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Elevated Proteins May Warn of Ovarian Cancer, But Sufficient Lead Time & Predictive Value Still Lacking

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Fred Hutchinson Cancer Center researchers discovered that concentrations of the serum biomarkers CA125, human epididymis protein 4 (HE4), and mesothelin began to rise 3 years before clinical diagnosis of ovarian cancer, according to a new study published online December 30 in the Journal of the National Cancer Institute. However, the biomarkers became substantially elevated only in the last year prior to diagnosis. … In an accompanying editorial to the study results reported by Anderson et. al., Patricia Hartge, ScD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, applauds the researchers for taking the field one step closer to successful screening study designs by showing that the levels of certain biomarkers do not increase early enough to be used for screening.

Fred Hutchinson Cancer Center researchers discovered that concentrations of the serum biomarkers CA125, human epididymis protein 4 (HE4), and mesothelin began to rise 3 years before clinical diagnosis of ovarian cancer, according to a new study published online December 30 in the Journal of the National Cancer Institute (JNCI). [1] However, the biomarkers became substantially elevated only in the last year prior to diagnosis.

Garnet L. Anderson, Ph.D., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

CA125, HE4, mesothelin, B7-H4, decoy receptor 3, and spondin-2 have been identified as potential ovarian cancer serum biomarkers, but their behavior in the prediagnostic period, with the exception of CA125, has not been evaluated.  In the JNCI study, Garnet L. Anderson, Ph.D., of the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, and colleagues analyzed prediagnostic serum samples and patient data from the Carotene and Retinol Efficacy Trial (CARET), a randomized, double-blind, placebo-controlled chemoprevention trial testing the effects of beta-carotene and retinol on lung cancer incidence among individuals at high risk for lung cancer. Prediagnostic serum samples (taken up to 18 years prior to diagnosis) were obtained for 34 CARET patients with ovarian cancer and 70 matched control CARET subjects. Changes in the levels of these biomarkers prior to ovarian cancer diagnosis were analyzed.

Anderson et. al. discovered that concentrations of CA125, HE4, and mesothelin (but not B7-H4, decoy receptor 3, and spondin-2) began to increase slightly in cancer patients relative to control subjects approximately 3 years before diagnosis, but became substantially elevated within one year prior to diagnosis. Thus, the diagnostic value of these biomarkers is limited because accuracy only increased shortly before diagnosis. “Although these markers are not accurate enough to prompt early intervention in existing screening protocols, the multivariable regression analyses identified modest but statistically significant increases in risk associated with CA125, HE4, and mesothelin, which are consistent with many of the established epidemiological risk factors for ovarian cancer,” say the authors of the study.

“I still think biomarkers may play a role in a cost-effective screening program, although none of these seem accurate enough either alone or together to justify their use in average-risk women,” Anderson told Medscape Oncology. “I do not know of any other currently identified biomarkers that hold more promise than these, but there has been a massive effort over the last few years to identify candidates and not all have been thoroughly vetted,” said Dr. Anderson.

One problem, cites Dr. Anderson, may lie in the approach used in identifying potential ovarian cancer biomarkers. “Most of the discovery work done so far has been conducted in women with advanced-stage disease and compared them to healthy women,” she explained. “If discovery work were done in samples like the ones we used here, representing specimens collected months to years prior to the advanced stage diagnosis, we might have a better chance of finding earlier signals of aggressive disease.”

Another opportunity for improving screening and early diagnosis lies in imaging, she adds. “Currently the most common and only affordable imaging option that could be considered for routine screening is transvaginal ultrasound, but it performs poorly in terms of accurately determining those women [who] have ovarian cancer from those who do not,” said Dr. Anderson. “A substantial improvement in this area would be very exciting.”

Study Limitations Cited By JNCI Editors

The JNCI editors state three limitations that they believe are associated with the study by Anderson et. al. First, the study sample size was small.  Second, all women who participated in CARET had a history of heavy smoking, and therefore, the JNCI editors believe that the blood serum testing results obtained by Anderson et. al. may not apply to other non-smoking groups. Third, the blood collected from women participating in CARET was collected at different times, but only a few samples were collected during the last 2–3 years before ovarian cancer diagnosis.

