Screening and Breast Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The article by Berry et al. (Oct. 27 issue)1 represents an impressive modeling exercise. However, the fact that all seven models of the effects of screening and adjuvant therapy on mortality from breast cancer yielded qualitatively similar results is not as remarkable as it might first appear. The reason is that the most likely source of bias is the combination of parameter estimates from different populations with different distributions of risk factors. Because all the models used the same data, any bias from the combination of different data sets would probably appear in all analyses. Another important consideration is how the models capture the effect of early detection on subsequent survival, which has a potentially large effect on the final results. A recent article reported that even after adjustment for tumor size, lymph-node status, and disease stage, there was a survival benefit for subjects whose breast cancer was detected by screening rather than clinically.2 To the credit of Berry et al., some of the models accounted for the method of detection in the estimation of survival after diagnosis, but some critical details were not provided. In future work, elucidation of this key point would be helpful.
Stuart G. Baker, Sc.D.
National Cancer Institute
Bethesda, MD 20892-7354
sb16i@nih.gov
References
Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353:1784-1792.
Shen Y, Yang Y, Inoue LYT, Munsell MF, Miller AB, Berry DA. Role of detection method in predicting breast cancer survival: analysis of randomized screening trials. J Natl Cancer Inst 2005;97:1195-1203.
To the Editor: The study by Berry et al. has estimated that mammographic screening in the United States has reduced mortality from breast cancer by 15 percent. The authors' conclusion is cautious because the increasing use of adjuvant therapy and screening occurred during the same time period. Another reason for caution is that some countries with national screening programs (e.g., Sweden) have had little change in mortality curves, whereas others without national screening (e.g., Germany and Austria) have had improvements in death rates paralleling that in the United States.1 Furthermore, the decrease in breast-cancer mortality in Europe was 16 percent among women under 50 years of age, for whom screening was not recommended, and only 9 percent among those in age groups for whom screening was recommended.1 This suggests that the estimate of 15 percent is a random high (i.e., that it is due to chance). The U.S. study should therefore be replicated in other countries, including those that have had a reduction in mortality without screening and those that have not had a reduction despite screening. The study should also include younger women, who are typically not invited to participate in screening.
Peter C. G?tzsche, Dr.Med.Sci.
Nordic Cochrane Center
DK-2100 Copenhagen, Denmark
pcg@cochrane.dk
References
Levi F, Lucchini F, Negri E, La Vecchia C. The fall in breast cancer mortality in Europe. Eur J Cancer 2001;37:1409-1412.
To the Editor: As a general internist who reads the Journal to foster his understanding of common medical conditions, I cannot help feeling perplexed after reviewing the article on breast-cancer screening by Berry et al. I do not refer so much to the never-ending debate about whether mammography does1 or does not2 save lives but, rather, to the communication of risk reduction with the use of relative risks and percentages. Few patients (and not every doctor) understand that the often quoted 25 percent reduction in relative risk associated with mammography means an absolute risk reduction of only 1 in 1000. Of 1000 women who do not undergo mammography, about 4 will die of breast cancer within 10 years, whereas out of 1000 women who have a mammogram, 3 will die.3 Better ways of explaining such information so that it is understandable are being developed,4 and the Journal should take the lead.
Piero Baglioni, M.D.
Prince Charles Hospital
Merthyr Tydfil CF47, United Kingdom
References
Olsen AH, Njor SH, Vejborg I, et al. Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study. BMJ 2005;330:220-220.
Elmore JG, Reisch LM, Barton MB, et al. Efficacy of breast cancer screening in the community according to risk level. J Natl Cancer Inst 2005;97:1035-1043.
Gigerenzer G, Edwards A. Simple tools for understanding risks: from innumeracy to insight. BMJ 2003;327:741-744.
Barratt A, Howard K, Irwig L, Salkeld G, Houssami N. Model of outcomes of screening mammography: information to support informed choices. BMJ 2005;330:936-936.
To the Editor: Berry et al. reported incorrect results in Table 3 of their article for "estimated reductions in the rate of death . . . attributed to adjuvant treatments and screening." The reductions due to both therapies and screening do not add to the overall number for any participant. Recomputed totals are greater by factors of 1.035 to 1.172. However, the proportions attributed to each component are numerically identical to those derived from adding the two components.
