Abstract IA15: Early detection of ovarian cancer: An update
Authors: Bast Robert C. 
Published: August 2018

Abstract
The rationale for early detection of ovarian cancer is compelling. Ovarian cancer confined to the ovaries (stage I) can be cured in up to 90% of patients with currently available therapy. Stage II disease confined to the pelvis is associated with a five-year survival of 70%. However, disease that has spread beyond the pelvis (stage III-IV) can be cured in only 20% or less. Only 20% of ovarian cancers are currently diagnosed in stage I-II. Computer simulations suggest that detection of preclinical disease at an earlier stage could improve survival by 10-30%.
The clinical requirements for early detection are stringent. Given the postmenopausal prevalence of 1:2,500, effective screening requires not only high sensitivity for preclinical disease of &gt;75%, but also very high specificity of 99.6% to achieve a positive predictive value of 10% (i.e., 10 operations for each case of ovarian cancer detected). Used alone, neither CA125 nor TVS has adequate specificity. Adequate specificity can be attained, however, by measuring the trend of CA125. Ovarian cancer is associated with rising CA125 and benign disease is not. A very high specificity and sensitivity can be attained when rising CA125 is used to trigger TVS in a two-stage strategy. The Risk of Ovarian Cancer Algorithm (ROCA), developed by Dr. Steven Skates, relies on each woman’s own baseline CA125 value to determine whether there has been a significant increase.
Over the last 17 years in the Normal Risk Ovarian Screening Study (NROSS) conducted with Dr. Karen Lu, 34,208 samples have been obtained from 5,711 postmenopausal women at conventional risk. Rising CA125 judged by the ROCA, prompted TVS, and sonographic findings compatible with cancer led to exploratory surgery. Less than 0.9% of these women have been referred for ultrasound after each annual screening and 2.6% over multiple years on study. Nineteen operations have been prompted by the algorithm and 12 cases of ovarian cancer have been detected—two borderline and 10 invasive high grade with 9 (75%) in stage I or II. Based on this experience, no more than three operations will be required to detect each case of ovarian cancer using this strategy. In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) led by Drs. Ian Jacobs and Usha Menon, &gt;200,000 postmenopausal women at average risk were randomized to three groups: control (101,359), annual TVS (50,639), and annual CA125 with ROCA prompting TVS (50,640). With the algorithm, only 3-4 operations were required to detect each case of ovarian cancer. The trend of CA125 analyzed with the ROCA detected approximately twice as many cases as an arbitrary threshold for CA125. A total of 641 subjects were screened to prevent one death. Excluding prevalent cases and primary peritoneal disease, a 20% reduction in mortality was observed (P=0.021). The statistical bounds around the estimate of reduction in mortality were, however, large and additional follow-up will be required to validate this estimate.
Whatever the reduction in mortality, there is room for improvement in both the first and second stage of the two-stage strategy. Use of CA125 as an initial step in two-stage screening will miss at least 20% of cancers, as only 80% of ovarian cancers express significant levels of CA125. Thus, additional marker(s) will be needed to detect early-stage disease. My laboratory’s goal has been to develop a biomarker panel that detects at least 90% of early-stage disease. We have evaluated 110 potential biomarkers. Addition of HE4 and CA72.4 detects 18% of cases missed by CA125, but does not provide lead time.
Autoantibodies could be stimulated by small volumes of cancer in the ovary or fallopian tube, providing greater sensitivity and earlier detection than CA125 or other assays that detect shed biomarkers. The TP53 tumor-suppressor gene is mutated in &gt;95% of high-grade serous ovarian cancers and autologous antibodies can be produced against TP53. At a specificity of 97%, autoantibodies could be detected in 21-30% of serum samples from ovarian cancer patients from MD Anderson, the Australian Ovarian Cancer Study, and the UKCTOCS. Among 164 cases with rising CA125 detected with the ROCA, 20.7% had elevated TP53 autoantibody. In cases missed by the ROCA, 16% of cases had elevated TP53 autoantibody. Of the 34 ovarian cancer cases detected with the ROCA, TP53 autoantibody titers were elevated 11.0 months before CA125. In the 9 cases missed by the ROCA, TP53 autoantibody was elevated 22.9 months before cancer diagnosis. Consequently, TP53 autoantibody levels provide the first biomarker with clinically significant lead time over elevation of CA125 or an elevated ROCA value.
With Drs. Skates, Menon, and her colleagues, we are developing a new ROCA algorithm that will incorporate multiple serum biomarkers, potentially including CA125, HE4, CA72.4, and TP53 autoantibodies to enhance sensitivity and lead time. The specificity and positive predictive value of this algorithm will be evaluated in a screening trial sponsored by the NCI Early Detection Research Network and the Cancer Prevention and Research Institute of Texas.
As TP53 autoantibody detects as few as 21% of cases, multiple groups are evaluating other autoantibodies to find a limited panel that could detect &gt;90% of cases. Our own work with Drs. Menon and Sam Hanash is focused on HE4 immune complexes and autoantibodies against cytokeratins and a number of other potential targets identified in a screen with 17,000 human proteins conducted in collaboration with Origene. Autoantibodies will need to be compared to stDNA in blood or cervical/endometrial secretions and to the contents of exosomes to determine the most sensitive and specific biomarkers.
The success of a two-stage strategy will depend critically on improving imaging or detection in the second stage. TVS has difficulty in visualizing fallopian tubes. We are collaborating with Drs. John Hazle, Kelsey Matthieu, and Imagion Biosystems to evaluate magnetic relaxometry (MRx) measured with Superconducting Quantum Interference Detection (SQUID). Anti-CA125 antibodies have been conjugated with ferritin nanoparticles. Only bound antibody-conjugated nanoparticles are detected, providing exceptional sensitivity. By improving both phases, detection of ovarian cancer could occur at an earlier stage and patient outcomes improved.
References:
Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet 2016;5;945-56. PMID: 26707054.
Lu KH, Skates S, Hernandez MA, Bedi D, Bevers T, Leeds L, Moore R, Granai C, Harris S, Newland W, Adeyinka O, Geffen J, Deavers M, Fritsche H, Bast RC Jr. A two-stage ovarian cancer screening strategy using the risk of ovarian cancer algorithm (ROCA) identifies early stage incident cancers and demonstrates high positive predictive value. Cancer 2013;119:3454-61. PMID: 23983047.
Matthieu K, Bedi D, Thrower S, Qayum A, Bast RC Jr. Screening for ovarian cancer: imaging challenges and opportunities for improvement. Ultrasound in Obstet Gynecol, in press.
Yang W-L, Lu Z, Bast RC Jr. The role of biomarkers in the management of epithelial ovarian cancer. Expert Review Mol Diagn 2017;17:577-91. PMID 28468520.
Citation Format: Robert C. Bast, Jr. Early detection of ovarian cancer: An update. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA15.