Designing Ovarian Cancer Early Detection Programs — Accompanying JNCI Editorial

Patricia Hartge, Sc.D. Deputy Director, Epidemiology and Biostatistics Program, Division of Cancer Epidemiology & Genetic, National Cancer Institute

In an accompanying editorial to the study results reported by Anderson et. al., Patricia Hartge, ScD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, applauds the researchers for taking the field one step closer to successful screening study designs by showing that the levels of certain biomarkers do not increase early enough to be used for screening. [2]

Dr. Hartge notes that despite the discovery that CA125 and other serum markers increase before the clinical onset of ovarian cancer, it has been exceedingly difficult to devise a successful ovarian cancer early screening program for asymptomatic women. Nevertheless, Hartge believes that Anderson et al. take a valuable step toward the design of such a successful screening program by demonstrating why screening regimens that are based on markers, or panels of markers, can fail. Specifically, the researchers discovered that blood levels of CA125, HE4, mesothelin, and three other promising markers did not increase early enough in the course of the disease to allow detection in early stages. Dr. Hartge emphasizes that the markers typically rose within one year of the disease symptoms that led to an accurate diagnosis, and therefore, many of the ovarian cancer patients were diagnosed with advanced stage disease.

Hartge further states “[t]hat the results of Anderson et al. are not the last word in serum markers or in combinations of markers.” “Serum markers likely will form a key element in any screening regimen, with the lead time and other parameters of each marker or combination of markers being taken into account. The careful evaluation technique applied in the current study fits into a staged approach necessary for testing performance of early markers of disease.” Hartge adds that “[o]nly the time-consuming, expensive, and demanding randomized clinical trial can reveal whether an early detection program that includes the biomarkers can save lives.”

In support of her position, Dr. Hartge observes that current randomized trials are testing the value of different screening programs that are built on combinations of CA125, ultrasound, and risk factor data (e.g., family history and age). After four rounds of screening 34,261 postmenopausal women for ovarian cancer with both CA125 and ultrasound, University of Alabama at Birmingham School of Medicine investigators of the large U.S. screening trial observed that the predictive value of a positive screen was quite low — approximately 1%. Of the 60 screen-detected cancers, 72% had already advanced to at least stage III. [3] In addition, of every 20 women who underwent surgery after a positive screen, only one women was diagnosed with cancer. Furthermore, in a recent UK trial with a slightly different design, positive predictive values from the first round of screening were higher; 35% in the 50,078 women whose risk was assessed with CA125 and risk factor data, followed by ultrasound only if indicated, and 3% in the 50,639 women screened first with ultrasound. [4] The effects on mortality in both trials remain to be determined.

Confronting The “Daunting Arithmetic” Required To Detect Early Stage Ovarian Cancer

Based upon the foregoing, Dr. Hartge highlights the “daunting arithmetic” required to detect early stage ovarian cancer. In the U.S., Surveillance, Epidemiology and End Results (SEER) data indicates that incidence amounts to 13 cases of ovarian cancer per 100,000 woman per year, referred to by Dr. Hartge as the “proverbial needles in the haystack.” [5] So as not to present a problem without a potential solution, Hartge provides a roadmap to additional factors that may help future researchers develop early screening methods to identify those rare cases of ovarian cancer in the general population.  Notably, SEER data also indicates that incidence of ovarian cancer steadily increases with age from 21 cases per 100,000 women per year within the 50-54 age range to 57 cases per 100,000 women per year within the 80-84 age range. [6] Furthermore, family history, low parity, and more ovulations over a woman’s lifetime predict additional risk, with the strongest but least common predictor being a mutation in the BRCA1 or BRCA2 gene. Thus, the general approach suggested by Hartge focuses on women with higher baseline risks, for whom the predictive value of a positive serum test tends to increase. Dr. Hartge believes that the performance of an overall screening program will improve by targeting higher-risk subgroups of women for screening by combining personal history, genetic abnormality status, and levels of serum markers in one prediction model. With ongoing advances in understanding the origin and causes of ovarian cancer, Hartge states that the risk models that are useful for screening programs should also improve.

