In their letter, it is suggested that our sample size of 6081 examinations was “small” and should be considered in the context of results across 25 series encompassing more than 363 000 screens. Of the studies cited, 18 were single-institution studies, and 12 had sample sizes smaller than our study. The studies also included heterogeneous populations of women with varying distributions of breast density and underlying risk, which precludes summation of conclusive evidence across studies, as suggested. Our study of women receiving screening ultrasonography as part of routine clinical practice in the United States reported significant increases in false-positive biopsy rates without significant increase in cancer detection rates or decrease in interval cancer rates. Our conclusions apply to the observed cohort, and our study of multiple facilities with linkage to state and regional cancer registries adds high-quality evidence to the published literature.
Another comment indicated that for some women, false-positive ultrasonography results may be well tolerated compared with late-stage cancer diagnosis after a false-negative results of a screening mammogram. We agree that a woman may accept a greater likelihood of a biopsy with benign results compared with an increased risk of being diagnosed with an advanced cancer. However, many women in our cohort were at low to average risk or had nondense breasts. For these women, supplemental ultrasonography screening may not have been a good recommendation or choice. Even in high-risk women, most will not have breast cancer. Consequently, many false-positive results will be incurred in healthy women for each potential false-negative result that may be averted by supplemental screening. It is a worthy goal to increase early breast cancer detection, but we need clear selection criteria for supplemental ultrasonography use and decision aids about the likelihood of additional downstream testing.
One noted flaw in our study was lack of information regarding specifics of ultrasonography technique and documentation. We recognized this limitation in the Discussion section of our article, and it is likely that experience and quality were variable. Thus, we stated the importance of ensuring increased capacity of skilled imaging technicians so that any woman who may benefit from supplemental ultrasonography screening will have access to a high-quality procedure.
We appreciate the opportunity to clarify a comment about omissions in reporting of prevalent vs incident examinations, interval cancers, and stage at diagnosis. We presented this information in the Results section: “When recall rate, biopsy recommendation rate, and cancer detection rate were stratified by first vs subsequent mammography plus ultrasonography examinations (n = 2040 and n = 4041, respectively), all rates declined significantly on subsequent examinations.”1(p662) In addition, interval cancer rates were presented in Table 3, and stage at diagnosis was presented in Table 4.
Table 3.
Estimated Performance Measures and Results From Log Binomial Regression Analysis
| Variable | Mammography Plus Ultrasonography | Mammography Alone (Matched) | Relative Risk (95% CI)a |
|---|---|---|---|
| BI-RADS end-of-day assessment, No. (%) | |||
| 0 (Needs additional imaging) | 21 (0.3) | 5159 (17.2) | NA |
| 1 (Negative) | 2689 (44.2) | 23 909 (79.5) | NA |
| 2 (Benign) | 2793 (45.9) | 878 (2.9) | NA |
