Skip to main content

Advertisement

SpringerLink
Log in

Clinically advanced and metastatic pure mucinous carcinoma of the breast: a comprehensive genomic profiling study

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Pure mucinous breast carcinoma (pmucBC) is a distinctive variant of breast cancer (BC) featuring an excellent overall prognosis. However, on rare occasions, pmucBC pursues an aggressive clinical course. We queried whether comprehensive genomic profiling (CGP) would uncover clinically relevant genomic alterations (CRGA) that could lead to targeted therapy treatment for patients with an advanced and metastatic form of pmucBC.

Methods

From a series of 51,238 total cancer samples, which included 5605 cases of clinically advanced BC and 22 cases of stage IV pmucBC, DNA was extracted from 40 microns of FFPE sections. Comprehensive genomic profiling was performed using a hybrid-capture, adaptor ligation-based next generation sequencing assay to a mean coverage depth of 564X. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select rearrangements, and copy number changes. Clinically relevant genomic alterations were defined as those indicating possible treatment with anti-cancer drugs on the market or in registered clinical trials.

Results

Samples were obtained from breast (11), lymph nodes (3), chest wall (2), liver (2), soft tissue (2), bone (1), and pleura (1). The median age of the 22 pmucBC patients was 57 years (range 32–79 years). Three pmucBCs were grade 1, 17 were grade 2, and 2 were grade 3. Twenty-one (95 %) pmucBC were ER+, 18 (82 %) were PR+, and 3 (14 %) were HER2+ by IHC and/or FISH. A total of 132 GA were identified (6.0 GA per tumor), including 53 CRGA, for a mean of 2.4 GA per tumor. Amplification of FGFR1 or ZNF703, located within the same amplicon, was found in 8 of 22 cases (36 %). This enrichment of FGFR1 amplification in 36 % of pmucBC versus 11 % of non-mucinous ER+ BC (601 cases) was significant (p < 0.005). Other frequently altered genes of interest in pmucBC were CCND1 and the FGF3/FGF4/FGF19 amplicon (27 %), often co-amplified together. ERBB2/HER2 alterations were identified in 5 pmucBC (23 %): ERBB2 amplification was found in 3 of 3 cases (100 %) that were HER2+ by IHC and/or FISH; 1 pmucBC was negative for HER2 overexpression by IHC, but positive for amplification by CGP; and 2 pmucBC harbored the ERBB2 substitutions D769Y and V777L (one sample also featured ERBB2 amplification). The enrichment of ERBB2 GA in metastatic pmucBC versus non-metastatic primary pmucBC was significant (p = 0.03). CRGA were also found in 20 additional genes including PIK3CA (5), BRCA1 (1), TSC2 (1), STK11 (1), AKT3 (1), and ESR1 (1).

Conclusions

Metastatic pmucBC is a distinct form of breast cancer that features a relatively high frequency of CRGA, including a significant enrichment of FGFR1 alterations and a high frequency of ERBB2 alterations when compared with non-metastatic pmucBC. These findings suggest that CGP can identify a variety of known and emerging therapy targets that have the potential to improve outcomes for patients with clinically advanced and metastatic forms of this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Diab SG, Clark GM, Osborne CK et al (1999) Tumor characteristics and clinical outcome of tubular and mucinous breast carcinomas. J Clin Oncol 17:1442–1448

    CAS  PubMed  Google Scholar 

  2. Barkley CR, Ligibel JA, Wong JS et al (2008) Mucinous breast carcinoma: a large contemporary series. Am J Surg 196:549–551. doi:10.1016/j.amjsurg.2008.06.013

    Article  PubMed  Google Scholar 

  3. Tan PH, Tse GMK, Bay BH (2008) Mucinous breast lesions: diagnostic challenges. J Clin Pathol 61:11–19. doi:10.1136/jcp.2006.046227

    Article  CAS  PubMed  Google Scholar 

  4. Di Saverio S, Gutierrez J, Avisar E (2008) A retrospective review with long term follow up of 11,400 cases of pure mucinous breast carcinoma. Breast Cancer Res Treat 111:541–547. doi:10.1007/s10549-007-9809-z

    Article  PubMed  Google Scholar 

  5. Tavassoli FA, Devilee P (2003) Pathology and genetics of tumours of the breast and female genital organs. IARC Press, Lyon

    Google Scholar 

  6. Clayton F (1986) Pure mucinous carcinomas of breast: morphologic features and prognostic correlates. Hum Pathol 17:34–38

