Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies

Abstract

Increased mammographic density (MD) has been shown beyond doubt to be a marker for increased breast cancer risk, though the underpinning pathobiology is yet to be fully elucidated. Estrogenic activity exerts a strong influence over MD, which consequently has been observed to change predictably in response to tamoxifen anti-estrogen therapy, although results for other selective estrogen receptor modulators and aromatase inhibitors are less consistent. In both primary and secondary prevention settings, tamoxifen-associated MD changes correlate with successful modulation of risk or outcome, particularly among pre-menopausal women; an observation that supports the potential use of MD change as a surrogate marker where short-term MD changes reflect longer-term anti-estrogen efficacy. Here we summarize endocrine therapy-induced MD changes and attendant outcomes and discuss both the need for outcome surrogates in such therapy, as well as make a case for MD as such a monitoring marker. We then discuss the process and steps required to validate and introduce MD into practice as a predictor or surrogate for endocrine therapy efficacy in preventive and adjuvant breast cancer treatment settings.

Heparanase promotes Syndecan-1 expression to mediate fibrillar collagen and mammographic density in human breast tissue culturedex vivo

“…However, these inhibitors have undesirable anti-angiogenic and other off-target effects when used systemically (Chhabra and Ferro 2020) and thus are unlikely MD-reducing agents to take forward to clinical trials. Tamoxifen reduces MD (Shawky, Martin et al 2017), however, its long-term use is associated with a wide range of potential side effects, some of which are intolerable (Thorneloe, Hall et al 2020). Both of these approaches are therefore potentially not feasible for MD reduction, although their mechanism of action provides important insight into how MD is governed, as our work alludes to, via the action of HPSE.…”

“…Recent data identifying a positive association of HMD with lifetime exposure to estrogens is also a key finding to our understanding of MD in BC (Huo, Chew et al 2015). Estrogen unequivocally promotes MD, as evidenced by data showing alterations of MD with hormone contraceptives, hormone replacement therapy (Greendale, Reboussin et al 1999, Byrne, Ursin et al 2017, menopause (Stone, Warren et al 2009), and treatment with anti-estrogenic drugs (Chew, Huo et al 2014, Shawky, Martin et al 2017. Estrogen also influences cells within the tumour microenvironment, causing immunosuppression (Rothenberger, Somasundaram et al 2018).…”

Breast Mammographic Density: Stromal Implications on Breast Cancer Detection and Therapy

“…Oestrogenic activity strongly influences MD, and accordingly MD can change in response to tamoxifen anti-oestrogen treatment. However, the results obtained using other oestrogen receptor modulators or aromatase inhibitors have proven less conclusive [22]. A relation between adjuvant therapy and MD changes among women with BC have been described [23].…”

“…Other studies have shown that this decline in MD due to tamoxifen treatment results in a reduced BC risk when administered as chemopreventive treatment and in better BC outcomes (such as a lower risk of recurrence and lower rates of BC specific death) when in adjuvant settings [23]. Other studies have demonstrated that tamoxifen-associated MD decline translates into reduced breast cancer risk in the chemopreventive setting and improved breast cancer outcomes, including reduced risk of recurrence and breast cancer specific death, in the adjuvant settings [22,24]. Once BC is diagnosed, a diminution of MD has also been proposed as a prognostic marker for better long-term survival among patients that have received adjuvant therapy [25].…”

Mammographic Density as a Criterion of the Efficiency of Treatment of Benign Breast Disease and Reducing Risk of Breast Cancer

“…В крупных интервенционных рандомизированных исследовани-ях доказано, что тамоксифен, ралоксифен и ингиби-торы ароматазы анастразол и экземестан при профи-лактическом применении существенно снижают риск развития рака МЖ [34]. В ряде исследований убеди-тельно доказано, что тамоксифен при длительном как профилактическом, так и лечебном приеме умень-шает МГП; в связи с этим МГП рекомендуется ис-пользовать в качестве промежуточного биомаркера оценки эффективности препаратов для химиопрофи-лактики рака МЖ [32,35].…”