What is the issue?
Breast cancer is a common cancer and cause of death in women worldwide. Treatment options for breast cancer include endocrine therapy. Endocrine therapy can also be used to prevent breast cancer for women who have not been diagnosed with breast cancer. It would help doctors and their patients to understand whether some patients are likely to have greater benefit from endocrine therapy than others. The structure of the breast is likely to change following endocrine therapy. These structural changes are seen when women have a mammogram (breast x-ray). They appear as a decrease in the area of white tissue (breast density) on the mammogram. We wanted to find out whether reductions in breast density after endocrine therapy can help to determine how well endocrine therapy works.
We searched for previously published studies. We assessed whether a reduction in breast density after receiving endocrine therapy was associated with better outcomes. For women without breast cancer, this focused on whether those with decreased breast density were less likely to develop breast cancer. For women with breast cancer, this included whether those with greater decreases in breast density were less likely to die from breast cancer.
We performed the search on 3 August 2020. We included studies of adult women with breast cancer if the women's breast cancer had been diagnosed at an early stage and could be treated with endocrine therapy (hormone receptor-positive breast cancer). We included drugs often used in practice (tamoxifen and aromatase inhibitors). We found a wide variety of studies. The studies varied in terms of how they had been planned and the characteristics of the women included in the studies, as well as in how breast density change was measured.
Most studies reported a reduced risk of breast cancer after endocrine therapy for women who had a breast density reduction compared with women who did not have a reduction. There was slightly stronger evidence for the drug tamoxifen.
• Two studies reported on breast density reduction following tamoxifen and risk of breast cancer death. The findings were based on 172 women who died from breast cancer. Overall, the certainty of the evidence was low.
• Two studies considered if breast cancer returned after treatment with tamoxifen. There were concerns about the study methods and certainty of findings in these two studies. Overall, the certainty of the evidence was very low.
• One study considered treatment with an aromatase inhibitor and the chance of breast cancer returning. There was considerable uncertainty about the effect size because there were only 175 women in the study. The certainty of the evidence was very low due to potential risk of bias in the study.
• One study considered if breast cancer returned locally or at a distance from the original tumour. There was risk of bias in reporting and uncertainty about the sizes of the effect. The certainty of the evidence for both outcomes was very low.
• Two studies looked at the chance of women with breast cancer being diagnosed later with a new breast cancer, such as in the opposite breast. There was risk of bias in reporting and uncertainty about the size of the effect. The certainty of the evidence was very low.
• One study considered women who had not previously had breast cancer and who received tamoxifen. Results were based on 51 women who developed breast cancer. Overall, the certainty of the evidence was low.
• One study considered whether the beneficial effect of tamoxifen could be explained by a decrease in breast density. There was some evidence to support this, but there was uncertainty about the strength of the effect. The results were based on 51 women who developed breast cancer after receiving tamoxifen. The certainty of the evidence was low.
Overall, we found some evidence that breast density change following tamoxifen therapy is useful information to help determine how well the drug will work in future. However, there is much uncertainty about the strength of this effect. This was due to small numbers of women in the studies, relatively few studies for each outcome, and limitations in many of the studies such as how breast density change was measured. More research is needed to help assess these issues.
Quality of the evidence
Overall, we assessed the certainty of the available evidence as low or very low.
There is low-/very low-certainty evidence to support the hypothesis that breast density change following endocrine therapy is a prognostic biomarker for treatment or prevention. Studies suggested a potentially large effect size with tamoxifen, but the evidence was limited. There was less evidence that breast density change following tamoxifen preventive therapy is a predictive biomarker than prognostic biomarker. Evidence for breast density change as a prognostic treatment biomarker was stronger for tamoxifen than aromatase inhibitors. There were no studies reporting mammographic density change following endocrine therapy as a predictive biomarker in the treatment setting, nor aromatase inhibitor therapy as a prognostic or predictive biomarker in the preventive setting. Further research is warranted to assess mammographic density as a biomarker for all classes of endocrine therapy and review endpoints.
Endocrine therapy is effective at preventing or treating breast cancer. Some forms of endocrine therapy have been shown to reduce mammographic density. Reduced mammographic density for women receiving endocrine therapy could be used to estimate the chance of breast cancer returning or developing breast cancer in the first instance (a prognostic biomarker). In addition, changes in mammographic density might be able to predict how well a woman responds to endocrine therapy (a predictive biomarker). The role of breast density as a prognostic or predictive biomarker could help improve the management of breast cancer.
