Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin

Abstract

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.

Keywords: COLORECTAL NEOPLASIA.

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Figures

Figure 1

CONSORT diagram of all enrolled subjects.

Figure 2

Plots of spectral markers for subjects treated with aspirin or placebo are shown as box plots of per cent changes in spectral slope (SPEC) (A) and fractal dimension (FRAC) (B) values at 3 months post-treatment with aspirin or placebo compared with baseline values, depicting mean (middle line), SD (box) and 95% confidence limits (whiskers). During field carcinogenesis, SPEC typically decreases and FRAC increases, so the data demonstrate a reversion towards less neoplastic signatures by aspirin.

Figure 3

Plots of changes in spectral markers versus changes in prostaglandin E2 (PGE2) expression in tissue are shown as scatter plots of changes in spectral slope (SPEC) (A and C) and fractal dimension (FRAC) (B and D) versus changes in PGE2 for individual patients treated with aspirin (A and B) or placebo (C and D).

Figure 4

Plots of spectral markers based on UDP-glucuronosyltransferase (UGT)1A6 genotypes are shown as box plots of changes in spectral slope (SPEC) (A) and fractal dimension (FRAC) (B) in UGT1A6 variant subjects and wild-type subjects treated with aspirin or placebo. Plots depict the mean (middle line), SD (box) and 95% confidence limits (whiskers); p values are differences between cohorts demarcated by brackets.