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Risk of second non-hematological malignancies among 376,825 breast cancer survivors

  • Epidemiology
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Abstract

Breast cancer survivors are at increased risk of treatment-related second cancers. This study is the first to examine risk 30 or more years after diagnosis and to present absolute risks of second cancer which accounts for competing mortality. We identified 23,158 second non-hematological malignancies excluding breast in a population-based cohort of 376,825 one-year survivors of breast cancer diagnosed from 1943 to 2002 and reported to four Scandinavian cancer registries. We calculated standardized incidence ratios (SIR) and utilized a competing-risk model to calculate absolute risk of developing second cancers. The overall SIR for second cancers was 1.15 (95% confidence interval [CI] = 1.14–1.17). The SIR for potentially radiotherapy-associated cancers 30 or more years after breast cancer diagnosis was 2.19 (95% CI = 1.87–2.55). However, the largest SIRs were observed for women aged <40 years followed for 1–9 years. At 20 years after breast cancer diagnosis, the absolute risk of developing a second cancer ranged from 0.6 to 10.3%, depending on stage and age; the difference in the absolute risk compared to the background population was greatest for women aged <40 years with localized disease, 2.3%. At 30 years post breast cancer diagnosis, this difference reached 3.2%. These risks were small compared to the corresponding risk of dying from breast cancer. Although the absolute risks were small, we found persistent risks of second non-hematological malignancies excluding breast 30 or more years after breast cancer diagnosis, particularly for women diagnosed at young ages with localized disease.

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References

  1. Colditz GA, Baer HJ, Tamimi RM (2006) Breast cancer. In: Schottenfeld D, Fraumeni JF Jr (eds) Cancer epidemiology and prevention. Oxford University Press, New York, pp 995–1012

    Google Scholar 

  2. American Cancer Society (2006) Cancer Facts and Figures 2006. American Cancer Society, Atlanta

  3. Ron E (2003) Cancer risks from medical radiation. Health Phys 85:47–59

    Article  PubMed  CAS  Google Scholar 

  4. Rowland J, Mariotto A, Aziz N, Tesauro G, Feuer EJ, Blackman D, Thompson P, Pollack L (2004) Cancer survivorship—United States, 1971–2001. MMWR Morbidity and Mortality Weekly Report 53:526–529

    Google Scholar 

  5. Van Leeuwen FE, Travis LB (2005) Second cancers. In: De Vita VT, Hellman S, Rosenberg SA (eds) Cancer: Principles and practice of oncology. Lippincott Williams & Wilkins, Philadelphia, pp 2575–2602

    Google Scholar 

  6. Mellemkjaer L, Friis S, Olsen JH, Scelo G, Hemminki K, Tracey E, Andersen A, Brewster DH, Pukkala E, McBride ML, Kliewer EV, Tonita JM, Kee-Seng C, Pompe-Kirn V, Martos C, Jonasson JG, Boffetta P, Brennan P (2006) Risk of second cancer among women with breast cancer. Int J Cancer 118:2285–2292

    Article  PubMed  CAS  Google Scholar 

  7. Matesich SM, Shapiro CL (2003) Second cancers after breast cancer treatment. Semin Oncol 30:740–748

    Article  PubMed  CAS  Google Scholar 

  8. Bernstein L, Deapen D, Cerhan JR, Schwartz SM, Liff J, McGann-Maloney E, Perlman JA, Ford L (1999) Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst 91:1654–1662

    Article  PubMed  CAS  Google Scholar 

  9. Curtis RE, Boice JD Jr., Shriner DA, Hankey BF, Fraumeni JF Jr. (1996) Second cancers after adjuvant tamoxifen therapy for breast cancer. J Natl Cancer Inst 88:832–834

    Article  PubMed  CAS  Google Scholar 

  10. Swerdlow AJ, Jones ME (2005) Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J Natl Cancer Inst 97:375–384

    PubMed  CAS  Google Scholar 

  11. Boice JD Jr (2006) Ionizing radiation. In: Schottenfeld D, Fraumeni JF Jr (eds) Cancer epidemiology and prevention. Oxford University Press, New York, pp 259–293

