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Journal of Clinical Oncology, Vol 25, No 27 (September 20), 2007: pp. 4210-4216 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.5056 Incidence and Prognosis of Synchronous and Metachronous Bilateral Breast Cancer
From the Department of Medical Epidemiology and Biostatistics, Stockholm Söder Hospital and Oncologic Center, Clintec, and Department of Oncology, Radiumhemmet, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; and the Department of Epidemiology, Harvard University, Boston, MA Address reprint requests to Mikael Hartman, MD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, 171 77 Stockholm, Sweden; e-mail: Mikael.Hartman{at}ki.se
Purpose Because the incidence of breast cancer is increasing and prognosis is improving, a growing number of women are at risk of developing bilateral disease. Little is known, however, about incidence trends and prognostic features of bilateral breast cancer. Patients and Methods Among 123,757 women with a primary breast cancer diagnosed in Sweden from 1970 to 2000, a total of 6,550 developed bilateral breast cancer. We separated synchronous (diagnosed within 3 months after a first breast cancer) and metachronous bilateral cancer, and analyzed incidence and mortality rates of breast cancer using Poisson regression models. Results The incidence of synchronous breast cancer increased by age and by 40% during the 1970s, whereas the incidence of metachronous cancer decreased by age and by approximately 30% since the early 1980s, most likely due to increasing use of adjuvant therapy. Women who developed bilateral cancer within 5 years and at age younger than 50 years were 3.9 times (95% CI, 3.5 to 4.5) more likely to die as a result of breast cancer than women with unilateral cancer. Women with a bilateral cancer diagnosed more than 10 years after the first cancer had a prognosis similar to that of a unilateral breast cancer. Adjuvant chemotherapy of primary cancer is a predictor of poor survival after diagnosis of early metachronous cancers. Conclusion We found profound differences in the incidence trends and prognostic outlook between synchronous and metachronous bilateral breast cancer diagnosed at different ages. Adjuvant chemotherapy therapy has a dual effect on metachronous cancer: it reduces the risk, while at the same time it seems to worsen the prognosis.
Globally, increasing breast cancer incidence rates, improved prognosis, and growing life expectancy have resulted in increasing number of women at risk of developing a bilateral primary breast cancer. There are an estimated 2.2 million women living in the United States who have been diagnosed at some time with breast cancer.1 Hence, optimal surveillance and clinical management of women who have had one or two primary breast cancers is a challenge. However, there are only limited data on incidence rates of synchronous and metachronous breast cancer,2,3 results on temporal trends in incidence are conflicting,4 and little is known about the prognostic outlook after treatment of a second primary cancer.5,6 We analyzed a large nationwide cohort of breast cancer patients in Sweden. We achieved complete follow-up with regard to incidence and survival during 1970 through 2000, a period when mammographic screening and adjuvant systemic treatment became broadly implemented. We also analyzed a separate cohort with detailed treatment information to understand better whether adjuvant chemotherapy of a first primary breast cancer might predict the prognosis of a metachronous bilateral cancer.
Study Cohort The study cohort was obtained from the nationwide Swedish Cancer Register, established in 1958 and estimated to be at least 98% complete.7 For each notified cancer, the register includes the individually unique national registration number, the International Classification of Diseases code, and the date of diagnosis, but no information on stage of disease or treatment. Using the national registration number, the Cancer Register can be linked to the nationwide Cause of Death Register and the Total Population Register. These linkages allow complete follow-up with regard to vital status, date and causes of death, as well as dates of immigration/emigration. Because laterality of breast cancer was not recorded before 1970, we restricted the study cohort to the 138,372 women with a first primary invasive breast cancer diagnosed in the period 1970 to 2000. We excluded 8,123 women for whom the history of breast cancer was uncertain because they had immigrated to Sweden, and also excluded 6,492 women with a primary malignant tumor other than in the breast before the first breast cancer. Hence, our cohort for final analysis comprised a total of 123,757 women.
