Breast cancer screening and prevention: Results that matter

Randomized controlled trials have established that mammography reduces breast cancer mortality.¹ However, mammography is less effective in women with dense breasts.  The American College of Radiology’s Breast Imaging Reporting and Data System (BIRADS) classifies breast density into 4 categories: almost entirely fatty, scattered areas of fibroglandular density, heterogeneously dense and extremely dense.  Approximately 43% of women between ages 40 and 74 have heterogeneously or extremely dense breasts, and the proportion is inversely related to age and BMI.² The relative hazard of breast cancer for these women ranges from 1.5 to 2.1 compared to women without dense breasts.³ Beginning in 2009, many states enacted mandatory reporting of breast density category to women at the time of their mammogram.  While the content and inclusion criteria of this notification varies from state to state, women classified as having heterogeneously or extremely dense breasts are urged to discuss alternatives to annual screening with health care providers. 

Low-risk women

Unfortunately, there is no consensus regarding the need for, and optimal type of, supplementary breast imaging for women at otherwise low risk for breast cancer.  Of the 30 states that currently mandate breast density notification, only 4 require insurers to cover additional testing, and a co-pay may be necessary. A woman with high-density breasts on mammogram who has chosen to have additional testing after discussion with her provider may incur out-of-pockets expenses of $100 to more than $1,000.  Supplementary testing in low-risk women with high-density breast tissue has not consistently demonstrated improved breast cancer detection and reduced mortality. A recent systematic review evaluated the reproducibility of the American College of Radiology’s Breast Imaging Reporting and Data System (BI-RADS), and the performance of supplementary screening of women with dense breasts to detect breast cancer.⁴ On subsequent screening, 13-19% of women were reclassified from dense to nondense breasts or vice versa on subsequent screening. Supplemental screening modalities for women with dense breasts on mammogram included breast ultrasound, breast magnetic resonance imaging (MRI) and digital breast tomosynthesis (DBT or 3D mammography).  From the limited available studies of women with dense breast tissue on mammogram, supplemental screening modalities found additional breast cancers, but also increased false-positive results and recall rates with no demonstrable improvement in breast cancer outcomes. DBT increased breast cancer detection (1.4-2.5 cases per 1,000 examinations) compared to mammography alone with the lowest recall rates (7-11%), with almost double the radiation exposure from each screening exam.⁴

Based upon current data, the American College of Obstetricians and Gynecologists has not endorsed routine use of adjunctive testing for women with dense breasts who are otherwise at low risk for breast cancer, given the uncertain benefits of enhanced breast cancer detection balanced against the associated costs and false positive screening results.

New findings using an online tool that incorporates clinical risk for breast cancer and breast density findings may facilitate more informed conversations about the benefit of supplementary imaging for women with dense breasts.⁵ The Breast Cancer Surveillance Consortium (BCCS) calculator (https://tools.bcsc-scc.org/bc5yearrisk/calculator.htm) has been validated to predict breast cancer in more than 1 million women who have had mammograms, and is equivalent to or slightly better than existing clinical models that predict cancer risk. The 5-year risk of breast cancer is derived from a woman’s age, race/ethnicity, family history of breast cancer, history of breast biopsy and BI-RADS breast density classification. In a prospective cohort of over 365,000 women, the BCSC calculator, which includes the BI-RADS classification of breast density findings on mammogram, better predicted rates of interval cancers within 12 months of a normal mammogram than BI-RADS dense breast classification alone.  The authors concluded that breast density alone should not be the sole criteria for deciding whether supplemental imaging is indicated because not all women with dense breasts have high rates of interval cancers.  Rather, the BCSC 5-year risk which includes BI-RADS breast density classification can better identify women with high risk of interval cancer to allow for more targeted approaches to breast cancer screening. 