    Google Scholar 

  12. Soerjomataram I, Louwman WJ, de Vries E, Lemmens VE, Klokman WJ, Coebergh JW (2005) Primary malignancy after primary female breast cancer in the South of the Netherlands, 1972–2001. Breast Cancer Res Treat 93:91–95

    Article  PubMed  CAS  Google Scholar 

  13. Rubino C, Shamsaldin A, Le MG, Labbe M, Guinebretiere JM, Chavaudra J, de Vathaire F (2005) Radiation dose and risk of soft tissue and bone sarcoma after breast cancer treatment. Breast Cancer Res Treat 89:277–288

    Article  PubMed  Google Scholar 

  14. Roychoudhuri R, Evans H, Robinson D, Moller H (2004) Radiation-induced malignancies following radiotherapy for breast cancer. Br J Cancer 91:868–872

    PubMed  CAS  Google Scholar 

  15. Deutsch M, Land SR, Begovic M, Wieand HS, Wolmark N, Fisher B (2003) The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Results of National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials B-04 and B-06. Cancer 98:1362–1368

    Article  PubMed  Google Scholar 

  16. Matheson JB, Burmeister BH, Smithers BM, Gotley D, Harvey JA, Doyle L (2002) Second primary oesophageal cancer following radiation for breast cancer. Radiother Oncol 65:159–163

    Article  PubMed  Google Scholar 

  17. Rubino C, de Vathaire F, Diallo I, Shamsaldin A, Grimaud E, Labbe M, Contesso G, Le M (2002) Radiation dose, chemotherapy and risk of lung cancer after breast cancer treatment. Breast Cancer Res Treat 75:15–24

    Article  PubMed  CAS  Google Scholar 

  18. Huang J, Mackillop WJ (2001) Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma. Cancer 92:172–180

    Article  PubMed  CAS  Google Scholar 

  19. Ahsan H, Neugut AI (1998) Radiation therapy for breast cancer and increased risk for esophageal carcinoma. Ann Int Med 128:114–117

    PubMed  CAS  Google Scholar 

  20. Karlsson P, Holmberg E, Johansson KA, Kindblom LG, Carstensen J, Wallgren A (1996) Soft tissue sarcoma after treatment for breast cancer. Radiother Oncol 38:25–31

    Article  PubMed  CAS  Google Scholar 

  21. Doherty MA, Rodger A, Langlands AO, Kerr GR (1993) Multiple primary tumours in patients treated with radiotherapy for breast cancer. Radiother Oncol 26:125–131

    Article  PubMed  CAS  Google Scholar 

  22. Neugut AI, Robinson E, Lee WC, Murray T, Karwoski K, Kutcher GJ (1993) Lung cancer after radiation therapy for breast cancer. Cancer 71:3054–3057

    Article  PubMed  CAS  Google Scholar 

  23. Shannon VR, Nesbitt JC, Libshitz HI (1995) Malignant pleural mesothelioma after radiation therapy for breast cancer. A report of two additional patients. Cancer 76:437–441

    CAS  Google Scholar 

  24. Ewertz M, Mouridsen HT (1985) Second cancer following cancer of the female breast in Denmark, 1943–80. Natl Cancer Inst Monogr 68:325–329

    PubMed  CAS  Google Scholar 

  25. Travis LB, Aziz N (2007) Therapy-induced neoplasms. In: Camus P, Rosenow E (eds) Drug-induced and iatrogenic lung disease. Hodder Arnold, London

  26. Cox J (1994) Moss’ radiation oncology rationale, technique, results. Mosby, St. Louis

    Google Scholar 

  27. Breslow NE, Day NE (1987) Statistical methods in cancer research. International Agency for Research on Cancer, Lyon, France

