Impact of systemic adjuvant therapy and CYP2D6 activity on mammographic density in a cohort of tamoxifen-treated breast cancer patients

Linda Thorén,Erik Eliasson,Mikael Eriksson,Jonatan D Lindh,Jonas Bergh,Sara Margolin,Kamila Czene,Per Hall

doi:10.1007/s10549-021-06386-2

Abstract

PurposeChange in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients.MethodsSwedish breast cancer patients (n = 699) operated 2006–2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity.ResultsMean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation.ConclusionOur results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.

Highlights

Postoperative tamoxifen treatment for 5 years substantially reduces the risk for recurrence as well as breast cancer mortality
Twelve percent of the patients switched from tamoxifen to an aromatase inhibitor, 6% were treated with a combination of tamoxifen and goserelin, and one percent received a combination of goserelin and aromatase inhibitor after tamoxifen
No further density decrease was seen in women discontinuing tamoxifen and switching to aromatase inhibitors or goserelin. In this cohort of tamoxifen-treated breast cancer patients neither aromatase inhibitors, goserelin nor chemotherapy were associated with significant additional mammographic density change

Summary

Introduction

Postoperative tamoxifen treatment for 5 years substantially reduces the risk for recurrence as well as breast cancer mortality. Women with high risk of recurrence are currently recommended extended treatment for 10 years [1], 2. Up to 40% of patients with early ER-positive breast cancer will, relapse within 20 years suggesting a wide variability in the response to adjuvant tamoxifen treatment [3]. There are no means of ascertaining the adjuvant effect of tamoxifen. Markers of early response to tamoxifen therapy are needed. A selective estrogen-receptor modulator (SERM), inhibits estrogen-stimulated proliferation in ERpositive breast cancer by competitively binding to the ER [4]. Tamoxifen is a weak antiestrogen and requires hepatic

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