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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2008

01-09-2008 | Preclinical Study

Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients

Authors: David S. P. Tan, Caterina Marchió, Robin L. Jones, Kay Savage, Ian E. Smith, Mitch Dowsett, Jorge S. Reis-Filho

Published in: Breast Cancer Research and Treatment | Issue 1/2008

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Abstract

Background

We analysed the clinical features, distribution of basal markers, prevalence of oncogene amplification, and outcome of triple negative (TN) compared to those of non-TN cancers in a series of adjuvant-anthracycline treated breast cancer patients.

Methods

We examined the prognostic impact of the TN and BL phenotype in 245 breast cancer patients uniformly treated with adjuvant anthracycline-based chemotherapy following primary surgery, with regards to local relapse-free (LRFS), metastasis free (MFS), and breast cancer specific survival (BCSS). A comparative analysis of the clinicopathological characteristics, expression of basal markers (cytokeratins (Cks) 5/6, 14, 17, EGFR, and caveolin 1 and 2), MIB-1, p53 and topoisomerase II alpha, and prevalence of CCND1, MYC and TOP2A amplification in TN and non-TN breast tumours was performed.

Results

TN cancers were significantly associated with the expression of basal markers (all P < 0.0001). However 19.4% of TN tumours were negative for basal markers, whilst 7.3% of non-TN tumours expressed basal markers. TN phenotype was significantly associated with p53, MIB-1 and topoisomerase II alpha (all, P < 0.01) expression. No TN cancer harboured amplification of CCND1 or TOP2A. In univariate analysis, TN and BL phenotype were significantly associated with shorter MFS (both, P < 0.01) and BCSS (both, P < 0.005) but not LRFS.

