Breast Cancer Research and Treatment

, Volume 158, Issue 1, pp 195–202 | Cite as

Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung

  • Brennan McCullar
  • Manjari Pandey
  • George Yaghmour
  • Felicia Hare
  • Kruti Patel
  • Matthew Stein
  • Rebecca Feldman
  • Jason C. Chandler
  • Michael G. Martin
Brief Report

Abstract

Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37–79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36–86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher’s exact test p = 0.005, OR 0.02 [0.00–0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the lung patients except RB1 in 19 % (p = 0.31). Small cell carcinoma of the breast is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between small cell carcinoma of the breast and small cell carcinoma of the lung with the exception an increased incidence of PIK3CA mutations in small cell carcinoma of the breast, which may have therapeutic implications.

References

  1. 1.
    Hare F, Giri S, Patel JK, Hahn A, Martin MG (2015) A population-based analysis of outcomes for small cell carcinoma of the breast by tumor stage and the use of radiation therapy. Springerplus. doi:10.1186/s40064-015-0913-y PubMedPubMedCentralGoogle Scholar
  2. 2.
    Grossman RA, Pedroso FE, Byrne MM, Koniaris LG, Misra S (2011) Does surgery or radiation therapy impact survival for patients with extrapulmonary small cell cancers? J Surg Oncol 104(6):604–612. doi:10.1002/jso.21976 CrossRefPubMedGoogle Scholar
  3. 3.
    van der Heijden HF, Heijdra YF (2005) Extrapulmonary small cell carcinoma. South Med J 98(3):345–349. doi:10.1097/01.smj.0000145724.40477.50 CrossRefPubMedGoogle Scholar
  4. 4.
    Lopez-Bonet E, Alonso-Ruano M, Barraza G, Vazquez-Martin A, Bernado L, Menendez JA (2008) Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 20(6):1369–1374PubMedGoogle Scholar
  5. 5.
    Boyd AS, Hayes BB (2012) Metastatic small cell neuroendocrine carcinoma of the breast. J Cutan Pathol 39(11):1042–1046. doi:10.1111/j.1600-0560.2012.01970.x CrossRefPubMedGoogle Scholar
  6. 6.
    Dores G, Qubaiah O, Mody A, Ghabach B, Devesa S (2015) A population-based study of incidence and patient survival of small cell carcinoma in the United States, 1992–2010. BMC Cancer 15:185. doi:10.1186/s12885-015-1188-y CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, Brodin O, Joss RA, Kies MS, Lebeau B et al (1992) A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New Engl J Med 327(23):1618–1624CrossRefPubMedGoogle Scholar
  8. 8.
    Adams RW, Dyson P, Barthelmes L (2014) Neuroendocrine breast tumours: breast cancer or neuroendocrine cancer presenting in the breast? Breast 23(2):120–127. doi:10.1016/j.breast.2013.11.005 CrossRefPubMedGoogle Scholar
  9. 9.
    Arsenic R, Treue D, Lehmann A, Hummel M, Dietel M, Denkert C, Budczies J (2015) Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of PIK3CA mutations in breast cancer. BMC Clin Pathol 15:20. doi:10.1186/s12907-015-0020-6 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hahn AW, Giri S, Patel D, Sluder H, Vanderwalde A, Martin MG (2015) Next-Generation Sequencing and In Silico Analysis Facilitate Prolonged Response to Pazopanib in a Patient With Metastatic Urothelial Carcinoma of the Renal Pelvis. J Natl Compr Canc Netw 13(10):1181–1185PubMedGoogle Scholar
  11. 11.
    PolyPhen-2: Prediction of Functional Effects of Human nsSNPs. Available at: http://genetics.bwh.harvard.edu/pph2/. Accessed September 2015
  12. 12.
    Adegbola T, Connolly CE, Mortimer G (2005) Small cell neuroendocrine carcinoma of the breast: a report of three cases and review of the literature. J Clin Pathol 58(7):775–778. doi:10.1136/jcp.2004.020792 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ge QD, Lv N, Cao Y, Wang X, Tang J, Xie ZM, Xiao XS, Liu P, Xie XM, Wei WD (2012) A case report of primary small cell carcinoma of the breast and review of the literature. Chin J Cancer 31(7):354–358. doi:10.5732/cjc.012.10012 PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kitakata H, Yasumoto K, Sudo Y, Minato H, Takahashi Y (2007) A case of primary small cell carcinoma of the breast. Breast Cancer 14(4):414–419CrossRefPubMedGoogle Scholar