    Article  CAS  PubMed  Google Scholar 

  7. Chen L, Fan Y, Lang R et al (2008) Breast carcinoma with micropapillary features: clinicopathologic study and long-term follow-up of 100 cases. Int J Surg Pathol 16:155–163. doi:10.1177/1066896907307047

    Article  CAS  PubMed  Google Scholar 

  8. Natrajan R, Wilkerson PM, Marchiò C et al (2014) Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast. J Pathol 232:553–565. doi:10.1002/path.4325

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Ross JS, Slodkowska EA, Symmans WF et al (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14:320–368. doi:10.1634/theoncologist.2008-0230

    Article  CAS  PubMed  Google Scholar 

  10. Adair JD, Harvey KP, Mahmood A et al (2008) Recurrent pure mucinous carcinoma of the breast with mediastinal great vessel invasion: hER-2/neu confers aggressiveness. Am Surg 74:113–116

    PubMed  Google Scholar 

  11. Ranade A, Batra R, Sandhu G et al (2010) Clinicopathological evaluation of 100 cases of mucinous carcinoma of breast with emphasis on axillary staging and special reference to a micropapillary pattern. J Clin Pathol 63:1043–1047. doi:10.1136/jcp.2010.082495

    Article  PubMed  Google Scholar 

  12. Vo T, Xing Y, Meric-Bernstam F et al (2007) Long-term outcomes in patients with mucinous, medullary, tubular, and invasive ductal carcinomas after lumpectomy. Am J Surg 194:527–531. doi:10.1016/j.amjsurg.2007.06.012

    Article  PubMed  Google Scholar 

  13. Fentiman IS, Millis RR, Smith P et al (1997) Mucoid breast carcinomas: histology and prognosis. Br J Cancer 75:1061–1065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Bae SY, Choi M-Y, Cho DH et al (2011) Mucinous carcinoma of the breast in comparison with invasive ductal carcinoma: clinicopathologic characteristics and prognosis. J Breast Cancer 14:308–313. doi:10.4048/jbc.2011.14.4.308

    Article  PubMed Central  PubMed  Google Scholar 

  15. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70. doi:10.1038/nature11412

    Article  Google Scholar 

  16. Dieci MV, Orvieto E, Dominici M et al (2014) Rare breast cancer subtypes: histological, molecular, and clinical peculiarities. Oncologist 19:805–813. doi:10.1634/theoncologist.2014-0108

    Article  PubMed Central  PubMed  Google Scholar 

  17. Horlings HM, Weigelt B, Anderson EM et al (2013) Genomic profiling of histological special types of breast cancer. Breast Cancer Res Treat 142:257–269. doi:10.1007/s10549-013-2740-6

    Article  CAS  PubMed  Google Scholar 

  18. Lacroix-Triki M, Suarez PH, MacKay A et al (2010) Mucinous carcinoma of the breast is genomically distinct from invasive ductal carcinomas of no special type. J Pathol 222:282–298. doi:10.1002/path.2763

    Article  CAS  PubMed  Google Scholar 

  19. Wetterskog D, Lopez-Garcia MA, Lambros MB et al (2012) Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers. J Pathol 226:84–96. doi:10.1002/path.2974

    Article  CAS  PubMed  Google Scholar 

  20. Frampton GM, Fichtenholtz A, Otto GA et al (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023–1031. doi:10.1038/nbt.2696

    Article  CAS  PubMed  Google Scholar 

  21. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129. doi:10.1038/nrc2780

    Article  CAS  PubMed  Google Scholar 

  22. Ma CX, Ellis MJ (2013) The Cancer Genome Atlas: clinical applications for breast cancer. Oncol (Williston Park, NY) 27(1263–1269):1274–1279

    Google Scholar 

  23. Elbauomy Elsheikh S, Green AR, Lambros MBK et al (2007) FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis. Breast Cancer Res 9:R23. doi:10.1186/bcr1665

    Article  PubMed Central  PubMed  Google Scholar 

  24. Andre F, Job B, Dessen P et al (2009) Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res 15:441–451. doi:10.1158/1078-0432.CCR-08-1791

    Article  CAS  PubMed  Google Scholar 

  25. Moelans CB, de Weger RA, Monsuur HN et al (2010) Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. Mod Pathol 23:1029–1039. doi:10.1038/modpathol.2010.84