| 3 (Probably benign) | 234 (3.8) | 64 (0.2) | NA |
| 4 (Suspicious) | 342 (5.6) | 49 (0.2) | NA |
| 5 (Highly suspicious) | 2 (0.0) | 3 (0.0) | NA |
| Total | 6081 (100) | 30 062 (100) | NA |
| Performance based on end-of-day assessment | |||
| Recall rate for additional imaging or biopsy, % (95% CI) | 9.9 (9.1–10.6) | 17.6 (17.1–18.0) | 0.52 (0.48–0.57) |
| End-of-day assessment of 0, 3, 4, 5, No. | 599 | 5275 | NA |
| Total examinations, No. | 6081 | 30 062 | NA |
| Final assessment, No. (%) | |||
| 0 (Needs additional imaging) | 5 (0.1) | 104 (0.3) | NA |
| 1 (Negative) | 2694 (44.3) | 26 848 (89.3) | NA |
| 2 (Benign) | 2798 (46.0) | 1936 (6.4) | NA |
| 3 (Probably benign) | 235 (3.9) | 341 (1.1) | NA |
| 4 (Suspicious) | 347 (5.7) | 792 (2.6) | NA |
| 5 (Highly suspicious) | 2 (0.0) | 41 (0.1) | NA |
| Total | 6081 (100) | 30 062 (100) | NA |
| Performance based on final assessment | |||
| Biopsy recommendation rate per 1000 screens (95% CI) | 57.4 (51.9–63.5) | 27.7 (25.9–29.7) | 2.05 (1.79–2.34) |
| Final assessment of 4, 5, No.b | 349 | 833 | NA |
| Total examinations, No. | 6081 | 30 062 | NA |
| Short-interval imaging follow-up rate (95% CI) | 3.9 (3.4–4.4) | 1.1 (1.0–1.3) | 3.10 (2.60–3.70) |
| Final assessment of 3, No. | 235 | 341 | NA |
| Total examinations, No. | 6081 | 30 062 | NA |
| Sensitivity (95% CI) | 78.6 (67.1–92.0) | 73.8 (68.1–80.0) | 1.08 (0.92–1.27) |
| Final assessment of 4, 5 and cancer, No. | 33 | 155 | NA |
| Total cancers, No. | 42 | 210 | NA |
| Specificity (95% CI) | 94.8 (94.2–95.3) | 97.7 (97.6–97.9) | 0.97 (0.97–0.98) |
| Final assessment of 0, 1, 2, 3 and no cancer, No. | 5719 | 29 169 | NA |
| Noncancers, No. | 6035 | 29 843 | NA |
| PPV2 (95% CI) | 9.5 (6.8–13.1) | 21.4 (19.6–23.5) | 0.50 (0.35–0.71) |
| Final assessment of 4, 5 and cancer | 33 | 367 | NA |
| Biopsy recommended (final assessment of 4, 5) | 349 | 1713 | NA |
| Cancer detection rate per 1000 screens (95% CI) | 5.4 (3.9–7.6) | 5.5 (4.7–6.4) | 1.14 (0.76–1.68) |
| Final assessment of 4, 5 and cancer | 33 | 165 | NA |
| Total examinations | 6081 | 30 062 | NA |
| False-negative rate per 1000 screens (95% CI)c | 1.5 (0.8–2.8) | 1.9 (1.4–2.4) | 0.67 (0.33–1.37) |
| Final assessment of 0, 1, 2, 3 and cancer, No. | 9 | 56 | NA |
| Total examinations, No. | 6081 | 30 062 | |
| Cancer rate per 1000 screens (95% CI) | 6.9 (5.1–9.3) | 7.4 (6.4–8.4) | 0.99 (0.70–1.42) |
| All cancers, No. | 42 | 221 | NA |
| Total examinations, No. | 6081 | 30 062 | NA |
| False-positive biopsy recommendation rate per 1000 (95% CI) | 52.0 (46.7–57.8) | 22.2 (20.6–24.0) | 2.23 (1.93–2.58) |
| Final assessment of 4, 5 and no cancer, No. | 316 | 668 | NA |
| Total examinations, No. | 6081 | 30 062 | NA |
Abbreviations: BI-RADS, Breast Imaging Reporting and Data System; DCIS, ductal carcinoma in situ; NA, not applicable; PPV2, positive predictive value of biopsy recommendation.
Relative risk is from log binomial model adjusted for site, age, menopausal status, first-degree family history of breast cancer, year of examination, prior benign biopsy result, and correlation among women within the same matched set using generalized estimated equations. Sensitivity was adjusted for site and first-degree family history of breast biopsy.
Final assessment of 4, 5 considered a positive examination result and was used to calculate performance measures.
False-negative rate includes both invasive and DCIS.
Table 4.