The totals shown for both therapies, tamoxifen and chemotherapy, differ from the sum given by 0.1 percent to 0.9 percent — a small difference, but too large to attribute to rounding error.
David W. Smith, Ph.D., M.P.H.
University of Texas School of Public Health
San Antonio, TX 78230
smithd2@uthscsa.edu
To the Editor: In the recent report on breast-cancer screening by Berry et al., it was assumed that tumor growth was continuous and that primary tumors and any residual micrometastases were autonomous. The assumption of continuous growth, however, is inconsistent with clinical data on recurrences.1 Moreover, the assumption of autonomous tumors is inconsistent with data that show a bimodal hazard of relapse in early-stage breast cancer after surgical removal of the primary tumor.2,3,4 This could explain both the counterintuitive early-mortality disadvantage and the overall long-term survival benefit for women between the ages of 40 and 49 years that is seen in randomized trials. Despite the conclusions of Berry et al., the situation is still partly contentious.
Michael W. Retsky, Ph.D.
Harvard Medical School
Boston, MA 02115
michael.retsky@childrens.harvard.edu
Romano Demicheli, M.D., Ph.D.
Istituto Nazionale Tumori
20137 Milan, Italy
William J.M. Hrushesky, M.D.
WJB Dorn Veterans Affairs Medical Center
Columbia, SC 29209
References
Demicheli R, Terenziani M, Valagussa P, Moliterni A, Zambetti, Bonadonna G. Local recurrences following mastectomy: support for the concept of tumour dormancy. J Natl Cancer Inst 1994;86:45-48.
Retsky M, Demicheli R, Hrushesky WJM. Does surgery induce angiogenesis in breast cancer? Indirect evidence from relapse pattern and mammography paradox. Int J Surgery 2005;3:179-87.
Jatoi I, Tsimelzon A, Weiss H, Clark GM, Hilsenbeck SG. Hazard rates of recurrence following diagnosis of primary breast cancer. Breast Cancer Res Treat 2005;89:173-178.
Jerez JM, Franco L, Alba E, et al. Improvement of breast cancer relapse prediction in high risk intervals using artificial neural networks. Breast Cancer Res Treat 2005;94:265-272.
The authors reply: We agree with Dr. Baker that the commonality of our conclusions is driven partly by the availability of common data sources. However, we had a wide variety of types of information available, and each of us selected data relevant to our particular models. Not all of us used the same data, and not all of us used the available data in the same way. Regarding the provision of critical details, additional information is available in the Supplementary Appendix (available with the full text of our article at www.nejm.org) and on our Web site (cisnet.cancer.gov). Still more descriptions of each model will be provided in future publications.
In reply to Dr. Retsky and colleagues: it is not true that all our models assumed continuous tumor growth over time. Some models specifically allowed for tumors — both in situ and invasive — that were not lethal. Moreover, one model did not consider tumor growth at all but, instead, was based on empirical information on survival according to tumor stage, hormonal status, method of detection, and treatment. Regarding women whose breast cancer is detected in their 40s: we did not address this issue separately, but we plan to do so in future work.
Dr. Smith comments on the lack of additivity in Table 3. These are not errors. We indicated in the article that "the combination of screening and adjuvant therapy reduced the rate of death by slightly less than the sum of the contributions from screening and adjuvant therapy alone." The approximate additivity of screening and adjuvant therapy is interesting, because it means that we concluded there was little synergism between the two interventions.
We agree with Dr. G?tzsche that our study should be repeated in other countries. We also agree that there is some randomness — we used the term "uncertainty" — associated with our conclusion that there was a 15 percent reduction associated with screening in the United States. As to whether 15 percent is a "random high," we point out that it was the median of seven estimates ranging from 7.5 percent to 22.7 percent.
With regard to the comments of Dr. Baglioni: our goal was to address the relative contributions of adjuvant therapy and screening to the observed decrease in breast-cancer mortality in the United States and not to address an individual woman's decision process. We agree with Dr. Baglioni that absolute survival benefit is the appropriate consideration for individual decision making.
