Modeling the Dynamics of High-Grade Serous Ovarian Cancer Progression for Transvaginal Ultrasound-Based Screening and Early Detection

open access
 June 3, 2016

Abstract

High-grade serous ovarian cancer (HGSOC) represents the majority of ovarian cancers and accounts for the largest proportion of deaths from the disease. A timely detection of low volume HGSOC should be the goal of any screening studies. However, numerous transvaginal ultrasound (TVU) detection-based population studies aimed at detecting low-volume disease have not yielded reduced mortality rates. A quantitative invalidation of TVU as an effective HGSOC screening strategy is a necessary next step. Herein, we propose a mathematical model for a quantitative explanation on the reported failure of TVU-based screening to improve HGSOC low-volume detectability and overall survival.We develop a novel in silico mathematical assessment of the efficacy of a unimodal TVU monitoring regimen as a strategy aimed at detecting low-volume HGSOC in cancer-positive cases, defined as cases for which the inception of the first malignant cell has already occurred. Our findings show that the median window of opportunity interval length for TVU monitoring and HGSOC detection is approximately 1.76 years. This does not translate into reduced mortality levels or improved detection accuracy in an in silico cohort across multiple TVU monitoring frequencies or detection sensitivities. We demonstrate that even a semiannual, unimodal TVU monitoring protocol is expected to miss detectable HGSOC. Lastly, we find that circa 50% of the simulated HGSOC growth curves never reach the baseline detectability threshold, and that on average, 5–7 infrequent, rate-limiting stochastic changes in the growth parameters are associated with reaching HGSOC detectability and mortality thresholds respectively. Focusing on a malignancy poorly studied in the mathematical oncology community, our model captures the dynamic, temporal evolution of HGSOC progression. Our mathematical model is consistent with recent case reports and prospective TVU screening population studies, and provides support to the empirical recommendation against frequent HGSOC screening.

Blogger's Note: some key items:

A recently proposed morphomolecular characterization of ovarian cancers underscores the importance of clear separation between the various subtypes of ovarian cancers with respect to the appropriate future therapeutic targeting [4]; therein, it is reported that epithelial ovarian cancers account for 85–90% of ovarian cancers, with a subset of epithelial ovarian cancers, high-grade serous ovarian cancers (HGSOCs) representing nearly 70% of all ovarian cancer cases. Focusing on HGSOC, clinical features of its progression prior to detection are difficult to observe. Only circa 15% of HGSOC are solely localized to the ovary or fallopian tubes at the time of diagnosis [1, 5] and about 35% of what is thought to be a malignant mass is actually an adnexal benign mass [6]. 

 Moreover, HGSOC does not follow a clearly distinguishable pathologic continuum of neoplasia compared to, for instance, subtypes of breast, bowel or cervical cancers [6, 11], and detecting HGSOC in its non-specific early stage phase remains challenging [5, 10, 12]. These findings are especially relevant when evaluating the efficacy of transvaginal ultrasound (TVU)-based HGSOC detection, as TVU represents an integral part of all reported major ovarian cancer screening trials, despite its well-recognized limitations (e.g. bilateral disease, or multiple foci spread throughout the peritoneal cavity) [13]. TVU is accurate in detecting abnormalities in ovarian volume and morphology, but is less reliable in differentiating benign from malignant tumors [7, 8, 14–18]. As a result, whether HGSOC constitutes a valid target for ovarian cancer screening remains unanswered and highly contentious with respect to either general-risk or high genetic-risk women, such as germline BRCA1 and BRCA2 mutation carriers, or women with a significant family history of breast or ovarian cancer.

More recently, data from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), the largest ever such screening study performed to date, underscored the failure of unimodal TVU examinations to improve ovarian cancer detectability and overall survival rates [8, 24]. The study, comprising of 202,638 general risk women, demonstrated that multimodal screening including serial TVU and CA125 level testing yielded a 15% mortality reduction rate compared with a 0% no screening or 11% unimodal TVU-based screening cohort mortality reduction rate over 0–14 follow-up year. Lastly, the US Preventive Services Task Force (USPSTF) has recently reconfirmed their previous recommendation against ovarian cancer screening in asymptomatic women without known genetic mutations that increase their risk for ovarian cancer [25).

 Based on 58,673 ovarian volume observations, the upper limit for normal ovarian volume therein was found to be 20 cm³ for pre- and 10 cm³ for postmenopausal women [38]