Novel mammographic software models that attempt to more reliably quantify dense breast tissue may better predict the risk of breast cancer.  One study compared 3 metrics for breast density: (1) software-modeled percentage of dense tissue; (2) software-modeled volume of dense tissue; and (3) conventional, qualitative BIRADS classification of density, in a cohort of 125 women with breast cancer and 274 controls. The qualitative BIRADS classification correlated better with breast cancer risk than either of the software modeled measures of breast density.⁶ A larger case-control study of 1,720 women with breast cancer and 3,330 controls found that the BCSC risk model with volumetric and BIRADS breast density outperformed the risk model with either measure of breast density alone.⁷

NEXT: High-risk women

High-risk women

Risk assessment and interventions to reduce breast cancer among high-risk women remain underutilized in the United States. Approximately 15% of women between ages 35 and 79 meet the criteria for elevated risk of breast cancer: 1.67% 5-year risk or lifetime risk of 20% or greater.⁸ Several breast cancer risk assessment tools exist that combine known major risk factors predicting the probability of a woman having a disease-causing mutation in genes such as BRCA, or of developing invasive breast cancer. In high-risk women, ancillary testing with annual MRI has resulted in better detection of breast cancer and fewer interval cancers following mammography, independent of breast density.⁹

Fewer than 5% of potentially eligible high-risk women have taken advantage of chemoprevention against breast cancer, including 2 US Food and Drug Administration- approved selective estrogen receptor modulators (tamoxifen and raloxifene), and more recently, the aromatase inhibitor exemestane. Patient acceptance of tamoxifen and raloxifene has been poor due to the drug’s rare but serious adverse side effects, including endometrial cancer and stroke. In a phase III trial of 4,500 women randomized to exemestane or placebo, exemestane reduced the incidence of invasive breast cancer by 65% with no serious adverse events and only minimal quality-of-life differences compared to placebo.⁹ Other promising chemopreventative drugs such as tibolone, lasofoxifene and arzoxifene appear to have more favorable side effect profiles and merit further study of patient acceptability.¹⁰

Take-home message

As primary health care providers for women, we need to educate ourselves, and our patients, about evolving technologies in breast cancer prevention and screening.  Ob/ gyns should be vigilant in screening women for potential hereditary cancer syndromes based upon their personal and family histories. Genetic counseling and testing can identify these high-risk women who benefit the most from effective risk-reducing interventions, including chemoprevention. For women with lower baseline risk of breast cancer, enhanced breast screening tests must demonstrate improved patient outcome and combine efficacy with acceptable cost. 

References

1.    Tabar L, Yen, Naik A, et al. Screening for breast cancer: an update for the U.S. Preventative Services Task Force. Ann Intern Med. 2009;151(10):727-37.

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

3.    ACOG Committee Opinion 625, Management of women with dense breasts diagnosed by mammography. 2015.

4.    Melkinow J, Fenton JJ, Whitlock EP, et al. Supplemental screening for breast cancer in women with dense breasts: a systematic review for the U.S. Preventative Task Force. Ann Intern Med. 2016;164(4):268-78.

5.    Kerlikowske K, Zhu W, Tosteson AN, et al. Identifying women with dense breasts at high risk for interval cancers, A cohort study. Ann Intern Medicine. 2015; 162:673-681.

6.    Jeffers AM, Sieh W, Lipson JA, et al Breast cancer risk and mammographic density assessed with semi-automated and fully automated methods and BI-RADS. Radiology. 2017;282(2):348-55.

7.    Kerlikowske K, Ma L, Scott CG, et al Combining quantitative and qualitative breast density measures to assess breast cancer risk. Breast Cancer Res. 2017;19(1).

8.    Goss PE, Ingle JN, Ales-Martinez JE et al, Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381-91.

9.    Berg WA. Tailored supplemental screening for breast cancer: what now and what next?  Am J Roentgenol. 2009;192(2): 390-9.

10. Mocellin S, Pilati P, Briarava M, Nitti D. Breast cancer chemoprevention: a network meta-analysis of randomized trials. J Natl Cancer Inst. 2015: 108(2).