Donald A. Berry, Ph.D.
M.D. Anderson Cancer Center
Houston, TX 77030
dberry@mdanderson.org
Sylvia K. Plevritis, Ph.D.
Stanford University
Stanford, CA 94305
Dennis G. Fryback, Ph.D.
University of Wisconsin–Madison
Madison, WI 53706
Stuart G. Baker, Sc.D.
National Cancer Institute
Bethesda, MD 20892-7354
sb16i@nih.gov
References
Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353:1784-1792.
Shen Y, Yang Y, Inoue LYT, Munsell MF, Miller AB, Berry DA. Role of detection method in predicting breast cancer survival: analysis of randomized screening trials. J Natl Cancer Inst 2005;97:1195-1203.
To the Editor: The study by Berry et al. has estimated that mammographic screening in the United States has reduced mortality from breast cancer by 15 percent. The authors' conclusion is cautious because the increasing use of adjuvant therapy and screening occurred during the same time period. Another reason for caution is that some countries with national screening programs (e.g., Sweden) have had little change in mortality curves, whereas others without national screening (e.g., Germany and Austria) have had improvements in death rates paralleling that in the United States.1 Furthermore, the decrease in breast-cancer mortality in Europe was 16 percent among women under 50 years of age, for whom screening was not recommended, and only 9 percent among those in age groups for whom screening was recommended.1 This suggests that the estimate of 15 percent is a random high (i.e., that it is due to chance). The U.S. study should therefore be replicated in other countries, including those that have had a reduction in mortality without screening and those that have not had a reduction despite screening. The study should also include younger women, who are typically not invited to participate in screening.
Peter C. G?tzsche, Dr.Med.Sci.
Nordic Cochrane Center
DK-2100 Copenhagen, Denmark
pcg@cochrane.dk
References
Levi F, Lucchini F, Negri E, La Vecchia C. The fall in breast cancer mortality in Europe. Eur J Cancer 2001;37:1409-1412.
To the Editor: As a general internist who reads the Journal to foster his understanding of common medical conditions, I cannot help feeling perplexed after reviewing the article on breast-cancer screening by Berry et al. I do not refer so much to the never-ending debate about whether mammography does1 or does not2 save lives but, rather, to the communication of risk reduction with the use of relative risks and percentages. Few patients (and not every doctor) understand that the often quoted 25 percent reduction in relative risk associated with mammography means an absolute risk reduction of only 1 in 1000. Of 1000 women who do not undergo mammography, about 4 will die of breast cancer within 10 years, whereas out of 1000 women who have a mammogram, 3 will die.3 Better ways of explaining such information so that it is understandable are being developed,4 and the Journal should take the lead.
Piero Baglioni, M.D.
Prince Charles Hospital
Merthyr Tydfil CF47, United Kingdom
References
Olsen AH, Njor SH, Vejborg I, et al. Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study. BMJ 2005;330:220-220.
Elmore JG, Reisch LM, Barton MB, et al. Efficacy of breast cancer screening in the community according to risk level. J Natl Cancer Inst 2005;97:1035-1043.
Gigerenzer G, Edwards A. Simple tools for understanding risks: from innumeracy to insight. BMJ 2003;327:741-744.
Barratt A, Howard K, Irwig L, Salkeld G, Houssami N. Model of outcomes of screening mammography: information to support informed choices. BMJ 2005;330:936-936.
To the Editor: Berry et al. reported incorrect results in Table 3 of their article for "estimated reductions in the rate of death . . . attributed to adjuvant treatments and screening." The reductions due to both therapies and screening do not add to the overall number for any participant. Recomputed totals are greater by factors of 1.035 to 1.172. However, the proportions attributed to each component are numerically identical to those derived from adding the two components.
The totals shown for both therapies, tamoxifen and chemotherapy, differ from the sum given by 0.1 percent to 0.9 percent — a small difference, but too large to attribute to rounding error.
David W. Smith, Ph.D., M.P.H.
