Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
We are pleased to see our trial continues to incite comment. In the additional response provided below, we concentrate on the points made by some of the authors which we feel indicates they did not fully understand our paper nor the study design.
In spite of rather extensive prior e-mail discussions, Mr Leonid Winestein (RR February 21) appears still not to understand the analysis of our study. The computation of over-diagnosis we made was based upon comparisons of cumulative incidence between our two study arms. It will be clear that the vast majority of women who were diagnosed with breast cancer in our study did not die of their disease. The computations of over-diagnosis relate to this group, so his comments on death from breast cancer are irrelevant in this context.
Elsebeth Lynge (RR February 19) also comments on our computations of over-diagnosis. She states that women should be followed for 8 years after cessation of screening to compensate for lead time. In fact we did, the excess at 15 years is 10 years after cessation of screening in our trial. Although she is correct that some women may have been screened subsequently in provincial programmes, the breast cancer cumulative incidence curves largely remained parallel after the end of the lead time period indicating that such screening was not differential between the two arms. Her concern about lead time leads her to criticise our presentation of mortality results at 5 years, but in fact, recognising this issue, we presented in the text results at 6 and 7 years, and they were almost identical to the 5-year results. In previous reports on the 11-16 years follow-up of the study we extended the time interval to 9 years with a similar result. In the present report we did not feel that it was necessary to report the findings at 9 years, as it is now recognized that previous estimates of the lead time gained by mammography have been too long. When corrections are applied for over-diagnosis, lead time approximates to 1-2 years.
John D Keen (RR February 17) requests estimates of over-diagnosis including in situ lesions. For DCIS, 93 were diagnosed in the mammography arm and 20 in the control arm, the corresponding numbers for LCIS were 27 and 8. A paper regarding the outcome of the patients with these diagnoses will shortly appear in the International Journal of Cancer (To T, Wall C, Baines CJ, Miller AB: Is Carcinoma in Situ a Precursor Lesion of Invasive Breast Cancer?). If these lesions are included in estimates of over-diagnosis on screening the percentage becomes 33% (198/604), and the equivalent in terms of mammography alone detected lesions 60% (198/332).
Peter Sasieni (RR February 17) sees little difference statistically between our results and those of others. However that ignores the difference between our trial and others in the control group, and the availability of adjuvant therapy in our trial, whereas it was not in the others, also ignored in the Marmot evaluation. Further, the fact that there was an initial excess mortality from breast cancer in the mammography compared to the control arm does not argue against over-diagnosis, but is compatible with theories over the potential immune balance between primary tumours and metastases, first identified by the Fishers and re-enforced by Retsky et al (1).
1. Retsky M, Demicheli R, Hrushesky W. Premenopausal status accelerates relapse in node positive breast cancer: hypothesis links angiogenesis, screening controversy. Breast Cancer Res Treat. 2001;65:217-24. [PMID: 11336243]
Competing interests:
No competing interests
22 February 2014
Anthony B. Miller
Professor Emeritus
Baines CJ, To T, Wall C Narod SN
Dalla Lana School of Public Health, University of Toronto
Rapid Response:
Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
We are pleased to see our trial continues to incite comment. In the additional response provided below, we concentrate on the points made by some of the authors which we feel indicates they did not fully understand our paper nor the study design.
In spite of rather extensive prior e-mail discussions, Mr Leonid Winestein (RR February 21) appears still not to understand the analysis of our study. The computation of over-diagnosis we made was based upon comparisons of cumulative incidence between our two study arms. It will be clear that the vast majority of women who were diagnosed with breast cancer in our study did not die of their disease. The computations of over-diagnosis relate to this group, so his comments on death from breast cancer are irrelevant in this context.
Elsebeth Lynge (RR February 19) also comments on our computations of over-diagnosis. She states that women should be followed for 8 years after cessation of screening to compensate for lead time. In fact we did, the excess at 15 years is 10 years after cessation of screening in our trial. Although she is correct that some women may have been screened subsequently in provincial programmes, the breast cancer cumulative incidence curves largely remained parallel after the end of the lead time period indicating that such screening was not differential between the two arms. Her concern about lead time leads her to criticise our presentation of mortality results at 5 years, but in fact, recognising this issue, we presented in the text results at 6 and 7 years, and they were almost identical to the 5-year results. In previous reports on the 11-16 years follow-up of the study we extended the time interval to 9 years with a similar result. In the present report we did not feel that it was necessary to report the findings at 9 years, as it is now recognized that previous estimates of the lead time gained by mammography have been too long. When corrections are applied for over-diagnosis, lead time approximates to 1-2 years.
John D Keen (RR February 17) requests estimates of over-diagnosis including in situ lesions. For DCIS, 93 were diagnosed in the mammography arm and 20 in the control arm, the corresponding numbers for LCIS were 27 and 8. A paper regarding the outcome of the patients with these diagnoses will shortly appear in the International Journal of Cancer (To T, Wall C, Baines CJ, Miller AB: Is Carcinoma in Situ a Precursor Lesion of Invasive Breast Cancer?). If these lesions are included in estimates of over-diagnosis on screening the percentage becomes 33% (198/604), and the equivalent in terms of mammography alone detected lesions 60% (198/332).
Peter Sasieni (RR February 17) sees little difference statistically between our results and those of others. However that ignores the difference between our trial and others in the control group, and the availability of adjuvant therapy in our trial, whereas it was not in the others, also ignored in the Marmot evaluation. Further, the fact that there was an initial excess mortality from breast cancer in the mammography compared to the control arm does not argue against over-diagnosis, but is compatible with theories over the potential immune balance between primary tumours and metastases, first identified by the Fishers and re-enforced by Retsky et al (1).
1. Retsky M, Demicheli R, Hrushesky W. Premenopausal status accelerates relapse in node positive breast cancer: hypothesis links angiogenesis, screening controversy. Breast Cancer Res Treat. 2001;65:217-24. [PMID: 11336243]
Competing interests: No competing interests