J Breast Cancer.  2015 Dec;18(4):378-385. 10.4048/jbc.2015.18.4.378.

Risk of Second Primary Malignancy in Breast Cancer Survivors: A Nested Population-Based Case-Control Study

• Marcheselli R
• Marcheselli L
• Cortesi L
• Bari A
• Cirilli C
• Pozzi S
• Ferri P
• Napolitano M
• Federico M
• Sacchi S

• KMID: 2176287
• DOI: http://doi.org/10.4048/jbc.2015.18.4.378

Abstract

PURPOSE
Evolving therapies have improved the prognoses of patients with breast cancer; and currently, the number of long-term survivors is continuously increasing. However, these patients are at increased risk of developing a second cancer. Thus, late side effects are becoming an important issue. In this study, we aimed to investigate whether patient and tumor characteristics, and treatment type correlate with secondary tumor risk.
METHODS
This case-control study included 305 patients with a diagnosed second malignancy after almost 6 months after the diagnosis of primary breast cancer and 1,525 controls (ratio 1:5 of cases to controls) from a population-based cohort of 6,325 women. The control patients were randomly selected from the cohort and matched to the cases according to age at diagnosis, calendar period of diagnosis, disease stage, and time of follow-up.
RESULTS
BRCA1 or BRCA2 mutation, human epidermal growth factor receptor 2 (HER2)+ status, chemotherapy, and radiotherapy were related to increased risk of developing a second cancer, whereas hormonotherapy showed a protective effect. Chemotherapy, radiotherapy, and estrogenic receptor level <10% increased the risk of controlateral breast cancer. HER2+ status increased the risk of digestive system and thyroid tumors, while BRCA1 or BRCA2 mutation increased the risk of cancer in the genital system.
CONCLUSION
Breast cancer survivors are exposed to an excess of risk of developing a second primary cancer. The development of excess of malignancies may be related either to patient and tumor characteristics, such as BRCA1 or BRCA2 mutation and HER2+ status, or to treatments factors.

Keyword

Breast neoplasms; Case-control studies; Human epidermal growth factor receptor 2; Second primary neoplasms

MeSH Terms

Breast Neoplasms*
Breast*
Case-Control Studies*
Cohort Studies
Diagnosis
Digestive System
Drug Therapy
Estrogens
Female
Follow-Up Studies
Humans
Neoplasms, Second Primary
Prognosis
Radiotherapy
Receptor, Epidermal Growth Factor
Survivors*
Thyroid Gland
Estrogens
Receptor, Epidermal Growth Factor

Figure

• 

  Figure 1 Flow-chart of patients included in the analysis, starting from 6,325 women with primary breast cancer recorded by Modena Cancer Registry between 1996 and 2007.

Reference

1. Hortobagyi GN, de la Garza Salazar J, Pritchard K, Amadori D, Haidinger R, Hudis CA, et al. The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer. 2005; 6:391–401.

2. De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE: 5-a population-based study. Lancet Oncol. 2014; 15:23–34.

3. Cortesi L, De Matteis E, Rashid I, Cirilli C, Proietto M, Rivasi F, et al. Distribution of second primary malignancies suggests a bidirectional effect between breast and endometrial cancer: a population-based study. Int J Gynecol Cancer. 2009; 19:1358–1363.

4. Mellemkjaer L, Friis S, Olsen JH, Scélo G, Hemminki K, Tracey E, et al. Risk of second cancer among women with breast cancer. Int J Cancer. 2006; 118:2285–2292.

5. Mellemkjær L, Christensen J, Frederiksen K, Pukkala E, Weiderpass E, Bray F, et al. Risk of primary non-breast cancer after female breast cancer by age at diagnosis. Cancer Epidemiol Biomarkers Prev. 2011; 20:1784–1792.

6. Rubino C, de Vathaire F, Diallo I, Shamsaldin A, Lê MG. Increased risk of second cancers following breast cancer: role of the initial treatment. Breast Cancer Res Treat. 2000; 61:183–195.