  15. 15.
    Shin SJ, DeLellis RA, Ying L, Rosen PP (2000) Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol 24(9):1231–1238CrossRefPubMedGoogle Scholar
  16. 16.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti–pd-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi:10.1056/NEJMoa1200690 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Antonia JS, Bendell JC, Taylor MH, Calvo E, Jaeger D, De Braud FG, Ott PA, Pietanza MC, Horn L, Le DT, Morse M, Lopez-Martin JA, Ascierto PA, Christensen O, Grosso J, Simon JS, Lin C, Eder JP (2015) Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol 33 suppl; abstr 7503Google Scholar
  18. 18.
    Ott PA, Fernandez ME, Hiret S, Kim D, Moss RA, Winser T, Yuan S, Cheng JD, Piperdi B, Mehnert JM (2015) Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results. J Clin Oncol 33, suppl; abstr 7502Google Scholar
  19. 19.
    Hua W, Sa KD, Zhang X, Jia LT, Zhao J, Yang AG, Zhang R, Fan J, Bian K (2015) MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha. Biochem Biophys Res Commun 463(4):1077–1083. doi:10.1016/j.bbrc.2015.06.061 CrossRefPubMedGoogle Scholar
  20. 20.
    Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, Bruzzi P (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100(1):14–20. doi:10.1093/jnci/djm252 CrossRefPubMedGoogle Scholar
  21. 21.
    Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LFA, de Jong D, Van de Vijver MJ, Van’t Veer LJ, Peterse JL (2008) Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol 216(2):141–150. doi:10.1002/path.2407 CrossRefPubMedGoogle Scholar
  22. 22.
    Wang X, Jiang Y, Liu X, Li J, Song C, Shao Z (2016) Difference in characteristics and outcomes between medullary breast carcinoma and invasive ductal carcinoma: a population based study from SEER 18 database. Oncotarget. doi:10.18632/oncotarget.8142 Google Scholar
  23. 23.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Davies C, Goodwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378(9793):771–784. doi:10.1016/S0140-6736(11)60993-8 CrossRefGoogle Scholar
  24. 24.
    BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes J, Price KN, Regan MM, Gelber RD, Coates AS (2009) Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 361(8):766–776. doi:10.1056/NEJMoa0810818 CrossRefGoogle Scholar
  25. 25.
    Kanat O, Kilickap S, Korkmaz T, Oven B, Canhoroz M, Cubukcu E, Tolunay S, Evrensel T, Manavoglu O (2011) Primary small cell carcinoma of the breast: report of seven cases and review of the literature. Tumori 97(4):473–478. doi:10.1700/950.10400 PubMedGoogle Scholar
  26. 26.
    Alkaied H, Harris K, Brenner A, Awasum M, Varma S (2012) Does Hormonal Therapy Have a Therapeutic Role in Metastatic Primary Small Cell Neuroendocrine Breast Carcinoma? Case Report and Literature Review. Clin Breast Cancer 12(3):226–230. doi:10.1016/j.clbc.2012.01.008 CrossRefPubMedGoogle Scholar
  27. 27.
    Nicoletti S, Papi M, Drudi F, Fantini M, Canuti D, Tamburini E, Possenti C, Pasquini E, Brisigotti M, Ravaioli A (2010) Small cell neuroendocrine tumor of the breast in a 40 year-old woman: a case report. J Med Case Rep. doi:10.1186/1752-1947-4-201 Google Scholar
  28. 28.
    Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441(7092):424–430CrossRefPubMedGoogle Scholar
  29. 29.
    Jerusalem G, Rorive A, Collignon J (2014) Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes. Breast Cancer 6:43–57. doi:10.2147/BCTT.S38679 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2(1):a001008. doi:10.1101/cshperspect.a001008 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Encinas G, Maistro S, Pasini FS, Katayama ML, Brentani MM, Bock GH, Folgueira MA (2015) Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis. Rev Assoc Med Bras 61(5):474–483. doi:10.1590/1806-9282.61.05.474 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.University of Tennessee Health Science CenterMemphisUSA

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