67 41 95 Granberg 1990 2 87 49 31 93 Sassone 1991 9 74 65 36 90 DePriest 1993 5 88 40 28 93 Lerner 1994 4 87 59 36 95 Ferrazzi E et al. Ultrasound Obstet Gynecol.1997;10:192-197.
    • 57. C- 58 Pivotal Trial Referral Patterns Gastroenterologist 0% Self-referred 1% Other 10% Gynecologist 69% Family Practitioner 9% Surgeon 2% Internist 9% N=524 of the 566 trial population Data on File, FDI.
    • 58. C- 59 ACOG Referral Guidelines • Premenopausal – CA125 > 200 – Ascites – Evidence of metastasis – Family history of breast or ovarian cancer • Postmenopausal – CA125 >35 – Ascites – Fixed or nodular mass – Evidence of metastasis – Family history of breast or ovarian cancer ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.