LETTER TO THE EDITOR
Response to Miller et al. To the Editor: Miller et al. (1) challenge our estimate (2) of the rate of advanced breast cancers, which we defined as the node positive cases in the Canadian Breast Cancer Screening Study (CNBSS), noting that “We have never reported node status of ascertained breast cancers year by year, but during the first year after randomisation, and then only to years 2–5 combined.” Although this is true, they have published sufficient data to carry out a more exact estimate of the cumulative advanced cancer rate. As we will demonstrate, contrary to Miller et al.’s assertion that “the data appears to have been derived by some obscure process which distorts the data we have previously reported,” we derived our estimate (see Fig. 1 and Table 1), from tabular data for women ages 40–49 and 50–59 years from Tables 6 and 7 in the same two manuscripts (3,4) cited by Miller, et al., as references 2 and 3 (1). The total number of node positive cases (number of nodes greater than 1) was 188 (77 in year 1, and 111 in years 2–5) in the mammography (M) arm, and 149 (58 in year 1, and 91 in years 2–5) in the usual care (UC) arm, which was derived from Table 7 in the two original papers (3,4). For the intervening years, we estimated the cumulative numbers by linear interpolation. The total person-years were 221,247 for the M arm and 222,004 for the UC arm derived from Table 6 in the two original papers (3,4). This gave a relative rate of 1.27 [(188/221,247)/(149/222,004)] of the advanced breast cancer rate (95% CI: 1.02–1.57), which is the RR value for the CNBSS we put in Figure 3 (a) in our manuscript in the Breast Journal (2). From the published results, we cannot reproduce the node positive rates of 447 per 100,000 in the M arm and 378 per 100,000 in the UC arm, as reported by Miller et al. in their letter (1). We therefore submit that our figure 3(a) should stand as a valid representation of the published trial results. The linear interpolaszlo Taba r, DepartAddress correspondence and reprint requests to: La ment of Mammography, Falun Central Hospital, 79182 Falun, Sweden, or e-mail: [email protected] DOI: 10.1111/tbj.12439 © 2015 Wiley Periodicals, Inc., 1075-122X/15 The Breast Journal, Volume 21 Number 4, 2015 459–461
Figure 1. Cumulative incidence of node positive disease by time, with interpolated estimates for years 2, 3 and 4.
tion we had to use in the absence of individual annual data appears to be a good approximation, when one compares the shape of our Figure 3(a) with Miller et al.’s Figure 1. The only explanation for the disparity is that the total counts they used to produce the new figure are different from those reported in the original papers. We can hardly be criticized for deriving our estimates from their published papers. But here is the important point—whether our figures are used or theirs, there still is an excess of advanced breast cancers at the end of the trial in the M arm compared with the UC arm, which is consistent with the CNBSS having not shown a mortality benefit from screening. If on the other hand, the new numbers cited here are correct, it is gratifying that the new results begin to be rather more in line with those of other trials and, as noted in their BMJ paper (5), when the prevalence screen tumors are excluded, a 10% reduction in breast cancer mortality is observed associated with an invitation to screening. Regarding tumor size larger than 2 cm, we used the same tabular data retrieved from the original papers (6,7) and we did the same calculation as for lymph node positive cases. The relative rate was 0.90 (95% CI: 0.75–1.08), which was very close to the figure 0.90 (95% CI: 0.74–1.10) reported in the letter to editor (1). However, we are very surprised to see that the cumulative rates for advanced breast cancer defined by tumor size larger than 2 cm are lower (342 per 100,000 in the M arm and 380 per 100,000 in the
460 • letter to the editor