    Google Scholar 

  28. Sahai H, Khurshid A (1996) Statistics in epidemiology: Methods, techniques, and applications. CRC Press, Boca Raton

    Google Scholar 

  29. Preston DL, Lubin JL, Pierce DA (1991) EPICURE user’s guide. HiroSoft International Corporation, Seattle

  30. Chen BE, Cook RJ (2004) Tests for multivariate recurrent events in the presence of a terminal event. Biostatistics 5:129–143

    Article  PubMed  Google Scholar 

  31. Miller DP, Liu G, De VI, Lynch TJ, Wain JC, Su L, Christiani DC (2002) Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res 62:2819–2823

    PubMed  CAS  Google Scholar 

  32. Rebbeck TR (1999) Inherited genetic predisposition in breast cancer. A population-based perspective. Cancer 86:2493–2501

    Article  PubMed  CAS  Google Scholar 

  33. Maggard MA, O’Connell JB, Lane KE, Liu JH, Etzioni DA, Ko CY (2003) Do young breast cancer patients have worse outcomes? J Surg Res 113:109–113

    Article  PubMed  Google Scholar 

  34. Colleoni M, Rotmensz N, Robertson C, Orlando L, Viale G, Renne G, Luini A, Veronesi P, Intra M, Orecchia R, Catalano G, Galimberti V, Nole F, Martinelli G, Goldhirsch A (2002) Very young women (<35 years) with operable breast cancer: features of disease at presentation. Ann Oncol 13:273–279

    Article  PubMed  CAS  Google Scholar 

  35. Chung M, Chang HR, Bland KI, Wanebo HJ (1996) Younger women with breast carcinoma have a poorer prognosis than older women. Cancer 77:97–103

    Article  PubMed  CAS  Google Scholar 

  36. Walker RA, Lees E, Webb MB, Dearing SJ (1996) Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer 74:1796–1800

    PubMed  CAS  Google Scholar 

  37. Prochazka M, Hall P, Gagliardi G, Granath F, Nilsson BN, Shields PG, Tennis M, Czene K (2005) Ionizing radiation and tobacco use increases the risk of a subsequent lung carcinoma in women with breast cancer: case-only design. J Clin Oncol 23:7467–7474

    Article  PubMed  Google Scholar 

  38. Ford MB, Sigurdson AJ, Petrulis ES, Ng CS, Kemp B, Cooksley C, McNeese M, Selwyn BJ, Spitz MR, Bondy ML (2003) Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer 98:1457–1464

    Article  PubMed  Google Scholar 

  39. Gilbert ES, Stovall M, Gospodarowicz M, Van Leeuwen FE, Andersson M, Glimelius B, Joensuu T, Lynch CF, Curtis RE, Holowaty E, Storm H, Pukkala E, van’t Veer MB, Fraumeni JF, Boice JD Jr., Clarke EA, Travis LB (2003) Lung cancer after treatment for Hodgkin’s disease: focus on radiation effects. Radiat Res 159:161–173

    Article  PubMed  CAS  Google Scholar 

  40. Travis LB, Gospodarowicz M, Curtis RE, Clarke EA, Andersson M, Glimelius B, Joensuu T, Lynch CF, Van Leeuwen FE, Holowaty E, Storm H, Glimelius I, Pukkala E, Stovall M, Fraumeni JF Jr, Boice JD Jr, Gilbert E (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94:182–192

    PubMed  Google Scholar 

  41. Anonymous (2000) United National Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Report to the General Assembly, with scientific annexes. Sources and effects of ionizing radiation. United Nations, New York

  42. Van Leeuwen FE, Klokman WJ, Stovall M, Hagenbeek A, van den Belt-Dusebout AW, Noyon R, Boice JD Jr., Burgers JM, Somers R (1995) Roles of radiotherapy and smoking in lung cancer following Hodgkin’s disease. J Natl Cancer Inst 87:1530–1537

