Re: Influence of breast density on breast cancer diagnosis. Authors reply

The authors would like to thank Dr Paula Gordon for her time and thought in reviewing our article and for providing valuable feedback for consideration. We agree that changes in menopausal status and hormone therapy use are known to affect assessed breast density, and physicians should consider these potential influences for patients with varying assessed density. Nevertheless, sequential variation in BI-RADS assessed density may have no apparent cause, and this is an attribute of current density assessment.

While our results were concordant with the previously reported phenomenon of population average breast density decreasing with age,[1] it is correct that we did not investigate the possibility of a concurrent influence of menopause. The observed distribution of breast density by age (Figure 3 in our article) does not confirm an aberration in the trend for each density category, but as indicated menopause may have been a factor.    

Regarding a possible influence of hormone therapy, of the 62 887 mammogram pairs eligible for the determination of the stability of reported breast density, reported usage (“no” or “yes”) was stable in 59 181, or 94%. This was unlikely, then, to have had a significant role in density assessment.

The reported relative risk of breast cancer for combined estrogen and progestin ranges from 1.3 to 2.0 for 5+ and 10+ years of usage respectively.[2,3] The available program data for hormone use were limited to self-reporting of current use only. It would have, therefore, been difficult to acquire reliable measures for the duration of usage, and this limitation was thus unavoidable. We do note that just under 10% of the cohort analyzed for breast cancer risk reported current hormone usage.

Currently our screening guidelines divide age-eligible women into two groups for mammography screening: average risk and higher-than-average risk (first-degree family history). We agree with Dr Gordon that within each group other factors influence an individual woman’s risk of breast cancer, but we used the existing determinants of screening frequency to present our findings.

We agree that a previous false positive screen has been shown to increase breast cancer risk. This has been demonstrated externally,[4] and also by a review of over 4 million mammograms of our provincial program from 1988–2013, which demonstrated a relative risk of 1.73 after an initial false positive.[5] In clarification of our methodology, please note that such cases were not necessarily excluded from our analysis. The inclusion criteria of a screening round included that it began with a negative screen, but the individual may have had a false positive in the past. This was done in recognition of the further testing that these individuals would have undergone and to minimize the possibility of subsequent screening mammography performance being influenced by factors other than breast density. Our results may thus be best suited for facilitating discussion with screening participants whose most recent screen was normal, but who may have had a prior abnormal screen.

The primary aim of population breast screening is to reduce the risk of death from breast cancer among BC women. While we concur that a decrease in interval cancer is likely a requisite of reduced mortality, we also note that it does not guarantee a reduction. Reduced risk of breast cancer death is most reliably indicated by reductions in the rate of advanced cancer at diagnosis. In considering the effect of screening on advanced cancer, it is important to consider both screen-detected and interval cancers as a whole, not just those cancers detected at screening: one extra early stage screen-detected cancer does not necessarily translate into one less advanced interval cancer. We would like to clarify that we have not stated that “there is no evidence to support supplemental screening,” as Dr Gordon writes in her letter. Indeed we have cited the same Japanese trial,[6] and agree that a decrease in interval cancers has been demonstrated for supplemental ultrasound in this randomized study. However, the first round of this trial, which compared mammography alone to mammography plus ultrasound, found that the addition of ultrasound resulted in a further detection (by ultrasound alone) of 61 cases of breast cancer of which 48 were early (9 stage 0 cases, and 39 stage I cases), but a reduction of only one case of stage II or worse interval cancer.

We have also referenced a meta-analysis of supplemental ultrasound[7] in order to report the increased cancer detection of this test, but we disagree that these additional cancers would necessarily present as interval cancers. The increased detection observed in the randomized trial, for example, exceeds the decrease in interval cancers.[6] The difference could include additional subsequent interval cancers, but the balance with cancers that would be detected at the next mammography screen and overdiagnosis has yet to be determined.

The authors completely agree that shared and informed decision making be facilitated as best possible, and this was a key objective of our article. Again, we are thankful to Dr Gordon for sharing her insight and for this discussion of such an important topic in breast health.
—Colin Mar, MD, FRCPC
Medical Director, BC Cancer Breast Screening Program
On behalf of all authors

This letter was submitted in response to “The influence of breast density on breast cancer diagnosis: A study of participants in the BC Cancer Breast Screening Program.”

References

1.    Sprague BL, Gangnon RE, Burt V, et al. Prevalence of mammographically dense breasts in the United States. J Natl Cancer Inst 2014;106:dju255.

2.    Singletary SE. Rating the risk factors for breast cancer. Ann Surg 2003;237:474-482.

3.    Thun MJ, Linet MS, Cerhan JR, et al. Editors. Schottenfeld and Fraumeni. Cancer epidemiology and prevention. 4th ed. New York, NY: Oxford University Press; 2018.

4.    Castells X, Torá-Rocamora I, Posso M, et al. Risk of breast cancer in women with false-positive results according to mammographic features. Radiology 2016;280:379-386.

5.    Rajapakshe R, Hui M, Farnquist BA, et al. Risk of breast cancer after a false-positive screening mammogram in relation to mammographic abnormality: Potential for prevention? Abstract presented at the 104th Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, USA, November 2018.

6.    Ohuchi N, Suzuki A, Sobue T, et al. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): A randomised controlled trial. Lancet 2016;387(10016):341-348.

7.    Rebolj M, Assi V, Brentnall A, et al. Addition of ultrasound to mammography in the case of dense breast tissue: Systematic review and meta-analysis. Br J Cancer 2018:1.