Validation Cohort
Statistical Analysis Deaths as a result of breast cancer were ascertained from the Cause of Death Registry with high reported accuracy.9 The mortality rate was calculated with the accumulated person-time at risk as the denominator. This time started at first diagnosis for unilateral and at second diagnosis for all bilateral breast cancer, and continued until diagnosis of bilateral cancer (for unilateral cancer), emigration, death, or end of follow-up (December 31, 2000), whichever came first. Any in situ breast cancer either before or after the first primary cancer was ignored. We used the Nelson-Aalen method to estimate cause-specific cumulative mortality. Poisson regression was used for modeling of both bilateral breast cancer incidence and survival. We adjusted for age and calendar period of diagnosis in the incidence analysis with additional adjustment for time since diagnosis in the survival analysis. Within the validation cohort additional adjustment was made for TNM stage, estrogen receptor status, and adjuvant treatment. We present 5-year cause-specific mortality, with the exception of Nelson-Aalen cause-specific cumulative mortality, for which we present complete follow-up. We censored follow-up at age 80 years because classification of cause of death may be less reliable in older women. All data preparation and analysis were done using the SAS Statistical package, version 8.2 (SAS Institute, Cary, NC).10
Incidence of Bilateral Breast Cancer In the cohort of 123,757 women with a first breast cancer diagnosed between 1970 and 2000, a total of 6,550 women developed synchronous (n = 1,893) or metachronous (n = 4,657) bilateral breast cancer during follow-up through 2000. Overall, approximately 1.6 synchronous cancers occurred per 105 person-years at risk. The incidence of synchronous cancer increased from 1970 until the mid-1980s and remained almost constant thereafter (Fig 1). The incidence rate of metachronous cancer decreased by almost one third during the study period from 640 per 105 person-years at risk in 1970 to 440 per 105 person-years at risk in 2000. This overall decreasing trend was similar for metachronous cancers diagnosed within 5 years of the first primary breast cancer. In a multivariate Poisson regression model of bilateral breast cancer in relation to calendar period adjusted for age, we observe the same increasing trend of synchronous cancer as seen in Figure 1 (P for trend < .001; data not shown). The multivariate analyses of metachronous bilateral cancer limited to the first 5 years of follow-up revealed a similar and significant decreasing trend during the study period, as seen in Figure 1 (P for trend < .001).
Survival of Patients With Bilateral Breast Cancer Women with synchronous bilateral breast cancer had a higher mortality from breast cancer than women with unilateral disease (P < .001; Fig 2A); after 10 years of follow-up, the cumulative breast cancer specific mortality was 45% (95% CI, 41.4% to 48.0%) and 33% (95% CI, 32.8% to 33.5%), respectively. Among women with metachronous breast cancer, the lowest mortality from breast cancer was seen for those with the longest time interval between the first and the second cancer (Fig 2B). After 10 years of follow-up, the cumulative breast cancer–specific mortality was 56% (95% CI, 53.0% to 58.5%) among women with bilateral cancer diagnosed within 5 years and 34% (95% CI, 28.6% to 39.8%) among those diagnosed with bilateral cancer more than 10 years after their first primary.
The 5-year breast cancer–specific mortality rate was only modestly related to age at diagnosis among women with unilateral disease (Fig 3A). After synchronous bilateral breast cancer, mortality decreased from 136 per 103 person-years at age younger than 40 years to 73 per 103 person-years at age 70 to 79 years at diagnosis. The modifying effect of age was even more pronounced for metachronous bilateral breast cancer, with a more than three-fold gradient in mortality between women aged younger than 40 years at diagnosis (178 per 103 person-years) and those aged 70 to 79 years at diagnosis (55 per 103 person-years).
The 5-year cause-specific mortality rate of synchronous cancer improved continuously during the study period from 124 per 103 person-years in 1970 to 1974 to 66 per 103 person-years in 1995 to 2000 (Fig 3B). Similarly, the 5-year cause-specific mortality rate of metachronous breast cancer improved during follow-up from 143 per 103 person-years to 68 per 103 person-years. This trend was less obvious for metachronous breast cancer diagnosed less than 5 years since unilateral breast cancer. We used Poisson regression to estimate how mortality after bilateral breast cancer is affected by age at diagnosis of the first cancer and time interval to diagnosis of second breast cancer (Table 1). Compared with women with unilateral disease, those with synchronous bilateral cancer had a 40% higher mortality rate if they were 50 years or older, but had a 120% higher mortality rate if they were age < 50 years. Compared with women age < 50 years at unilateral breast cancer diagnosis, those who developed a metachronous cancer before 50 years of age within 5 years of their first breast cancer had an almost four-fold higher breast cancer mortality rate. This difference in prognosis between uni- and bilateral disease was reduced in older women and with longer time interval between the two cancers. Women with bilateral metachronous cancers diagnosed more than 10 years after initial diagnosis had a 5-year breast cancer mortality not significantly different from that of women of the same age with a unilateral breast cancer.