Characteristics of Breast Cancers Occurring Within 1 Year of the Screening Examination Among the Study Groups
| No./Total No. (%) | |||
|---|---|---|---|
| Mammography Plus Ultrasonography | Mammography Alone (Matched) | Mammography Alone (Overall) | |
| Total | 249 | 470 | 719 |
| Cancer histology | |||
| Noninvasive (DCIS) | 20/42 (47.6) | 77/221 (34.8) | 249/719 (34.6) |
| Invasive | 22/42 (52.4) | 144/221 (65.2) | 470/719(65.4) |
| Ductal | 19/20 (95.0) | 113/141 (80.1) | 384/458 (83.8) |
| Lobular | 1/20 (5.0) | 20/141 (14.2) | 50/458 (10.9) |
| Mixed | 0/20 | 8/141 (5.7) | 24/458 (5.2) |
| Other/unknown | 2 | 3 | 12 |
| Invasive tumor size, mm | |||
| 1–5 | 2/20 (10.0) | 8/140 (5.7) | 48/454 (10.6) |
| 6–10 | 5/20 (25.0) | 37/140 (26.4) | 116/454 (25.6) |
| 11–15 | 3/20 (15.0) | 25/140 (17.9) | 87/454 (19.2) |
| 16–20 | 3/20 (15.0) | 26/140 (18.6) | 74/454 (16.3) |
| >20 | 7/20 (35.0) | 44/140 (31.4) | 129/454 (28.4) |
| Unknown | 2 | 4 | 16 |
| Minimal cancer | |||
| No | 13/41 (31.7) | 95/210 (45.2) | 290/691 (42.0) |
| Yes | 28/41 (68.3) | 115/210 (54.8) | 401/691 (58.0) |
| Unknown | 1 | 11 | 28 |
| Axillary lymph node status | |||
| Negative | 35/41 (85.4) | 183/219 (83.6) | 620/708 (87.6) |
| Positive | 6/41 (14.6) | 36/219 (16.4) | 88/708 (12.4) |
| Unknown | 1 | 2 | 11 |
| AJCC stage | |||
| 0 | 20/41 (48.8) | 77/219 (35.2) | 249/706 (35.3) |
| I | 11/41 (26.8) | 85/219 (38.8) | 297/706 (42.1) |
| II | 8/41 (19.5) | 43/219 (19.6) | 131/706 (18.6) |
| III | 2/41 (4.9) | 13/219 (5.9) | 24/706 (3.4) |
| IV | 0/41 | 1/219 (0.5) | 5/706 (0.7) |
| Unknown | 1 | 2 | 13 |
| Grade of invasive cancer | |||
| 1 | 8/19 (42.1) | 48/138 (34.8) | 173/448 (38.6) |
| 2 | 8/19 (42.1) | 62/138 (44.9) | 191/448 (42.6) |
| 3 | 3/19 (15.8) | 28/138 (20.3) | 84/448 (18.8) |
| Unknown | 3 | 6 | 22 |
| Hormone receptor status of invasive cancer | |||
| ER+ or PR+ | 17/21 (81.0) | 134/142 (94.4) | 426/457 (93.2) |
| ER− and PR− | 4/21 (19.0) | 8/142 (5.6) | 31/457 (6.8) |
| Unknown | 1 | 2 | 13 |
Abbreviation: AJCC, American Joint Committee on Cancer; DCIS, ductal carcinoma in situ; ER, estrogen receptor; PR, progesterone receptor.
Referring health care providers, radiologists, and women in our care need evidence that supplemental ultrasonography outside of experimental settings can be delivered with a more favorable tradeoff of benefits (as measured by reduction in rates of interval cancers, advanced cancers, or both) vs harms than we observed in our data.
Acknowledgments
We thank Mendelson and colleagues for their interest in our study.1
Footnotes
Conflict of Interest Disclosures: Dr Lee reports receiving a research grant from the National Institutes of Health’s National Cancer Institute (P01CA154292) as well serving as a consultant for GE Healthcare. No other disclosures are reported.
References
- 1.Lee JM, Arao RF, Sprague BL, et al. Performance of screening ultrasonography as an adjunct to screening mammography in women across the spectrum of breast cancer risk. JAMA Intern Med. 2019;179(5):658–667. doi: 10.1001/jamainternmed.2018.8372 [DOI] [PMC free article] [PubMed] [Google Scholar]