7. Molina-Montes E, Requena M, Sánchez-Cantalejo E, Fernández MF, Arroyo-Morales M, Espën J, et al. Risk of second cancers cancer after a first primary breast cancer: a systematic review and meta-analysis. Gynecol Oncol. 2015; 136:158–171.

8. Langballe R, Olsen JH, Andersson M, Mellemkjær L. Risk for second primary non-breast cancer in pre- and postmenopausal women with breast cancer not treated with chemotherapy, radiotherapy or endocrine therapy. Eur J Cancer. 2011; 47:946–952.

9. Beadle G, Baade P, Fritschi L. Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers. Ann Oncol. 2009; 20:103–109.

10. Vuong NT, Boucher E, Gedouin D, Vauleon E, Le Prise E, Raoul JL. Radiation-induced oesophageal carcinoma after breast carcinoma: a report of five cases including three successfully treated by radiochemotherapy. Acta Oncol. 2007; 46:1184–1186.

11. Karlsson P, Holmberg E, Samuelsson A, Johansson KA, Wallgren A. Soft tissue sarcoma after treatment for breast cancer: a Swedish population-based study. Eur J Cancer. 1998; 34:2068–2075.

12. Kmet LM, Cook LS, Weiss NS, Schwartz SM, White E. Risk factors for colorectal cancer following breast cancer. Breast Cancer Res Treat. 2003; 79:143–147.

13. Berrington de Gonzalez A, Curtis RE, Kry SF, Gilbert E, Lamart S, Berg CD, et al. Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol. 2011; 12:353–360.

14. Berrington de Gonzalez A, Curtis RE, Gilbert E, Berg CD, Smith SA, Stovall M, et al. Second solid cancers after radiotherapy for breast cancer in SEER cancer registries. Br J Cancer. 2010; 102:220–226.

15. Stovall M, Smith SA, Langholz BM, Boice JD Jr, Shore RE, Andersson M, et al. Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study. Int J Radiat Oncol Biol Phys. 2008; 72:1021–1030.

16. Bouchardy C, Benhamou S, Fioretta G, Verkooijen HM, Chappuis PO, Neyroud-Caspar I, et al. Risk of second breast cancer according to estrogen receptor status and family history. Breast Cancer Res Treat. 2011; 127:233–241.

17. Malone KE, Begg CB, Haile RW, Borg A, Concannon P, Tellhed L, et al. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol. 2010; 28:2404–2410.

18. Hemminki K, Zhang H, Sundquist J, Lorenzo Bermejo J. Modification of risk for subsequent cancer after female breast cancer by a family history of breast cancer. Breast Cancer Res Treat. 2008; 111:165–169.

19. McIntosh A, Shaw C, Evans G, Turnbull N, Bahar N, Barclay M, et al. Clinical Guidelines and Evidence Review for the Classification and Care of Women at Risk of Familial Breast Cancer. London: National Collaborating Centre for Primary Care/University of Sheffield;2004.

20. Mondi MM, Rich R, Ituarte P, Wong M, Bergman S, Clark OH, et al. HER2 expression in thyroid tumors. Am Surg. 2003; 69:1100–1103.

21. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999; 18:695–706.

22. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999; 94:496–509.

23. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol. 1. The Analysis of Case-Control Studies. Lyon: International Agency for Research on Cancer;1980.

24. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989; 244:707–712.

25. Tomizawa K, Suda K, Onozato R, Kosaka T, Endoh H, Sekido Y, et al. Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer. 2011; 74:139–144.

26. Kremser R, Obrist P, Spizzo G, Erler H, Kendler D, Kemmler G, et al. Her2/neu overexpression in differentiated thyroid carcinomas predicts metastatic disease. Virchows Arch. 2003; 442:322–328.

27. Jørgensen JT. Targeted HER2 treatment in advanced gastric cancer. Oncology. 2010; 78:26–33.

28. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008; 65:1566–1584.

29. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006; 7:505–516.

30. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006; 7:606–619.