Conclusions

Despite treatment with standard dose anthracycline-based chemotherapy, the clinical outcome of TN and BL cancers remains poor. Alternative chemotherapeutic regimens and/or novel therapeutic approaches are warranted. Although a significant phenotypic overlap exists between TN and basal-like tumours, the TN phenotype is not an ideal surrogate marker for basal-like breast cancers.
Literature
1.
Lacroix M, Toillon RA, Leclercq G (2004) Stable ‘portrait’ of breast tumors during progression: data from biology, pathology and genetics. Endocr Relat Cancer 11:497–522PubMedCrossRef
2.
Reis-Filho JS, Simpson PT, Gale T et al (2005) The molecular genetics of breast cancer: the contribution of comparative genomic hybridization. Pathol Res Pract 201:713–725PubMedCrossRef
3.
Bauer KR, Brown M, Cress RD et al (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer 109:1721–1728PubMedCrossRef
4.
Carey LA, Dees EC, Sawyer L et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329–2334PubMedCrossRef
5.
Haffty BG, Yang Q, Reiss M et al (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24:5652–5657PubMedCrossRef
6.
Rakha EA, El-Sayed ME, Green AR et al (2007) Prognostic markers in triple-negative breast cancer. Cancer 109:25–32PubMedCrossRef
7.
Dent R, Trudeau M, Pritchard KI et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13:4429–4434PubMedCrossRef
8.
Foulkes WD, Metcalfe K, Hanna W et al (2003) Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 98:1569–1577PubMedCrossRef
9.
Harris LN, Broadwater G, Lin NU et al (2006) Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342. Breast Cancer Res 8:R66PubMedCrossRef
10.
Morris GJ, Naidu S, Topham AK et al (2007) Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology, and end results database. Cancer 110:876–884PubMedCrossRef
11.
Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef
12.
Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874PubMedCrossRef
13.
Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423PubMedCrossRef
14.
Gusterson BA, Ross DT, Heath VJ et al (2005) Basal cytokeratins and their relationship to the cellular origin and functional classification of breast cancer. Breast Cancer Res 7:143–148PubMedCrossRef
15.
Lakhani SR, O’Hare MJ (2001) The mammary myoepithelial cell–Cinderella or ugly sister? Breast Cancer Res 3:1–4PubMedCrossRef
16.
Rakha EA, Reis Filho J, Ellis IO (2007) Basal-like breast cancer: a critical review. J Clin Oncol (in press)
17.
Matos I, Dufloth R, Alvarenga M et al (2005) p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Arch 447:688–694PubMedCrossRef
18.
Pinilla SM, Honrado E, Hardisson D et al (2006) Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat 99:85–90PubMedCrossRef
19.
Hu Z, Fan C, Oh DS et al (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7:96PubMedCrossRef
20.
Nielsen TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374PubMedCrossRef
21.
van de Rijn M, Perou CM, Tibshirani R et al (2002) Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome. Am J Pathol 161:1991–1996PubMed
22.
Abd El-Rehim DM, Ball G, Pinder SE et al (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116:340–350PubMedCrossRef
23.
Savage K, Lambros MB, Robertson D et al (2007) Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis. Clin Cancer Res 13:90–101PubMedCrossRef
24.
Savage K, Leung S, Todd Sk et al (2007) Distribution and significance of Caveolin 2 expression in normal breast and invasive breast cancer: an immunofluorescence and immunohistochemical analysis. Breast Cancer Res Treat (in press)
25.
Bidard FC, Conforti R, Boulet T et al (2007) Does triple-negative phenotype accurately identify basal-like tumour? An immunohistochemical analysis based on 143 ‘triple-negative’ breast cancers. Ann Oncol 18:1285–1286PubMedCrossRef
26.
Reis-Filho JS, Tutt A (2007) Triple negative breast cancer: a critical review. Histopathology (in press)
27.
Rouzier R, Perou CM, Symmans WF et al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685PubMedCrossRef
28.
Fulford LG, Reis-Filho JS, Ryder K et al (2007) Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res 9:R4PubMedCrossRef
29.
Hicks DG, Short SM, Prescott NL et al (2006) Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 30:1097–1104PubMed
30.
Tischkowitz M, Brunet JS, Begin LR et al (2007) Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 7:134PubMedCrossRef
31.
Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410PubMedCrossRef
32.
Singletary SE, Connolly JL (2006) Breast cancer staging: working with the sixth edition of the AJCC Cancer Staging Manual. CA Cancer J Clin 56:37–47 (quiz 50–1)PubMedCrossRef
33.
Reis-Filho JS, Savage K, Lambros MB et al (2006) Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Mod Pathol 19:999–1009PubMedCrossRef
34.
Reis-Filho JS, Steele D, Di Palma S et al (2006) Distribution and significance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue. Mod Pathol 19:307–319PubMedCrossRef
35.
Arriola E, Rodriguez-Pinilla SM, Lambros MB et al (2007) Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res Treat (Epub ahead of print)
36.
Reis-Filho JS, Milanezi F, Carvalho S et al (2005) Metaplastic breast carcinomas exhibit EGFR, but not HER2, gene amplification and overexpression: immunohistochemical and chromogenic in situ hybridization analysis. Breast Cancer Res 7:R1028–R1035PubMedCrossRef
37.
Rodriguez-Pinilla SM, Jones RL, Lambros MB et al (2006) MYC amplification in breast cancer: a chromogenic in situ hybridisation study. J Clin Pathol (Epub ahead of print)
38.
Reis-Filho JS, Simpson PT, Jones C et al (2005) Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol 207:1–13PubMedCrossRef
39.
Bhargava R, Gerald WL, Li AR et al (2005) EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol 18:1027–1033PubMedCrossRef
40.
Pauletti G, Dandekar S, Rong H et al (2000) Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol 18:3651–3664PubMed
41.
Livasy CA, Karaca G, Nanda R et al (2006) Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19:264–271PubMedCrossRef
42.
Fan C, Oh DS, Wessels L et al (2006) Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 355:560–569PubMedCrossRef
43.
Sotiriou C, Neo SY, McShane LM et al (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100:10393–10398PubMedCrossRef
44.
Tanner M, Isola J, Wiklund T et al (2006) Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 24:2428–2436PubMedCrossRef
45.
Falo C, Moreno A, Varela M et al (2007) HER-2/neu status and response to CMF: retrospective study in a series of operable breast cancer treated with primary CMF chemotherapy. J Cancer Res Clin Oncol 133:423–429PubMedCrossRef
46.
Gianni L, Baselga J, Eiermann W et al (2005) Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res 11:8715–8721PubMedCrossRef
47.
Fisher B, Brown AM, Dimitrov NV et al (1990) Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483–1496PubMed
48.
Martin M, Villar A, Sole-Calvo A et al (2003) Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol 14:833–842PubMedCrossRef
49.
Calza S, Hall P, Auer G et al (2006) Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients. Breast Cancer Res 8:R34PubMedCrossRef
50.
Urruticoechea A, Smith IE, Dowsett M (2005) Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 23:7212–7220PubMedCrossRef
51.
Mueller RE, Parkes RK, Andrulis I et al (2004) Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples. Genes Chromosomes Cancer 39:288–297PubMedCrossRef
52.
Elsheikh S, Green AR, Aleskandarany MA et al (2007) CCND1 amplification and cyclin D1 expression in breast cancer and their relation with proteomic subgroups and patient outcome. Breast Cancer Res Treat (Epub ahead of print)
53.
Osin PP, Lakhani SR (1999) The pathology of familial breast cancer: Immunohistochemistry and molecular analysis. Breast Cancer Res 1:36–40PubMedCrossRef
54.
Vaziri SA, Tubbs RR, Darlington G et al (2001) Absence of CCND1 gene amplification in breast tumours of BRCA1 mutation carriers. Mol Pathol 54:259–263PubMedCrossRef
55.
Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4:814–819PubMedCrossRef
56.
Turner NC, Reis-Filho JS (2006) Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25:5846–5853PubMedCrossRef
57.
Brown MT, Cooper JA (1996) Regulation, substrates and functions of src. Biochim Biophys Acta 1287:121–149PubMed
58.
Charafe-Jauffret E, Ginestier C, Monville F et al (2006) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25:2273–2284PubMedCrossRef
59.
Finn RS, Dering J, Ginther C et al (2007) Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat (Epub ahead of print)
60.
Huang F, Reeves K, Han X et al (2007) Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer Res 67:2226–2238PubMedCrossRef
Metadata
Title
Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients
Authors
David S. P. Tan
Caterina Marchió
Robin L. Jones
Kay Savage
Ian E. Smith
Mitch Dowsett
Jorge S. Reis-Filho
Publication date
01-09-2008
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2008
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-007-9756-8

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