The Quest for Ovarian Cancer's Holy Grail: Can CA-125 Still Be the Chalice of Early Detection?
Authors: Beth Y. Karlan, Martin McIntosh
Journal: Journal of Clinical Oncology (2007)

Since its discovery more than 25 years ago, the CA-125 tumor antigen has become the standard for monitoring ovarian cancer patients’ response to therapy and for surveillance for recurrent disease. Its usefulness for screening, early detection, and risk prediction, however, has been limited by both false-positive and falsenegative results. Thus, the quest for an effective ovarian cancer screening test has become a goal intensely sought after by investigators, both in the clinic and in the laboratory. Two approaches to improve early detection include evaluating ever more sophisticated uses of CA-125 alone, or looking toward the discovery of novel ovarian cancer biomarkers to augment or replace CA-125. We believe that, despite the work by Hermsen et al published in this issue of the Journal of Clinical Oncology, the latter approach, involving new biomarker discovery and multiplexing combinations of markers, holds greater promise of successfully achieving this goal. Hermsen et al studied a cohort of 424 high-risk women attending their Family Cancer Clinic and report on the performance of CA-125 in finding early cancers and precancers in this population. These women were between the ages of 21 and 70 years, and nearly 80% were premenopausal; approximately one third were known to carry BRCA mutations, and one third had a prior history of breast cancer. The study’s findings remind us once again of the many physiologic and benign conditions that can influence an individual’s CA-125 value, such as age, menopausal status, fibroids, and pregnancy—all factors that contribute to the false-positive and false-negative results that hamper CA-125’s usefulness in screening. The authors claim that the change in serial CA-125 values, at least the difference between the last value taken 6 to 13 months before surgery and the one drawn at the time of surgery, was strongly predictive of ovarian cancer. This change-from-previous measure is one form of a longitudinal algorithm that has been hypothesized as a potential boon to early detection. There are others as well, including the Risk of Ovarian Cancer (ROC) algorithm of Skates et al, which uses a highly complex algorithm to assess specific growth shapes predictive of cancer. Another algorithm used in screening a high-risk population of women (similar to the one reported here by Hermsen et al) is the Parametric Empiric Bayes (PEB) algorithm. The PEB algorithm is intended for CA-125 results or novel markers and is, perhaps, more appropriate for the study population than either the ROC or simple change-score that the authors applied. In the PEB model, each woman’s complete screening history, not only her most recent index value, acts as her own control, and the slightest deviation from that person-specific norm is used to detect elevated values at a fixed specificity. This algorithm is vastly superior to any singlethreshold cutoff for CA-125 and takes into account the individual’s underlying nonovarian conditions, such as fibroids or her menopausal status. It is appealing to think of CA-125 as a dynamic marker of ovarian cancer growth in this way. Its behavior on the “down slope” predicts ovarian cancer cell death and response to therapy, and its rise on the “up slope” is often the first indication of recurrent disease. De novo ovarian cancer growth has been more difficult to define; however, each of these “dynamic” approaches should certainly be able to improve screening compared to simple threshold-cutoff approaches. But the field needs to discuss how often they matter in a clinical sense: how many stage I ovarian cancers can be detected using CA-125 alone? Adding to other evidence against CA-125 alone as being sufficient to be clinically relevant is found in Table 4 of the article by Hermsen et al. The CA-125 (and ultrasound) results described therein are really quite discouraging! The serial CA-125 values preceding the diagnosis of ovarian carcinoma in these six cases do not show any trend that would suggest a precancer screening window to allow for early intervention. That is, even the most complex and most simple biomarker rules would have led to the same screening decisions as did the CA-125 values in these index cases. The prediagnostic CA-125 values reported do not demonstrate any trend, up or down, and do not suggest any increased risk of ovarian cancer beyond these women’s known high risk because of their family histories or BRCA gene mutations. Thus, despite the great attention to novel uses of CA-125, all attempts are falling short of demonstrating CA-125’s clinical usefulness as an early diagnostic biomarker in this high-risk group of women. One is left still searching for new markers or a composite of markers that would point to early diagnosis. With the vast majority of women still presenting with advanced metastatic disease, and the unlikely event that monitoring CA-125 alone will make much of a difference, there is an urgent need for effective means to detect ovarian cancer while it is still confined to the ovary and imminently curable. This need is, perhaps, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 11 APRIL 1