    Article  PubMed  Google Scholar 

  43. Neugut AI, Murray T, Santos J, Amols H, Hayes MK, Flannery JT, Robinson E (1994) Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer 73:1615–1620

    Article  PubMed  CAS  Google Scholar 

  44. Prochazka M, Hall P, Granath F, Czene K (2006) Family history of breast cancer and young age at diagnosis of breast cancer increase risk of second primary malignancies in women: a population-based cohort study. Br J Cancer 95:1291–1295

    Article  PubMed  CAS  Google Scholar 

  45. Raymond JS, Hogue CJ (2006) Multiple primary tumours in women following breast cancer, 1973–2000. Br J Cancer 94:1745–1750

    PubMed  CAS  Google Scholar 

  46. Yu GP, Schantz SP, Neugut AI, Zhang ZF (2006) Incidences and trends of second cancers in female breast cancer patients: a fixed inception cohort-based analysis (United States). Cancer Causes Control 17:411–420

    Article  PubMed  Google Scholar 

  47. Levi F, Te VC, Randimbison L, La Vecchia C (2003) Cancer risk in women with previous breast cancer. Ann Oncol 14:71–73

    Article  PubMed  CAS  Google Scholar 

  48. Evans HS, Lewis CM, Robinson D, Bell CM, Moller H, Hodgson SV (2001) Incidence of multiple primary cancers in a cohort of women diagnosed with breast cancer in southeast England. Br J Cancer 84:435–440

    Article  PubMed  CAS  Google Scholar 

  49. Volk N, Pompe-Kirn V (1997) Second primary cancers in breast cancer patients in Slovenia. Cancer Causes Control 8:764–770

    Article  PubMed  CAS  Google Scholar 

  50. Harvey EB, Brinton LA (1985) Second cancer following cancer of the breast in Connecticut, 1935–82. Natl Cancer Inst Monogr 68:99–112

    PubMed  CAS  Google Scholar 

  51. Teppo L, Pukkala E, Saxen E (1985) Multiple cancer–an epidemiologic exercise in Finland. J Natl Cancer Inst 75:207–217

    PubMed  CAS  Google Scholar 

  52. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366:2087–2106

    PubMed  CAS  Google Scholar 

  53. Darby SC, McGale P, Taylor CW, Peto R (2005) Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 6:557–565

    Article  PubMed  Google Scholar 

  54. Kirova YM, Vilcoq JR, Asselain B, Sastre-Garau X, Fourquet A (2005) Radiation-induced sarcomas after radiotherapy for breast carcinoma: a large-scale single-institution review. Cancer 104:856–863

    Article  PubMed  Google Scholar 

  55. Zablotska LB, Chak A, Das A, Neugut AI (2005) Increased risk of squamous cell esophageal cancer after adjuvant radiation therapy for primary breast cancer. Am J Epidemiol 161:330–337

    Article  PubMed  Google Scholar 

  56. Rubino C, de Vathaire F, Shamsaldin A, Labbe M, Le MG (2003) Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment. Br J Cancer 89:840–846

    Article  PubMed  CAS  Google Scholar 

  57. Zablotska LB, Neugut AI (2003) Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma. Cancer 97:1404–1411

    Article  PubMed  Google Scholar 

  58. Prochazka M, Granath F, Ekbom A, Shields PG, Hall P (2002) Lung cancer risks in women with previous breast cancer. Eur J Cancer 38:1520–1525

    Article  PubMed  CAS  Google Scholar 

  59. Yap J, Chuba PJ, Thomas R, Aref A, Lucas D, Severson RK, Hamre M (2002) Sarcoma as a second malignancy after treatment for breast cancer. Int J Radiat Oncol Biol Phys 52:1231–1237

    Article  PubMed  Google Scholar 

  60. Scholl B, Reis ED, Zouhair A, Chereshnev I, Givel JC, Gillet M (2001) Esophageal cancer as second primary tumor after breast cancer radiotherapy. Am J Surg 182:476–480

