Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy

Cody Ramin; Ruth M Pfeiffer; Sharon Fan; Maeve Mullooly; Roni T Falk; Kristine Jones; Neil E Caporaso; Lisa Bey-Knight; Mark A Sak; Michael S Simon; David H Gorski; Haythem Ali; Peter Littrup; Neb Duric; Mark E Sherman; Gretchen L Gierach

doi:10.1038/s41523-023-00511-8

Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy

NPJ Breast Cancer. 2023 Mar 15;9(1):12. doi: 10.1038/s41523-023-00511-8.

Authors

Cody Ramin¹, Ruth M Pfeiffer², Sharon Fan², Maeve Mullooly³, Roni T Falk², Kristine Jones^{2

4}, Neil E Caporaso², Lisa Bey-Knight⁵, Mark A Sak⁶, Michael S Simon⁵, David H Gorski^{5

7}, Haythem Ali⁸, Peter Littrup⁶, Neb Duric^{6

9}, Mark E Sherman¹⁰, Gretchen L Gierach²

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. [email protected].
² Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
³ School of Population Health, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
⁴ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Fredrick, MD, USA.
⁵ Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
⁶ Delphinus Medical Technologies, Novi, MI, USA.
⁷ Michael and Marian Ilitch Department of Surgery, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
⁸ Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, USA.
⁹ Department of Imaging Sciences, University of Rochester, Rochester, NY, USA.
¹⁰ Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.

Abstract

Although breast density decline with tamoxifen therapy is associated with greater therapeutic benefit, limited data suggest that endocrine symptoms may also be associated with improved breast cancer outcomes. However, it is unknown whether endocrine symptoms are associated with reductions in breast density after tamoxifen initiation. We evaluated treatment-associated endocrine symptoms and breast density change among 74 women prescribed tamoxifen in a 12-month longitudinal study. Treatment-associated endocrine symptoms and sound speed measures of breast density, assessed via novel whole breast ultrasound tomography (m/s), were ascertained before tamoxifen (T0) and at 1-3 (T1), 4-6 (T2), and 12 months (T3) after initiation. CYP2D6 status was genotyped, and tamoxifen metabolites were measured at T3. Using multivariable linear regression, we estimated mean change in breast density by treatment-associated endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline density. Significant breast density declines were observed in women with treatment-associated endocrine symptoms (mean change (95% confidence interval) at T1:-0.26 m/s (-2.17,1.65); T2:-2.12 m/s (-4.02,-0.22); T3:-3.73 m/s (-5.82,-1.63); p-trend = 0.004), but not among women without symptoms (p-trend = 0.18) (p-interaction = 0.02). Similar declines were observed with increasing symptom frequency (p-trends for no symptoms = 0.91; low/moderate symptoms = 0.03; high symptoms = 0.004). Density declines remained among women with detectable tamoxifen metabolites or intermediate/efficient CYP2D6 metabolizer status. Emergent/worsening endocrine symptoms are associated with significant, early declines in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations predict clinical outcomes. If confirmed, endocrine symptoms may be a proxy for tamoxifen response and useful for patients and providers to encourage adherence.