Table 1. Calculation of cumulative incidence of node positive disease from published CNBSS tables Person-years (A) Study (MP) 0 1
2 3 4 5 2–5
Year 1–5 Control (UC/PO) 0 1
44,614
Cases with nodes positive (B)
77
44,425 44,262 44,054 43,892 176,633
27.75 27.75 27.75 27.75 111
221,247
188
44,700
58
2 3 4 5 2–5
44,553 44,403 44,246 44,102 177,304
Year 1–5
222,004
22.75 22.75 22.75 22.75 91
Rate
Cum Rate
172.59
0 172.59
62.46 62.69 62.99 63.22
235.06 297.75 360.74 423.97
Sources for (B)
(33 SDs + 8 ICs) (for 40–49, Ref 3, Table 7)+ (31 SDs + 5 ICs) (for 50–59, Ref 4, Table 7) = 77
(33 SDs + 13 ICs + 9 Incident cases) (for 40–49, Ref 3, Table 7)+ (40 SDs + 10 ICs + 6 Incident cases) (for 50–59, Ref 4, Table 7) = 111
129.75
0 129.75
51.06 51.24 51.42 51.58
180.82 232.05 283.47 335.05
(21 SDs + 7 ICs) (for 40–49, Ref 3, Table 7)+ (22 SDs + 8 ICs) (for 50–59, Ref 4, Table 7)
(35 Incident cancers) (for 40–49, Ref 3, Table 7)+ (32 SDs + 18 ICs + 6 Incident cancers) (for 50–59, Ref 4, Table 7) = 91
149
Column (A) and Column (C) come from the reported person-years (shown in the original Table 6) in the two accompanying papers for 40–49 and 50–59 in 1992 Can Med Assoc J (3,4).
UC arm) than those for advanced breast cancer defined by node status (447 per 100,000 in the M arm and 378 per 100,000 in the UC arm). What is commonly observed is just the opposite, i.e., the cumulative rates for node positive cancers are lower than those for tumor sizes larger than 2.0 cm, simply because some large tumors are node negative (8). The explanation of ascertainment bias as the source of the higher rate of node positivity in the M arm appears to us to raise more questions than it answers. If axillary evaluations were more thorough in the M arm compared with the UC arm, there is now another cause for concern about the validity and credibility of the CNBSS end results because it suggests another source of bias not overcome by the randomization. L aszl o Tab ar, MD PhD* Hsiu-Hsi Chen, PhD† Amy Ming-Fang Yen, PhD‡ Sam Li-Sheng Chen, PhD‡ Jean Ching-Yuan Fann, PhD§
Sherry Yueh-Hsia Chiu, PhD¶ Robert A. Smith, PhD** Stephen W.Duffy, Msc†† *Department of Mammography Central Hospital Falun Sweden; † Graduate Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan; ‡ School of Oral Hygiene Taipei Medical University Taipei Taiwan; § Department of Health Industry Management School of Healthcare Management Kainan University Taoyuan Taiwan;
Letter to the Editor • 461
¶
Department and Graduate Institute of Health Care Management Chang Gung University Taoyuan Taiwan; **American Cancer Society Atlanta Georgia; and ††Centre for Cancer Prevention Wolfson Institute of Preventive Medicine Queen Mary University of London London UK REFERENCES
1. Miller AB, Wall C, Baines CJ, To T. Re: Insights from the breast cancer screening trials: how screening affects the natural history of breast cancer and implications for evaluating service screening programs. Breast J 2015. In press. 2. Tab ar L, Yen AM, Wu WY, et al. Insights from the breast cancer screening trials: how screening affects the natural history of breast cancer and implications for evaluating service screening programs. Breast J 2015;21:13–20.
3. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years [published erratum appears in Can Med Assoc J 1993 Mar 1;148(5):718] [see comments]. CMAJ 1992;147:1459–76. 4. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years [published erratum appears in Can Med Assoc J 1993 Mar 1;148(5):718] [see comments]. CMAJ 1992;147:1477–88. 5. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014;348:g366. 6. Miller AB, To T, Baines CJ, Wall C. Canadian national breast screening study-2: 13-year results of a randomized trial in women aged 50-59 years [In Process Citation]. J Natl Cancer Inst 2000;92:1490–9. 7. Miller AB, To T, Baines CJ, Wall C. The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med 2002;137: 305–12. 8. Tabar L, Fagerberg G, Duffy SW, Day NE, Gad A, Grontoft O. Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 1992;30: 187–210.