Further technology advancements may also improve future ovarian cancer early detection screening models, says Hartege. For example, a screening program that is based on a panel of biomarkers can be improved by developing new medical imaging technology that is more specific than current ultrasound technology.  If better imaging existed, fewer women would undergo surgery following a suspicious biomarker finding.  Similarly, development of less invasive surgery could further reduce harmful side effects.  Although Hartge observes that a highly accurate biomarker(s) or an overall screening program does not yet exist, she also explains that the current study by Anderson et. al., with its sobering implications, brings future researchers closer to understanding the crucial elements in designing an effective early detection program for ovarian cancer.

References:

1/Anderson GL , McIntosh M, Wu L, et. al. Assessing Lead Time of Selected Ovarian Cancer Biomarkers: A Nested Case–Control Study. Journal of the National Cancer Institute Advance Access published on January 6, 2010, DOI 10.1093/jnci/djp438. J. Natl. Cancer Inst. 102: 26-38.

2/Hartge P. Designing Early Detection Programs for Ovarian Cancer. Journal of the National Cancer Institute Advance Access published on January 6, 2010, DOI 10.1093/jnci/djp450. J. Natl. Cancer Inst. 102: 3-4.

3/Partridge E, Kreimer AR, Greenlee RT, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol (2009) 113(4):775–782. [PMCID: PMC2728067; PMID: 19305319].

4/Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol (2009) 10(4):327–340. [PMID: 19282241]

5/ Horner MJ, Ries LAG, Krapcho M, et al, eds. SEER Cancer Stat Fact Sheets (2009) Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed December 2, 2009.

6/Horner MJ, Ries LAG, Krapcho M, et. al., eds. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006, based on November 2008 SEER data submission, posted to the SEER web site, 2009 [See Table 21.6: Incidence & Mortality Rates By Age].

Sources:

Preliminary Findings of a Large British Study Indicate That CA-125 Blood Test & Transvaginal Ultrasound Test Can Detect Early Ovarian Cancer

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“Ovarian cancer has a high case—fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. …”

“Background

Ovarian cancer has a high case—fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS.

earlydetecttrialdesign1

The United Kingdom Collaborative Trial of Ovarian Cancer Screening - Overall Trial Design

Methods

Between 2001 and 2005, a total of 202,638 post-menopausal women aged 50—74 years were randomly assigned to [1] no treatment (control; n=101,359); [2] annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50,640); or [3] annual screening with transvaginal ultrasound (USS; n=50,639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032.

Findings

In the prevalence screen, 50,078 (98.9%) women underwent MMS, and 48,230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1,490 USS). Overall, 4,355 of 50,078 (8.7%) women in the MMS group and 5,779 of 48,230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1,894 (3.9%) women in the USS group required clinical evaluation. 97 of 50,078 (0.2%) women from the MMS group and 845 of 48,230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0—61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers.

Interpretation

The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

Funding

Medical Research Council, Cancer Research UK and the Department of Health, UK; with additional support from the Eve Appeal, Special Trustees of Bart’s and the London, and Special Trustees of University College London Hospital.”

Primary Source

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS); Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS); Usha Menon MD, Aleksandra Gentry-Maharaj Ph.D., Rachel Hallett Ph.D. et. al, The Lancet Oncology, Early Online Publication, 11 March 2009 doi:10.1016/S1470-2045(09)70026-9.

Comment

During an interview with the New York Times, Dr. Ian Jacobs, director of the Institute for Women’s Health at University College London, and director of the trial, discussed the optimism and the caveats associated with the preliminary clinical study results as follows:

We have now demonstrated we can pick up the vast majority of women with ovarian cancer earlier than they would have otherwise been detected and before they have symptoms, .. and that a good proportion of those women have earlier stage disease than we would normally expect them to have. … [W]omen thinking of having this must understand and realize that there’s a possibility it will do more harm than good. We have reason to think it will save lives, … and then the question is, will it save enough lives to balance out the harm it does? [Emphasis added].

Robert Smith, director of cancer screening for the American Cancer Society informed the New York Times that “[w]e’re not even remotely close to knowing how to screen women of average risk with these tests, or even if we should.” Mr Smith added that it is important to run large clinical trials, but that the preliminary results of this study must be interpreted with caution.

Secondary Sources