Can a middling biomarker and a sophisticated algorithm improve clinical outcomes?
Interview by Steve Halasey
Over the past 40 years, early detection and improved treatments have helped to reduce the mortality rates for many types of cancers. But over the same period, the mortality rate for ovarian cancer has declined only slightly. In the United States, ovarian cancer is the fifth leading cause of cancer-related death among women, and is responsible for more than 14,000 deaths annually.1
Ovarian cancer survival rates are much lower than for other cancers that affect women. Survival rates for ovarian cancer are higher among women whose disease is diagnosed at an early stage, before the cancer has spread. But only about 15% of ovarian cancer patients are diagnosed with early-stage disease.
Abcodia Ltd, a clinical-stage company based in Cambridge, UK, with US headquarters in Boston, is investigating approaches to fulfill the need for a test that can identify ovarian cancer at an early stage. The company’s first product is the ROCA test, designed to indicate a woman’s likelihood of having ovarian cancer.2
Already CE marked and available in the private healthcare market in the UK, in December 2015 the ROCA test also became available in select US states as a service performed by Abcodia’s CLIA-registered clinical laboratory in Memphis, Tenn. Currently, the ROCA test is available in 15 states (Arizona, Georgia, Illinois, Massachusetts, Michigan, Missouri, Nevada, New Jersey, North Carolina, Ohio, Oregon, Texas, Virginia, Washington, Wisconsin) and the District of Columbia). According to a company release, “women can obtain the ROCA test by downloading and completing an online request form, securing their physician’s approval, and having a blood sample collected by a healthcare professional.”
“Initially,” the company added, “the ROCA test will be available only on a self-pay basis while Abcodia establishes its reimbursement strategy through public and private payers.” To find out more about the company’s strategy for rolling out the ROCA test onto the international market, CLP recently spoke with Nadia Altomare, CEO of Abcodia.
CLP: As a potential biomarker for ovarian cancer, CA-125 has a long history. Where did it fall short as an independent marker?
Nadia Altomare: Data from studies examining CA-125 testing for the early detection of ovarian cancer have proven that it is inadequate for this indication. CA-125 works well for monitoring patients undergoing treatment for ovarian cancer, as an elevated CA-125 level is generally the earliest sign of recurrent disease. However, studies show that when CA-125 is used to screen asymptomatic women, it lacks adequate sensitivity and specificity. Most notably, in a major US screening trial for ovarian cancer—the National Cancer Institute’s prostate, lung, colorectal, and ovarian cancer screening trial (PLCO)—annual CA-125 testing in women without symptoms of ovarian cancer failed to accurately detect ovarian cancer early enough to save lives.3 Moreover, in the PLCO study, annual testing with CA-125 referred many women without ovarian cancer for unnecessary surgery.
These results are disappointing, but are partly a result of the traditional assumption that blood levels of CA-125 greater than 35 IU/mL are indicative of cancer, while levels below this cut-off are considered normal. It is generally appreciated that CA-125 levels are elevated in women with ovarian cancer, but some women with ovarian cancer may have CA-125 levels below 35 IU/mL; and some women without ovarian cancer may have baseline levels of CA-125 above 35 IU/ml—and sometimes as high as 100 IU/mL. Moreover, levels can vary with menopause status, during menstruation, during pregnancy, or in cases of appendicitis, endometriosis, fibroids, or pelvic inflammatory disease.
CLP: The risk of ovarian cancer algorithm (ROCA) is based on serial measurements of CA-125, but incorporates additional factors. How were those additional factors determined, incorporated, and studied to validate the overall algorithm?
Altomare: Additional factors that are used as inputs for the ROCA test are age, family history, menopausal status, and genetic predisposition to ovarian cancer. These factors determine a woman’s baseline lifetime risk, which is then modified by the determination of any significant change in her CA-125 level to provide the risk of a woman having ovarian cancer at the time of that blood test.
