Objective A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy.
Design We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints.
Results At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=−0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention.
Conclusions We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice.
Trial Number NCT00468910
- COLORECTAL NEOPLASIA
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RCB and VB contributed equally.
Contributors The study idea was conceived by HKR and VB. The study was designed by HKR, BJ, GD, AU, LR, RCB and VB. Samples were acquired by HKR, MJG, LB, DTR and AB. Samples were processed for spectral markers by VT, AJR and VB, for immunohistochemistry by RW, MDLC and CTW, for prostaglandin measurement by RC and for polymorphism analysis by XH and SS. Data were analysed by HKR, BJ, GD, AU, LR, RCB, KP, ER and VB. All statistical analyses were performed by BJ and IBH The manuscript was initially drafted by HKR and then reviewed by all.
Funding This work was supported by funding from the United States National Institutes of Health N01-CN-35157 to RCB and HKR.
Competing interests HKR, MJG and VB are co-founders and shareholders of American BioOptics LLC and Nanocytomics LLC. These corporations were formed by these authors to advance the technology used within this manuscript.
Patient consent Obtained.
Ethics approval Institutional review boards of all sites.
Provenance and peer review Not commissioned; externally peer reviewed.