Table 1 also lists results for the validation cohort with additional adjustment for TNM stage, estrogen receptor status (negative, < 0.05 fmol/µg DNA), and adjuvant treatment of primary cancer (for unilateral cancer) and second primary cancer (for bilateral cancer). Women with synchronous cancer had a 60% higher mortality rate compared with women with unilateral cancer. Women with metachronous cancer less than 5 years since primary had a more than four-fold higher mortality rate compared with women with unilateral cancer. Women with bilateral metachronous cancers diagnosed more than 10 years after initial diagnosis had a 5-year breast cancer mortality not significantly different from that of women of the same age with a unilateral breast cancer.
We next analyzed type of bilateral disease (synchronous v metachronous) and calendar time, stratified by age at first diagnosis, as determinants of survival (Fig 4A). Women age < 50 years diagnosed with synchronous breast cancer in 1970 to 1974 were approximately two times more likely to die as a result of breast cancer than women of the same age with unilateral breast cancer, a difference that varied only modestly over calendar period. In contrast, the excess death rate among women age
Finally, we analyzed the validation cohort to assess the effect of adjuvant treatment on breast cancer mortality among women diagnosed with metachronous cancer within 5 years of primary cancer (Table 2). Women who had received adjuvant chemotherapy after their first diagnosis were at 2.4-fold higher risk of death as a result of breast cancer compared with women who had received no such treatment when we adjusted for follow-up time, age, calendar period, TNM stage, hormone receptor status, and adjuvant treatment of the second cancer. Analysis of the mortality in women with TNM stage 1 to 2 at primary diagnosis revealed a similar significant two-fold excess mortality rate after adjuvant chemotherapy of primary cancer. For comparison, we calculated the mortality in women with bilateral disease depending on if they received adjuvant chemotherapy for the second primary cancer (Table 2). We observed no excess mortality in women subjected to adjuvant chemotherapy after the second primary cancer. In addition, we observed that women diagnosed with a first primary TNM stage 2 and 3 cancer were at a two-fold (mortality rate ratio [MRR], 1.9; 95% CI, 1.0 to 3.9) and five-fold (MRR, 5.4; 95% CI, 2.4 to 12.1) increased risk of death as a result of the disease, respectively, compared with women with stage 1 first primary cancer. In comparison, women diagnosed with a second primary TNM stage 2 and 3 were at a three-fold (MRR, 2.6; 95% CI, 1.4 to 5.1) and seven-fold (MRR, 7.2; 95% CI, 3.3 to 15.8) increased risk of death as a result of the disease, respectively, compared with women with stage 1 first primary cancers.
We analyzed the occurrence pattern and prognosis of bilateral breast cancer and found marked differences between synchronous and metachronous cancer during the 30-year period of our study. The incidence pattern of synchronous cancer is similar to that of unilateral disease, although without any notable trends in recent decades. Metachronous disease, on the other hand, was much more common in younger patients and incidence rates declined steadily from approximately 1980, most likely due to the expanding use of adjuvant systemic therapy.11 Striking features of the survival analyses included the much higher excess mortality after metachronous than synchronous disease and among younger than older women. When women with metachronous disease were compared with those with unilateral disease, the excess mortality increased markedly during calendar time and was remarkably influenced by time since first breast cancer. The excess mortality of metachronous disease seems to be due in part to treatment of the primary cancer. Strengths of our study include the large size, the population-based prospective design, the possibility to define laterality, and the completeness of follow-up. Misclassification of metastatic disease as a second primary breast cancer is generally considered a smaller problem and could not explain the pattern of these findings. Indeed, there is no evidence that such misclassification, if it exists, would change during calendar time or differ by age.12 Admittedly, the prognosis of bilateral breast cancer is difficult to assess because it is conditional on age and the woman surviving her first malignancy; deaths cannot be attributed unequivocally to first or second cancer. The gradual increase in the incidence of synchronous disease during the 1970s coincides with the introduction of routine and bilateral mammography as part of the diagnostic work-up in women with unilateral cancer.13 Such work-up may entail that some preclinical bilateral cancers are detected early and classified as synchronous disease14 (perhaps in an earlier and more favorable stage15) rather than diagnosed later as metachronous disease.16 The overall incidence rate of metachronous bilateral cancer in our study is also compatible with previous reports (Fig 1).3,4,17-19 During the period of our study, adjuvant systemic therapy, mainly tamoxifen and chemotherapy, became clinical practice. Because such treatment reduces the incidence of local