Abstract
Purpose
The aim of this study was to assess the frequency of second primary non-breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features.
Methods
Data from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52–2.53)], uterine cancers [SIR 1.44 (1.17–1.74)], ovarian cancers [SIR 1.67 (1.31–2.10)], thyroid tumors [SIR 1.54 (1.23–1.92)], and leukemia [SIR 1.57 (1.11–2.16)].
Results
Clinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91–6.29)], G3 tumors [HR 2.54 (1.10–5.83)] and in positive breast cancer family history [HR 2.19 (1.22–3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46–10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28–0.76)].
Conclusions
Older age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status.

Similar content being viewed by others
References
Bray F, Ferlay J, Laversanne M, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, Steliarova-Foucher E, Swaminathan R, Antoni S, Soerjomataram I, Forman D (2015) Cancer incidence in five continents: inclusion criteria, highlights from volume X and the global status of cancer registration. Int J Cancer 13:2060–2071
Carioli G, Malvezzi M, Rodriguez T, Bertuccio P, Negri E, La Vecchia C (2017) Trends and predictions to 2020 in breast cancer mortality in Europe. Breast 36:89–95
Corso G, Figueiredo J, Biffi R, Trentin C, Bonanni B, Feroce I, Serrano D, Cassano E, Annibale B, Melo S, Seruca R, De Lorenzi F, Ferrara F, Piagnerelli R, Roviello F, Galimberti V (2014) E-cadherin germline mutation carriers: clinical management and genetic implications. Cancer Metastasis Rev 33:1081–1094
Coyte A, Morrison DS, McLoone P (2014) Second primary cancer risk—the impact of applying different definitions of multiple primaries: results from a retrospective population-based cancer registry study. BMC Cancer 14:272
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359-386
Grantzau T, Overgaard J (2016) Risk of second non-breast cancer among patients treated with and without postoperative radiotherapy for primary breast cancer: a systematic review and meta-analysis of population-based studies including 522,739 patients. Radiother Oncol 121:402–413
Kaplan HG, Malmgren JA, Atwood MK (2011) Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990–2005. BMC Cancer 11:260
Liu L, De Vries E, Louwman M, Aben K, Janssen-Heijnen M, Brink M, Coebergh JW, Soerjomataram I (2011) Prevalence of multiple malignancies in the Netherlands in 2007. Int J Cancer 128:1659–1667
Malvezzi M, Carioli G, Bertuccio P, Boffetta P, Levi F, La Vecchia C, Negri E (2017) European cancer mortality predictions for the year 2017, with focus on lung cancer. Ann Oncol 28:1117–1123
Mamby CC, Love RR, Lee KE (1995) Thyroid function test changes with adjuvant tamoxifen therapy in postmenopausal women with breast cancer. J Clin Oncol 13:854–857
Paleari L, Gandini S, Provinciali N, Puntoni M, Colombo N, Decensi A (2017) Clinical benefit and risk of death with endocrine therapy in ovarian cancer: a comprehensive review and meta-analysis. Gynecol Oncol 146:504–513
Raymond JS, Hogue CJ (2006) Multiple primary tumours in women following breast cancer, 1973–2000. Br J Cancer 94:1745–1750
Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK (eds) (2004) SEER cancer statistics review, 1975–2001. National Cancer Institute, Bethesda
Silverman BG, Lipshitz I, Keinan-Boker L (2016) Second primary cancers after primary breast cancer diagnosis in Israeli Women, 1992 to 2006. J Glob Oncol 3:135–142
Swerdlow AJ, Jones ME, British Tamoxifen Second Cancer Study Group (2005) Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. J Natl Cancer Inst 97:375–384
Wong-Brown MW, Meldrum CJ, Carpenter JE, Clarke CL, Narod SA, Jakubowska A, Rudnicka H, Lubinski J, Scott RJ (2015) Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. Breast Cancer Res Treat 150:71–80
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
Acknowledgements
We acknowledge William Russell-Edu for his support in editing the draft of this manuscript, and Maria Grazia Villardita for her editorial assistance.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Human and animal rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study. The manuscript was approved by the local scientific committee (IEO Research Platform Protocol nr. RB025, 16 Feb 2017).
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Corso, G., Veronesi, P., Santomauro, G.I. et al. Multiple primary non-breast tumors in breast cancer survivors. J Cancer Res Clin Oncol 144, 979–986 (2018). https://doi.org/10.1007/s00432-018-2621-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-018-2621-9