    Article  PubMed  CAS  Google Scholar 

  61. Sun EC, Curtis R, Melbye M, Goedert JJ (1999) Salivary gland cancer in the United States. Cancer Epidemiol Biomarkers Prev 8:1095–1100

    PubMed  CAS  Google Scholar 

  62. Saku T, Hayashi Y, Takahara O, Matsuura H, Tokunaga M, Tokunaga M, Tokuoka S, Soda M, Mabuchi K, Land CE (1997) Salivary gland tumors among atomic bomb survivors, 1950–1987. Cancer 79:1465–1475

    Article  PubMed  CAS  Google Scholar 

  63. Travis LB, Curtis RE, Inskip PD, Hankey BF (1995) Re: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 87:60–61

    Article  PubMed  CAS  Google Scholar 

  64. Taghian A, de Vathaire F, Terrier P, Le M, Auquier A, Mouriesse H, Grimaud E, Sarrazin D, Tubiana M (1991) Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 21:361–367

    PubMed  CAS  Google Scholar 

  65. Adami HO, Bergkvist L, Krusemo U, Persson I (1984) Breast-cancer as a risk factor for other primary malignant diseases—a nationwide cohort study. J Natl Cancer Inst 73:1049–1055

    PubMed  CAS  Google Scholar 

  66. Eerola H, Pukkala E, Pyrhonen S, Blomqvist C, Sankila R, Nevanlinna H (2001) Risk of cancer in BRCA1 and BRCA2 mutation-positive and -negative breast cancer families (Finland). Cancer Causes Control 12:739–746

    Article  PubMed  CAS  Google Scholar 

  67. Schairer C, Mink PJ, Carroll L, Devesa SS (2004) Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst 96:1311–1321

    PubMed  Google Scholar 

  68. Chen Y, Thompson W, Semenciw R, Mao Y (1999) Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev 8:855–861

    PubMed  CAS  Google Scholar 

  69. Boice JD Jr., Harvey EB, Blettner M, Stovall M, Flannery JT (1992) Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326:781–785

    Article  PubMed  Google Scholar 

  70. Satagopan JM, Ben Porat L, Berwick M, Robson M, Kutler D, Auerbach AD (2004) A note on competing risks in survival data analysis. Br J Cancer 91:1229–1235

    Article  PubMed  CAS  Google Scholar 

  71. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van d V, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009

    Article  PubMed  Google Scholar 

  72. Buyse M, Loi S, van’t Veer L, Viale G, Delorenzi M, Glas AM, d’Assignies MS, Bergh J, Lidereau R, Ellis P, Harris A, Bogaerts J, Therasse P, Floore A, Amakrane M, Piette F, Rutgers E, Sotiriou C, Cardoso F, Piccart MJ (2006) Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98:1183–1192

    Article  PubMed  CAS  Google Scholar 

  73. Sorlie T, Wang Y, Xiao C, Johnsen H, Naume B, Samaha RR, Borresen-Dale AL (2006) Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. BMC Genomics 7:127

    Article  PubMed  CAS  Google Scholar 

  74. Stovall M, Smith SA, Rosenstein M (1989) Tissue doses from radiotherapy of cancer of the uterine cervix. Med Phys 16:726–733

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics. We thank Jeremy Miller, Information Management Services, Inc., Rockville, MD, for exceptional data management and computer support and Dr. Marilyn Stovall and Cathy Kasper, The University of Texas M. D. Anderson Cancer Center, Houston, TX, for estimation of radiation doses.

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Correspondence to Linda Morris Brown.

 

 

Appendix Estimated dose to selected organs (Gy) after radiation treatment for breast cancer

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Brown, L.M., Chen, B.E., Pfeiffer, R.M. et al. Risk of second non-hematological malignancies among 376,825 breast cancer survivors. Breast Cancer Res Treat 106, 439–451 (2007). https://doi.org/10.1007/s10549-007-9509-8

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