Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors

Abstract

Purpose: To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer.

Experimental design: An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor-positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy.

Results: In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), -14.6 to -4.7] at 12 months, an absolute decrease of -1.4% (95% CI, -2.5 to -0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40).

Conclusions: This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.

Trial registration: ClinicalTrials.gov NCT00245024.

©2021 American Association for Cancer Research.

Figures

Figure 1.

Consort for Two Study Groups.

Figure 2.. Second-Harmonics Generated (SHG) Microscopy of Breast Tissue Biopsy Samples at Baseline and 6 months after Sulindac Treatment.

Panel A shows a representative breast biopsy tissue section and region of interest from a single patient and mean straightness value before sulindac (left) and 6 months after sulindac (right) stained with hematoxylin and eosin (H&E) under light microscopy (top row), fibrillary collagen SHG image using two-photon laser scanning confocal microscopy with an excitation wavelength of 890 nm (middle) and colorized (middle) the same region of interest post processing using the computer assisted image feature extraction software CT-FIRE. Panel B shows change in mean collagen straightness between baseline and 6 months in 32 pre/post paired sulindac tissue biopsy specimens (unadjusted p value = 0.032). The referenced case highlighted in panel A is represented in the thicker black line in panel B with mean straightness values of 0.925 and 0.918 at baseline and post sulindac, respectively.