The ROCA test works by using these factors to calculate a woman’s initial risk of ovarian cancer, which is then modified based on how closely her CA-125 measurements match the profiles seen in healthy women and women with ovarian cancer. The more a woman’s profile is like the profile seen in previous ovarian cancer cases, the greater her estimated risk.
The key element that gives the ROCA test its power and accuracy is the fact that it uses historic patterns of change in CA-125 that derive from a cohort of 22,000 women, with and without ovarian cancer, over several years. The ROCA test calls on this information to match a woman’s evolving CA-125 profile with other known profiles to provide an accurate result.
Once built using this initial data set from 22,000 women, the ROCA test was validated in several prospective studies.
CLP: How did ROCA become the basis for Abcodia’s development of the ROCA test?
Altomare: The ROCA test is the commercially available version of the risk of ovarian cancer algorithm (ROCA) that was coinvented by Steven Skates, PhD, a researcher at Massachusetts General Hospital, and Ian Jacobs, MBBS, a researcher formerly at University College London, and now president and vice chancellor of the University of New South Wales. ROCA was licenced to Abcodia in 2014. Extensive testing in our CLIA-registered laboratory has confirmed equivalence of the ROCA test to the original algorithm licensed from the inventors.
CLP: What additional studies has the company undertaken to assess the clinical utility of the ROCA test?
Altomare: Four key prospective studies are being conducted to evaluate the performance of the ROCA test. Two trials are in asymptomatic postmenopausal women, and two in women who are at higher risk of developing ovarian cancer because of a strong family history. The UK collaborative trial of ovarian cancer screening (UKCTOCS) is the largest study among postmenopausal women, and is being replicated by a US trial conducted by the MD Anderson Cancer Center. The high-risk trials include the UK familial ovarian cancer screening study (UKFOCSS), and a US study supported by the National Cancer Institute’s early detection research network. Both of these trials are expected to report in full shortly.
CLP: Published in December, the results of UKCTOCS were expected to determine whether multimodal screening initiated by ROCA reduces ovarian cancer mortality. What did those results show?
Altomare: The results published in December report on a number of assessments made as part of the UKCTOCS study.4 On its surface, the recent publication demonstrates that use of the ROCA test to guide multimodal screening can reduce ovarian cancer mortality by an estimated 20%. These results come on the back of previous papers reporting that the ROCA test has high sensitivity and specificity of 85.8% and 99.8% respectively.5
Using the statistical test that was planned from the start of the trial—the Cox test—the average reduction in mortality across study years 0–14 was 15%—a finding that was not considered statistically significant. However, using a weighted log-rank test, which was the model adopted for the National Cancer Institute’s PLCO ovarian cancer screening trial, there was a significant reduction in mortality of 22%. Moreover, the publication also calculates that if women who already had cancer at the start of screening are excluded (on the assumption that screening is unlikely to reduce deaths among those women), there is a significant mortality reduction of 20%.
But in light of the fact that statistical analysis using the Cox test does not agree with weighted log-rank or incidence screening mortality analysis, it is not absolutely certain that multimodal screening saves lives. Continued follow-up of the women who took part in the UKCTOCS trial for another 2 to 3 years will enable us to definitely confirm or refute the existence of a mortality reduction.
The potential mortality reduction resulting from multimodal screening using the ROCA test is consistent with a significant increase in the detection of early-stage cancers (stage I and II) in the multimodal screening arm (38%) vs. no screening (24%, P<0.001). This so-called stage shift is an important result, as it reaffirms the hypothesis that removal of low-volume tumors during the early stage of the disease can improve survival from ovarian cancer.
Overall, current evidence suggests that the ROCA test has the highest sensitivity for detection of ovarian cancer, the lowest number of false positive results when combined with ultrasound as a secondary test and, of the available tests, is most likely to save lives.
CLP: As a multimodal screening pathway, the ROCA test compared favorably to no screening at all. How did it perform relative to ultrasound screening?
