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Surrogate response biomarkers in prevention research: do they point the way or lead us astray?

Modulation of reversible-risk biomarkers in preliminary studies of new cancer prevention interventions is increasingly being used as a preliminary indication of efficacy before advancement to a resourceintensive cancer incidence reduction trial. However, we have little evidence from prospective studies that this approach is effective or efficient in breast cancer prevention research. In this issue of Journal of Clinical Oncology, Decensi et al correlate cancer outcomes at 5 years with modulation of two risk biomarkers—mammographic density and plasma insulin-like growth factor 1 (IGF-1)—after 2 years of treatment with low-dose tamoxifen, fenretinide, or a combination of the two. This four-arm, placebocontrolled trial in premenopausal women was designed to detect synergistic interaction of tamoxifen and fenretinide using modulation of IGF-1 and mammographic density as primary end points. Trial accrual was stopped prematurely at 235 patients because of a lack of interaction, at least for IGF-1 levels. However, long-term follow-up of the cohort allowed investigators to address the perhaps more important question of utility of biomarker modulation in predicting cancer outcome. Unfortunately, favorable modulation of mammographic density and IGF-1 observed with low-dose tamoxifen and a combination of tamoxifen and fenretinide did not translate into reduction in cancer events, although the hazard ratio of 0.70 for ductal carcinoma in situ (DCIS) and invasive cancer in the tamoxifen-alone arm was numerically less than that for placebo. Surprisingly, fenretinide as a single agent, which was associated with minimal modulation of IGF-1 and no modulation of density when compared with placebo, was associated with significant reduction in cancer events (hazard ratio, 0.38). How confident are we that changes (or lack thereof) in mammographic density and plasma IGF-1 are reflective of changes in breast tissue? Circulating IGF-1 is at best only modestly associated with breast cancer risk in premenopausal women. Reduction in plasma IGF-1 after tamoxifen may actually be reflective of estrogenic action of oral selective estrogen receptor modulators (SERMs) on liver synthesis of IGF-1, because oral estrogen also results in reduced circulating IGF-1 levels. Because modulation of circulating IGF-1 may be related more to the pharmacodynamic properties of SERMs than to any underlying tissue change, it is a suboptimal primary surrogate response biomarker. Mammographic density, which is reflective of the amount of collagen and stroma, is a strong and well-accepted risk biomarker for premenopausal breast cancer. Women who have density greater than 75% have a five-fold greater risk for breast cancer than women with essentially no density. It has been hypothesized that risk associated with breast density is at least partially explained by elevated systemic or tissue IGF-1 levels or by the ratio of IGF-1 to its binding proteins. The increase in relative risk with 75% or higher density is similar to the five-fold increase in risk observed with histologic or cytologic evidence of atypia. Tamoxifen consistently reduces mammographic density in premenopausal women, and both tamoxifen and fenretenide have been shown to reduce plasma IGF-1 levels. Given this seemingly strong reasoning, what explains the contradiction reported by Decensi et al between biomarker results and cancer outcome? There are multiple possibilities. First, the cohort was small, and it may have been too late in the precancer pathway for change in breast density and plasma IGF-1 to predict outcome. Second, there may have been analytic problems with IGF-1 or breast-density measurements. Third, the effects of fenretinide on progression or recurrence of in situ and invasive cancers are not mediated predominately via reduction in IGF-1 or the physiologic processes responsible for mammographic density. Fourth, tamoxifen-associated decreases in IGF-1 and mammographic density are not necessarily synonymous with a riskreduction effect and are in part likely the results of pharmacodynamic changes common to most SERMs. It should be noted that this was not a typical cohort for primary prevention; 77% of the women enrolled onto this study had developed a T1a invasive cancer, DCIS, or lobular carcinoma in situ within 3 years before random assignment. There is little information on whether modulation of density or plasma IGF-1 might be expected to correlate with outcome in the setting of advanced intraepithelial neoplasia and small invasive cancers. Seventy-seven percent of subsequent breast cancer events resulted from development or recurrence of DCIS or invasive cancer in the ipsilateral breast, and 98% of women who developed a cancer event had baseline in situ or invasive cancer. Consequently, this study likely examined the effect of tamoxifen and fenretinide on progression or recurrence of in situ or invasive disease. In this cohort, in which some of the premenopausal women had estrogen receptor (ER) –negative DCIS and invasive cancers, low-dose tamoxifen—which only prevents ER-positive cancer—may have been at a disadvantage compared with fenretinide, which may have activity in both ER-negative and ER-positive lesions. Analysis issues or technical factors may have affected the correlations of mammographic density and cancer outcome. Sixteen percent of women did not have a mammogram at baseline, and there was no attempt to control for phase of menstrual cycle in those who did. Density is known to be higher in the luteal than follicular phase of the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 23 AUGUST 1