recurrences, bilateral cancer, and distant metastasis,11,20-22 it likely explains the substantial reduction in the incidence of metachronous bilateral disease during calendar time. Similar trends have been found in the United States23 but not in Canada.4 Women diagnosed with unilateral cancer early in life and bilateral cancer within 5 years had a four times higher mortality rate than women with unilateral breast cancer after adjustment for age at diagnosis and calendar period (Table 1). The pattern persisted but the effect of time since first cancer was weaker in older age groups. In contrast, we observed that women with metachronous cancers diagnosed more than 10 years after initial diagnosis had a prognosis similar to that of a woman with unilateral cancer. This mortality pattern for women with bilateral cancer became even stronger after adjustment of stage and adjuvant treatment in the validation cohort. It is indeed notable that women with metachronous cancer diagnosed within 5 years after unilateral cancer have a higher mortality rate than women with synchronous bilateral cancer. Our findings are supported by previous studies,6,24 although there are studies detecting no increased mortality for bilateral disease.5,25 These differences may be attributed to variations in sample size, age, follow-up, and treatment regimes. We also found that compared with women with unilateral disease, the prognostic outlook among women with metachronous disease deteriorated over time concomitantly with the decreasing incidence (Fig 4). This novel finding suggests that adjuvant systemic treatment selectively prevents the occurrence of cancers with a favorable prognosis, allowing those with a more aggressive phenotype to surface clinically. Adjuvant chemotherapy is administered more often to premenopausal women, whereas antiestrogens have been the primary choice among older women. Thus, the much stronger increase in mortality over time among women with bilateral cancer younger than age 50 years compared with women with unilateral disease suggests that chemotherapy exerts a stronger selection pressure than adjuvant endocrine treatment. Results from our validation cohort supported this interpretation by showing a stage-adjusted 2.4-fold higher mortality rate among women who received adjuvant chemotherapy after their first primary breast cancer (Table 2). One explanation for this finding would be that chemotherapy is administered to women with more aggressive tumors and hence with poorer survival. Conversely, excess mortality after chemotherapy of primary cancer was also observed for women with TNM stage 1 to 2 cancer, whereas we observed no increased mortality among women treated with adjuvant chemotherapy after the second primary cancer. We believe that the findings support a selection process of more malignant second primary cancers, given the bias by indication for adjuvant chemotherapy should be similar for the choice of treatment of primary and second primary cancer. The result of the validation cohort thus suggests that such bias is minor. Our findings also may be relevant for clinical management of women with breast cancer. It is not surprising that women diagnosed with two simultaneous cancers have an increased mortality compared with women with one cancer. What is puzzling is the strong age dependency of this effect. Perhaps even more challenging to explain is the remarkable excess mortality among women who develop short latency metachronous disease at young ages. There is no obvious reason why there should be a difference in biologic behavior between the first and second tumor because the breast tissue is influenced uniformly by the same genetic and environmental factors. Hence, we have to invoke either changes in tumor-host relationships after a first cancer or progression to a therapy-resistant phenotype after treatment of the first primary breast cancer. We found profound differences in the incidence trends and prognostic outlook between synchronous and metachronous bilateral breast cancer diagnosed at different ages. Adjuvant chemotherapy has a dual effect on metachronous cancer: it reduces the risk while at the same time seems to worsen the prognosis. Finally, additional research into the complex behavior of bilateral breast cancer may provide important new insights into both biologic and clinical factors.
The author(s) have no conflicts statement.
Conception and design: Mikael Hartman, Kamila Czene, Marie Reilly, Paul W. Dickman, Per Hall Financial support: Mikael Hartman, Kamila Czene, Marie Reilly, Per Hall Administrative support: Mikael Hartman, Kamila Czene, Per Hall Provision of study materials or patients: Mikael Hartman, Jan Adolfsson Collection and assembly of data: Mikael Hartman, Per Hall Data analysis and interpretation: Mikael Hartman, Kamila Czene, Marie Reilly, Jan Adolfsson, Jonas Bergh, Hans-Olov Adami, Paul W. Dickman, Per Hall Manuscript writing: Mikael Hartman, Kamila Czene, Marie Reilly, Jan Adolfsson, Jonas Bergh, Hans-Olov Adami, Paul W. Dickman, Per Hall Final approval of manuscript: Mikael Hartman, Kamila Czene, Marie Reilly, Jan Adolfsson, Jonas Bergh, Hans-Olov Adami, Paul W. Dickman, Per Hall
We thank the Stockholm Breast Cancer Study Group for providing the validation cohort of women with bilateral breast cancer.