Response to Miller et al. To the Editor: Miller et al. (1) challenge our estimate (2) of the rate of advanced breast cancers, which we defined as the node positive cases in the Canadian Breast Cancer Screening Study (CNBSS), noting that “We have never reported node status of ascertained breast cancers year by year, but during the first year after randomisation, and then only to years 2–5 combined.” Although this is true, they have published sufficient data to carry out a more exact estimate of the cumulative advanced cancer rate. As we will demonstrate, contrary to Miller et al.’s assertion that “the data appears to have been derived by some obscure process which distorts the data we have previously reported,” we derived our estimate (see Fig. 1 and Table 1), from tabular data for women ages 40–49 and 50–59 years from Tables 6 and 7 in the same two manuscripts (3,4) cited by Miller, et al., as references 2 and 3 (1). The total number of node positive cases (number of nodes greater than 1) was 188 (77 in year 1, and 111 in years 2–5) in the mammography (M) arm, and 149 (58 in year 1, and 91 in years 2–5) in the usual care (UC) arm, which was derived from Table 7 in the two original papers (3,4). For the intervening years, we estimated the cumulative numbers by linear interpolation. The total person-years were 221,247 for the M arm and 222,004 for the UC arm derived from Table 6 in the two original papers (3,4). This gave a relative rate of 1.27 [(188/221,247)/(149/222,004)] of the advanced breast cancer rate (95% CI: 1.02–1.57), which is the RR value for the CNBSS we put in Figure 3 (a) in our manuscript in the Breast Journal (2). From the published results, we cannot reproduce the node positive rates of 447 per 100,000 in the M arm and 378 per 100,000 in the UC arm, as reported by Miller et al. in their letter (1). We therefore submit that our figure 3(a) should stand as a valid representation of the published trial results. The linear interpolaszlo Taba r, DepartAddress correspondence and reprint requests to: La ment of Mammography, Falun Central Hospital, 79182 Falun, Sweden, or e-mail: [email protected] DOI: 10.1111/tbj.12439 © 2015 Wiley Periodicals, Inc., 1075-122X/15 The Breast Journal, Volume 21 Number 4, 2015 459–461
Figure 1. Cumulative incidence of node positive disease by time, with interpolated estimates for years 2, 3 and 4.
tion we had to use in the absence of individual annual data appears to be a good approximation, when one compares the shape of our Figure 3(a) with Miller et al.’s Figure 1. The only explanation for the disparity is that the total counts they used to produce the new figure are different from those reported in the original papers. We can hardly be criticized for deriving our estimates from their published papers. But here is the important point—whether our figures are used or theirs, there still is an excess of advanced breast cancers at the end of the trial in the M arm compared with the UC arm, which is consistent with the CNBSS having not shown a mortality benefit from screening. If on the other hand, the new numbers cited here are correct, it is gratifying that the new results begin to be rather more in line with those of other trials and, as noted in their BMJ paper (5), when the prevalence screen tumors are excluded, a 10% reduction in breast cancer mortality is observed associated with an invitation to screening. Regarding tumor size larger than 2 cm, we used the same tabular data retrieved from the original papers (6,7) and we did the same calculation as for lymph node positive cases. The relative rate was 0.90 (95% CI: 0.75–1.08), which was very close to the figure 0.90 (95% CI: 0.74–1.10) reported in the letter to editor (1). However, we are very surprised to see that the cumulative rates for advanced breast cancer defined by tumor size larger than 2 cm are lower (342 per 100,000 in the M arm and 380 per 100,000 in the
460 • letter to the editor
Table 1. Calculation of cumulative incidence of node positive disease from published CNBSS tables Person-years (A) Study (MP) 0 1
2 3 4 5 2–5
Year 1–5 Control (UC/PO) 0 1
44,614
Cases with nodes positive (B)
77
44,425 44,262 44,054 43,892 176,633
27.75 27.75 27.75 27.75 111
221,247
188
44,700
58
2 3 4 5 2–5
44,553 44,403 44,246 44,102 177,304
Year 1–5
222,004
22.75 22.75 22.75 22.75 91
Rate
Cum Rate
172.59
0 172.59
62.46 62.69 62.99 63.22
235.06 297.75 360.74 423.97
Sources for (B)
(33 SDs + 8 ICs) (for 40–49, Ref 3, Table 7)+ (31 SDs + 5 ICs) (for 50–59, Ref 4, Table 7) = 77
(33 SDs + 13 ICs + 9 Incident cases) (for 40–49, Ref 3, Table 7)+ (40 SDs + 10 ICs + 6 Incident cases) (for 50–59, Ref 4, Table 7) = 111
129.75
0 129.75
51.06 51.24 51.42 51.58
180.82 232.05 283.47 335.05
(21 SDs + 7 ICs) (for 40–49, Ref 3, Table 7)+ (22 SDs + 8 ICs) (for 50–59, Ref 4, Table 7)
(35 Incident cancers) (for 40–49, Ref 3, Table 7)+ (32 SDs + 18 ICs + 6 Incident cancers) (for 50–59, Ref 4, Table 7) = 91
149
Column (A) and Column (C) come from the reported person-years (shown in the original Table 6) in the two accompanying papers for 40–49 and 50–59 in 1992 Can Med Assoc J (3,4).