    Article  CAS  PubMed  Google Scholar 

  26. Tiburcio M, Costa SMA, Fatima Duarte MDE et al (2012) Characterization of PAR1 and FGFR1 expression in invasive breast carcinomas: prognostic significance. Oncol Lett 4:647–657. doi:10.3892/ol.2012.806

    PubMed Central  PubMed  Google Scholar 

  27. Turner N, Pearson A, Sharpe R et al (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70:2085–2094. doi:10.1158/0008-5472.CAN-09-3746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Gozgit JM, Wong MJ, Moran L et al (2012) Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 11:690–699. doi:10.1158/1535-7163.MCT-11-0450

    Article  CAS  PubMed  Google Scholar 

  29. van der Graaf WTA, Blay J-Y, Chawla SP et al (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Lond Engl 379:1879–1886. doi:10.1016/S0140-6736(12)60651-5

    Article  Google Scholar 

  30. Alsner J, Jensen V, Kyndi M et al (2008) A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients. Acta Oncol Stockh Swed 47:600–607. doi:10.1080/02841860802047411

    Article  CAS  Google Scholar 

  31. Alkam Y, Mitomi H, Nakai K et al (2013) Protein expression and methylation of DNA repair genes hMLH1, hMSH2, MGMT and BRCA1 and their correlation with clinicopathological parameters and prognosis in basal-like breast cancer. Histopathology 63:713–725. doi:10.1111/his.12220

    PubMed  Google Scholar 

  32. Uji K, Naoi Y, Kagara N et al (2014) Significance of TP53 mutations determined by next-generation “deep” sequencing in prognosis of estrogen receptor-positive breast cancer. Cancer Lett 342:19–26. doi:10.1016/j.canlet.2013.08.028

    Article  CAS  PubMed  Google Scholar 

  33. Olivier M, Langerød A, Carrieri P et al (2006) The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167. doi:10.1158/1078-0432.CCR-05-1029

    Article  CAS  PubMed  Google Scholar 

  34. Végran F, Rebucci M, Chevrier S et al (2013) Only missense mutations affecting the DNA binding domain of p53 influence outcomes in patients with breast carcinoma. PLoS One 8:e55103. doi:10.1371/journal.pone.0055103

    Article  PubMed Central  PubMed  Google Scholar 

  35. Forbes SA, Beare D, Gunasekaran P et al (2015) COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res 43:D805–D811. doi:10.1093/nar/gku1075

    Article  PubMed Central  PubMed  Google Scholar 

  36. Hirai H, Arai T, Okada M et al (2010) MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther 9:514–522

    Article  CAS  PubMed  Google Scholar 

  37. Bridges KA, Hirai H, Buser CA et al (2011) MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res 17:5638–5648. doi:10.1158/1078-0432.CCR-11-0650

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Samuels Y, Diaz LA, Schmidt-Kittler O et al (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573. doi:10.1016/j.ccr.2005.05.014

    Article  CAS  PubMed  Google Scholar 

  39. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562. doi:10.1038/nrc2664

    Article  CAS  PubMed  Google Scholar 

  40. Kalinsky K, Jacks LM, Heguy A et al (2009) PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 15:5049–5059. doi:10.1158/1078-0432.CCR-09-0632

    Article  CAS  PubMed  Google Scholar 

  41. Barbareschi M, Buttitta F, Felicioni L et al (2007) Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:6064–6069. doi:10.1158/1078-0432.CCR-07-0266

    Article  CAS  PubMed  Google Scholar 

  42. Kehr EL, Jorns JM, Ang D et al (2012) Mucinous breast carcinomas lack PIK3CA and AKT1 mutations. Hum Pathol 43:2207–2212. doi:10.1016/j.humpath.2012.03.012

    Article  CAS  PubMed  Google Scholar 

  43. Buttitta F, Felicioni L, Barassi F et al (2006) PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol 208:350–355. doi:10.1002/path.1908

    Article  CAS  PubMed  Google Scholar 

  44. Janku F, Tsimberidou AM, Garrido-Laguna I et al (2011) PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther 10:558–565. doi:10.1158/1535-7163.MCT-10-0994

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Baselga J, Campone M, Piccart M et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529. doi:10.1056/NEJMoa1109653

    Article  CAS  PubMed  Google Scholar 

  46. Miller TW, Rexer BN, Garrett JT, Arteaga CL (2011) Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 13:224. doi:10.1186/bcr3039

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Loi S, Michiels S, Baselga J et al (2013) PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer. PLoS One 8:e53292. doi:10.1371/journal.pone.0053292