To assess the evidence that a reduction in mammographic density following endocrine therapy for breast cancer prevention in women without previous breast cancer, or for treatment in women with early-stage hormone receptor-positive breast cancer, is a prognostic or predictive biomarker.
We searched the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers on 3 August 2020 along with reference checking, bibliographic searching, and contact with study authors to obtain further data.
We included randomised, cohort and case-control studies of adult women with or without breast cancer receiving endocrine therapy. Endocrine therapy agents included were selective oestrogen receptor modulators and aromatase inhibitors. We required breast density before start of endocrine therapy and at follow-up. We included studies published in English.
We used standard methodological procedures expected by Cochrane. Two review authors independently extracted data and assessed risk of bias using adapted Quality in Prognostic Studies (QUIPS) and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tools. We used the GRADE approach to evaluate the certainty of the evidence. We did not perform a quantitative meta-analysis due to substantial heterogeneity across studies.
Eight studies met our inclusion criteria, of which seven provided data on outcomes listed in the protocol (5786 women). There was substantial heterogeneity across studies in design, sample size (349 to 1066 women), participant characteristics, follow-up (5 to 14 years), and endocrine therapy agent. There were five breast density measures and six density change definitions. All studies had at least one domain as at moderate or high risk of bias. Common concerns were whether the study sample reflected the review target population, and likely post hoc definitions of breast density change.
Most studies on prognosis for women receiving endocrine therapy reported a reduced risk associated with breast density reduction. Across endpoints, settings, and agents, risk ratio point estimates (most likely value) were between 0.1 and 1.5, but with substantial uncertainty. There was greatest consistency in the direction and magnitude of the effect for tamoxifen (across endpoints and settings, risk ratio point estimates were between 0.3 and 0.7). The findings are summarised as follows.
Prognostic biomarker findings:
Breast cancer mortality
Two studies of 823 women on tamoxifen (172 breast cancer deaths) reported risk ratio point estimates of ~0.4 and ~0.5 associated with a density reduction. The certainty of the evidence was low.
Two studies of 1956 women on tamoxifen reported risk ratio point estimates of ~0.4 and ~0.7 associated with a density reduction. There was risk of bias in methodology for design and analysis of the studies and considerable uncertainty over the size of the effect.
One study of 175 women receiving an aromatase inhibitor reported a risk ratio point estimate of ~0.1 associated with a density reduction. There was considerable uncertainty about the effect size and a moderate or high risk of bias in all domains.
One study of 284 women receiving exemestane or tamoxifen as part of a randomised controlled trial reported risk ratio point estimates of ~1.5 (loco-regional recurrence) and ~1.3 (distance recurrence) associated with a density reduction. There was risk of bias in reporting and study confounding, and uncertainty over the size of the effects.
The certainty of the evidence for all recurrence endpoints was very low.
Incidence of a secondary primary breast cancer
Two studies of 451 women on exemestane, tamoxifen, or unknown endocrine therapy reported risk ratio point estimates of ~0.5 and ~0.6 associated with a density reduction. There was risk of bias in reporting and study confounding, and uncertainty over the effect size. The certainty of the evidence was very low.
We were unable to find data regarding the remaining nine outcomes prespecified in the review protocol.
Incidence of invasive breast cancer and ductal carcinoma in situ (DCIS)
One study of 507 women without breast cancer who were receiving preventive tamoxifen as part of a randomised controlled trial (51 subsequent breast cancers) reported a risk ratio point estimate of ~0.3 associated with a density reduction. The certainty of the evidence was low.
Predictive biomarker findings:
One study of a subset of 1065 women from a randomised controlled trial assessed how much the effect of endocrine therapy could be explained by breast density declines in those receiving endocrine therapy. This study evaluated the prevention of invasive breast cancer and DCIS. We found some evidence to support the hypothesis, with a risk ratio interaction point estimate ~0.5. However, the 95% confidence interval included unity, and data were based on 51 women with subsequent breast cancer in the tamoxifen group. The certainty of the evidence was low.