UC arm) than those for advanced breast cancer defined by node status (447 per 100,000 in the M arm and 378 per 100,000 in the UC arm). What is commonly observed is just the opposite, i.e., the cumulative rates for node positive cancers are lower than those for tumor sizes larger than 2.0 cm, simply because some large tumors are node negative (8). The explanation of ascertainment bias as the source of the higher rate of node positivity in the M arm appears to us to raise more questions than it answers. If axillary evaluations were more thorough in the M arm compared with the UC arm, there is now another cause for concern about the validity and credibility of the CNBSS end results because it suggests another source of bias not overcome by the randomization. L aszl o Tab ar, MD PhD* Hsiu-Hsi Chen, PhD† Amy Ming-Fang Yen, PhD‡ Sam Li-Sheng Chen, PhD‡ Jean Ching-Yuan Fann, PhD§
Sherry Yueh-Hsia Chiu, PhD¶ Robert A. Smith, PhD** Stephen W.Duffy, Msc†† *Department of Mammography Central Hospital Falun Sweden; † Graduate Institute of Epidemiology and Preventive Medicine College of Public Health National Taiwan University Taipei Taiwan; ‡ School of Oral Hygiene Taipei Medical University Taipei Taiwan; § Department of Health Industry Management School of Healthcare Management Kainan University Taoyuan Taiwan;
Letter to the Editor • 461
¶
Department and Graduate Institute of Health Care Management Chang Gung University Taoyuan Taiwan; **American Cancer Society Atlanta Georgia; and ††Centre for Cancer Prevention Wolfson Institute of Preventive Medicine Queen Mary University of London London UK REFERENCES
1. Miller AB, Wall C, Baines CJ, To T. Re: Insights from the breast cancer screening trials: how screening affects the natural history of breast cancer and implications for evaluating service screening programs. Breast J 2015. In press. 2. Tab ar L, Yen AM, Wu WY, et al. Insights from the breast cancer screening trials: how screening affects the natural history of breast cancer and implications for evaluating service screening programs. Breast J 2015;21:13–20.
3. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years [published erratum appears in Can Med Assoc J 1993 Mar 1;148(5):718] [see comments]. CMAJ 1992;147:1459–76. 4. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years [published erratum appears in Can Med Assoc J 1993 Mar 1;148(5):718] [see comments]. CMAJ 1992;147:1477–88. 5. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014;348:g366. 6. Miller AB, To T, Baines CJ, Wall C. Canadian national breast screening study-2: 13-year results of a randomized trial in women aged 50-59 years [In Process Citation]. J Natl Cancer Inst 2000;92:1490–9. 7. Miller AB, To T, Baines CJ, Wall C. The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med 2002;137: 305–12. 8. Tabar L, Fagerberg G, Duffy SW, Day NE, Gad A, Grontoft O. Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 1992;30: 187–210.