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Ramirez-Ardila DE, Helmijr JC, Look MP et al (2013) Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen. Breast Cancer Res Treat 139:39–49. doi:10.1007/s10549-013-2529-7

    Article  CAS  PubMed  Google Scholar 

  49. Chakrabarty A, Rexer BN, Wang SE et al (2010) H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 29:5193–5203. doi:10.1038/onc.2010.257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Kataoka Y, Mukohara T, Shimada H et al (2010) Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol 21:255–262. doi:10.1093/annonc/mdp304

    Article  CAS  PubMed  Google Scholar 

  51. Wang L, Zhang Q, Zhang J et al (2011) PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer 11:248. doi:10.1186/1471-2407-11-248

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Barbareschi M, Cuorvo LV, Girlando S et al (2012) PI3KCA mutations and/or PTEN loss in Her2-positive breast carcinomas treated with trastuzumab are not related to resistance to anti-Her2 therapy. Virchows Arch Int J Pathol 461:129–139. doi:10.1007/s00428-012-1267-2

    Article  CAS  Google Scholar 

  53. Tseng H-S, Lin C, Chan S-E et al (2013) Pure mucinous carcinoma of the breast: clinicopathologic characteristics and long-term outcome among Taiwanese women. World J Surg Oncol 11:139. doi:10.1186/1477-7819-11-139

    Article  PubMed Central  PubMed  Google Scholar 

  54. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792. doi:10.1056/NEJM200103153441101

    Article  CAS  PubMed  Google Scholar 

  55. Verma S, Miles D, Gianni L et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791. doi:10.1056/NEJMoa1209124

    Article  CAS  PubMed  Google Scholar 

  56. Baselga J, Cortés J, Kim S-B et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109–119. doi:10.1056/NEJMoa1113216

    Article  CAS  PubMed  Google Scholar 

  57. Swain SM, Kim S-B, Cortés J et al (2013) Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461–471. doi:10.1016/S1470-2045(13)70130-X

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Ali SM, Alpaugh RK, Downing SR et al (2014) Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol 32:e88–e91. doi:10.1200/JCO.2013.49.0599

    Article  PubMed  Google Scholar 

  59. Jankowitz RC, Abraham J, Tan AR et al (2013) Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2-positive breast cancer: an NSABP Foundation Research Program phase I study. Cancer Chemother Pharmacol 72:1205–1212. doi:10.1007/s00280-013-2262-2

    Article  CAS  PubMed  Google Scholar 

  60. Martin M, Bonneterre J, Geyer CE et al (2013) A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer Oxf Engl 49:3763–3772. doi:10.1016/j.ejca.2013.07.142

    Article  CAS  Google Scholar 

  61. Bose R, Kavuri SM, Searleman AC et al (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224–237. doi:10.1158/2159-8290.CD-12-0349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by Foundation Medicine, Inc. and samples in this study were analyzed using FoundationOne genomic profiling.

Author information

Authors and Affiliations

  1. Department of Pathology, Mail Code 81, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA

    Jeffrey S. Ross, Sahar Nozad & Ann Boguniewicz

  2. Foundation Medicine, Inc., Cambridge, MA, USA

    Jeffrey S. Ross, Laurie M. Gay, Kai Wang, Siraj M. Ali, Depinder Khaira, Adrienne Johnson, Julia A. Elvin, Jo-Anne Vergilio, James Suh, Vincent A. Miller & Philip J. Stephens

Authors
  1. Jeffrey S. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurie M. Gay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sahar Nozad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Siraj M. Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ann Boguniewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Depinder Khaira
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adrienne Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Julia A. Elvin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jo-Anne Vergilio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. James Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vincent A. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Philip J. Stephens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey S. Ross.

Ethics declarations

Conflict of Interest

J Ross, L Gay, K Wang, S Ali, D Khaira, A Johnson, J Elvin, J Vergilio, J Suh, V Miller, and P Stephens are employees of Foundation Medicine, Inc. and own stock or hold stock options in the company. S Nozad and A Boguniewicz declare that they have no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 19 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ross, J.S., Gay, L.M., Nozad, S. et al. Clinically advanced and metastatic pure mucinous carcinoma of the breast: a comprehensive genomic profiling study. Breast Cancer Res Treat 155, 405–413 (2016). https://doi.org/10.1007/s10549-016-3682-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-016-3682-6

Keywords

Search

Navigation