University of Texas School of Public Health
San Antonio, TX 78230
smithd2@uthscsa.edu
To the Editor: In the recent report on breast-cancer screening by Berry et al., it was assumed that tumor growth was continuous and that primary tumors and any residual micrometastases were autonomous. The assumption of continuous growth, however, is inconsistent with clinical data on recurrences.1 Moreover, the assumption of autonomous tumors is inconsistent with data that show a bimodal hazard of relapse in early-stage breast cancer after surgical removal of the primary tumor.2,3,4 This could explain both the counterintuitive early-mortality disadvantage and the overall long-term survival benefit for women between the ages of 40 and 49 years that is seen in randomized trials. Despite the conclusions of Berry et al., the situation is still partly contentious.
Michael W. Retsky, Ph.D.
Harvard Medical School
Boston, MA 02115
michael.retsky@childrens.harvard.edu
Romano Demicheli, M.D., Ph.D.
Istituto Nazionale Tumori
20137 Milan, Italy
William J.M. Hrushesky, M.D.
WJB Dorn Veterans Affairs Medical Center
Columbia, SC 29209
References
Demicheli R, Terenziani M, Valagussa P, Moliterni A, Zambetti, Bonadonna G. Local recurrences following mastectomy: support for the concept of tumour dormancy. J Natl Cancer Inst 1994;86:45-48.
Retsky M, Demicheli R, Hrushesky WJM. Does surgery induce angiogenesis in breast cancer? Indirect evidence from relapse pattern and mammography paradox. Int J Surgery 2005;3:179-87.
Jatoi I, Tsimelzon A, Weiss H, Clark GM, Hilsenbeck SG. Hazard rates of recurrence following diagnosis of primary breast cancer. Breast Cancer Res Treat 2005;89:173-178.
Jerez JM, Franco L, Alba E, et al. Improvement of breast cancer relapse prediction in high risk intervals using artificial neural networks. Breast Cancer Res Treat 2005;94:265-272.
The authors reply: We agree with Dr. Baker that the commonality of our conclusions is driven partly by the availability of common data sources. However, we had a wide variety of types of information available, and each of us selected data relevant to our particular models. Not all of us used the same data, and not all of us used the available data in the same way. Regarding the provision of critical details, additional information is available in the Supplementary Appendix (available with the full text of our article at www.nejm.org) and on our Web site (cisnet.cancer.gov). Still more descriptions of each model will be provided in future publications.
In reply to Dr. Retsky and colleagues: it is not true that all our models assumed continuous tumor growth over time. Some models specifically allowed for tumors — both in situ and invasive — that were not lethal. Moreover, one model did not consider tumor growth at all but, instead, was based on empirical information on survival according to tumor stage, hormonal status, method of detection, and treatment. Regarding women whose breast cancer is detected in their 40s: we did not address this issue separately, but we plan to do so in future work.
Dr. Smith comments on the lack of additivity in Table 3. These are not errors. We indicated in the article that "the combination of screening and adjuvant therapy reduced the rate of death by slightly less than the sum of the contributions from screening and adjuvant therapy alone." The approximate additivity of screening and adjuvant therapy is interesting, because it means that we concluded there was little synergism between the two interventions.
We agree with Dr. G?tzsche that our study should be repeated in other countries. We also agree that there is some randomness — we used the term "uncertainty" — associated with our conclusion that there was a 15 percent reduction associated with screening in the United States. As to whether 15 percent is a "random high," we point out that it was the median of seven estimates ranging from 7.5 percent to 22.7 percent.
With regard to the comments of Dr. Baglioni: our goal was to address the relative contributions of adjuvant therapy and screening to the observed decrease in breast-cancer mortality in the United States and not to address an individual woman's decision process. We agree with Dr. Baglioni that absolute survival benefit is the appropriate consideration for individual decision making.
Donald A. Berry, Ph.D.
M.D. Anderson Cancer Center
Houston, TX 77030
dberry@mdanderson.org
Sylvia K. Plevritis, Ph.D.
Stanford University
Stanford, CA 94305
Dennis G. Fryback, Ph.D.
University of Wisconsin–Madison
Madison, WI 53706