Supported by US Army Grant No. DAMD 17-03-1-1-0771. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ries LAG EM, Kosary CL, Hankey BF, et al: (eds): SEER Cancer Statistics Review, 1975-2001. Bethesda, MD, National Cancer Institute, 2004 2. Robbins GF, Berg JW: Bilateral primary breast cancer: A prospective clinicopathological study. Cancer 17:1501-1527, 1964[CrossRef][Medline] 3. Chen Y, Thompson W, Semenciw R, et al: Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev 8:855-861, 1999 4. Chen Y, Semenciw R, Kliewer E, et al: Incidence of second primary breast cancer among women with a first primary in Manitoba, Canada. Breast Cancer Res Treat 67:35-40, 2001[CrossRef][Medline] 5. Robinson E, Rennert G, Rennert HS, et al: Survival of first and second primary breast cancer. Cancer 71:172-176, 1993[CrossRef][Medline] 6. Holmberg L, Adami HO, Ekbom A, et al: Prognosis in bilateral breast cancer: Effects of time interval between first and second primary tumours. Br J Cancer 58:191-194, 1988[Medline] 7. Mattsson B, Wallgren A: Completeness of the Swedish Cancer Register: Non-notified cancer cases recorded on death certificates in 1978. Acta Radiol Oncol 23:305-313, 1984[Medline] 8. Stockholms Läns Landsting: Onkologiskt Centrum. http://www.sll.se/oc 9. Larsson LG, Nystrom L, Wall S, et al: The Swedish randomised mammography screening trials: Analysis of their effect on the breast cancer related excess mortality. J Med Screen 3:129-132, 1996[Medline] 10. SAS Institute: SAS/STAT User's Guide: Version 8.2. Cary, NC, SAS Institute Inc, 1999 11. Early Breast Cancer Trialists’ Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 12. Janschek E, Kandioler-Eckersberger D, Ludwig C, et al: Contralateral breast cancer: Molecular differentiation between metastasis and second primary cancer. Breast Cancer Res Treat 67:1-8, 2001[CrossRef][Medline] 13. Olsson S, Andersson I, Karlberg I, et al: Implementation of service screening with mammography in Sweden: From pilot study to nationwide programme. J Med Screen 7:14-18, 2000 14. Hungness ES, Safa M, Shaughnessy EA, et al: Bilateral synchronous breast cancer: Mode of detection and comparison of histologic features between the 2 breasts. Surgery 128:702-707, 2000[CrossRef][Medline] 15. Shen Y, Yang Y, Inoue LY, et al: Role of detection method in predicting breast cancer survival: Analysis of randomized screening trials. J Natl Cancer Inst 97:1195-1203, 2005 16. Lehman CD, Gatsonis C, Kuhl CK, et al: MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med 356:1295-1303, 2007 17. Adami HO, Bergstrom R, Hansen J: Age at first primary as a determinant of the incidence of bilateral breast cancer: Cumulative and relative risks in a population-based case-control study. Cancer 55:643-647, 1985[CrossRef][Medline] 18. Hemminki K, Vaittinen P, Easton D: Familial cancer risks to offspring from mothers with 2 primary breast cancers: Leads to cancer syndromes. Int J Cancer 88:87-91, 2000[CrossRef][Medline] 19. Hartman M, Czene K, Reilly M, et al: Genetic implications of bilateral breast cancer: A population based cohort study. Lancet Oncol 6:377-382, 2005[CrossRef][Medline] 20. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 88:1529-1542, 1996 21. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 351:1451-1467, 1998[CrossRef][Medline] 22. Polychemotherapy for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 352:930-942, 1998[CrossRef][Medline] 23. Bernstein JL, Thompson WD, Risch N, et al: Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol 136:925-936, 1992 24. Mariani L, Coradini D, Biganzoli E, et al: Prognostic factors for metachronous contralateral breast cancer: A comparison of the linear Cox regression model and its artificial neural network extension. Breast Cancer Res Treat 44:167-178, 1997[CrossRef][Medline] 25. Verkooijen HM, Chatelain V, Fioretta G, et al: Survival after bilateral breast cancer: Results from a population-based study. Breast Cancer Res Treat [epub ahead of print on December 21, 2006] Submitted December 20, 2006; accepted June 22, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 years with metachronous disease increased from less than three-fold to about five-fold during the study period. For women older than 50 years of age at diagnosis of breast cancer, the mortality rate ratio increased steadily from 1.2 to 1.7 (