Altomare: In the UKCTOCS trial, only 75% of ovarian cancers were picked up by using annual transvaginal ultrasound screening (TVUS) alone. Nearly 86% of cancers were detected in the group evaluated with multimodal screening initiated by the ROCA test. In addition, the study found that annual ultrasound screening can lead to many unnecessary operations. In fact, 34 of 35 operations in the study were for noncancerous tumors.
CLP: Why did Abcodia launch the ROCA test onto the private UK healthcare market, instead of pursuing coverage through the National Health Service (NHS)?
Altomare: We initially wanted to make the ROCA test immediately available to the many women who have expressed interest in our technology either because of previous ovarian cancer in their families or simply because of a wish to be proactive about their health. Some of these women were already being screening using CA-125 or annual TVUS, but wanted to switch to the ROCA test because of its stronger performance.
CLP: Are the UKCTOCS results strong enough to support an appeal for NHS coverage?
Altomare: In the UK, we anticipate interest from the NHS as they work through their assessment of the economic implications and clinical benefit of the ROCA test. This will likely be after the additional follow up of UKCTOCS, in 2 to 3 years.
CLP: Abcodia decided to adopt a similar launch strategy in the United States—making the test available in just a few states, without either a national or regional coverage determination for Medicare, and without coverage from any private payers. Why?
Altomare: Given the promise of our technology, and because of the significant public interest, we wanted to make the ROCA test available to women as soon as possible. For decades, women have been eager for a more effective way to detect ovarian cancer early and we’ve set the price point at a level that will be accessible to many women.
CLP: What will be Abcodia’s strategy for obtaining public and private reimbursement coverage in the United States?
Altomare: Abcodia is currently establishing its reimbursement strategy through public and private payers. We are still working through the details and have not yet publicly disclosed specifics.
CLP: From where the company stands now, how long do you think it will take to roll out the ROCA test throughout the United States? How long before coverage and payment policies catch up with that availability?
Altomare: We initially focused on five key states to ensure that our service works optimally, and we have been collaborating closely with physicians in those areas. We will be expanding availability throughout 2016, supporting inquiries and test orders from physicians across the entire United States, and expect availability in almost all states by the end of the year. It is difficult to determine a timeline for coverage and payment milestones at this time, but we plan to actively work to establish a strategic approach for reimbursement.
CLP: The UKCTOCS study concludes that “further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening.” Is Abcodia prepared to support additional studies on the scale of the UKCTOCS study?
Altomare: Further follow-up will be reported from UKCTOCS in a few years. Once a mortality benefit is confirmed, there will be no need to replicate a study of that magnitude. However, Abcodia will continue to report on the effectiveness of its ROCA testing service through its key opinion leaders, and will also be embarking on validation studies for new cancer early-detection products to build on its current capability and offering.
Steve Halasey is chief editor of CLP. He can be reached via [email protected].
- Statistics: what is ovarian cancer? [online]. Washington, DC: Ovarian Cancer National Alliance, 2015. Available at: www.ovariancancer.org/about/statistics. Accessed January 12, 2016.
- Abcodia announces initial US availability of the ROCA test to aid in the early detection of ovarian cancer [press release]. Cambridge, UK: Abcodia Ltd, 2015. Available at: www.abcodia.com/news_021215.php. Accessed January 12, 2016.
- Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal, and ovarian (PLCO) cancer screening randomized controlled trial. JAMA. 2011;305(22):2295–2303; doi: 10.1001/jama.2011.766.
- Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK collaborative trial of ovarian cancer screening (UKCTOCS): a randomized controlled trial. The Lancet. Published online December 17, 2015; doi: 10.1016/S0140-6736(15)01224-6. Accessed December 20, 2015.
- Menon U, Ryan A, Kalsi J, et al. A risk algorithm using serial biomarker measurements doubles the number of screen-detected cancers compared to a single-threshold rule in the united kingdom collaborative trial of ovarian cancer screening (UKCTOCS). J Clin Oncol. Published online before print, May 11, 2015; doi: 10.1200/JCO.2014.59.4945.