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Yale University School of Medicine

Deborah Toppmeyer

Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School

Bruce G. Haffty

Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School

The basal-like, or triple-negative subtype, has recently emerged from microarray profiling studies as a molecularly distinct subtype of breast cancer.¹ These tumors typically express one or more of the basal cytokeratins (CK5/6, CK14) and have a higher frequency of distant relapse.^2-4 Unfortunately, the pathogenesis of these tumors is poorly understood and it remains unclear what drives these tumor cells to proliferate and metastasize. They are thought to be insensitive to estrogen receptor (ER) and human epidermal growth factor receptor 2 receptor (HER2)-directed inhibitors, which may explain the worse prognosis observed across multiple breast cancer data sets. However, there is tantalizing evidence to suggest that these tumors are particularly sensitive to systemic chemotherapy.⁵ Altundag et al raise a controversial and compelling topic: what is the optimal therapy for triple negative breast cancer? Perhaps we need to take one step back and ask, what is basal-like breast cancer? While profiling studies suggest that basal-like tumors represent a distinct class of breast cancer, the expectation that these tumors will respond uniformly to treatment may be simplistic. Histopathologic studies suggest that breast tumors with the basal immunoprofile represent a heterogeneous group from both the molecular and clinical perspective.⁶ For example, adenoid cystic carcinoma is among the least aggressive breast neoplasms.⁷ In addition, medullary carcinoma is a subtype occurring more frequently among BRCA1-positive women and may have a more favorable outcome.⁸ Furthermore, basal breast tumors of myoepithelial origin may have a more favorable prognosis than tumors with a dominant basal pattern.³ Finally, while tumors of basal origin are frequently ER–, progesterone receptor–, and HER2–negative, this is not always the case.^9,10 Thus, correlative studies which use the absence of ER, progesterone receptor, and HER2 to identify this subtype are likely to be composed of a mixture of basaloid tumors with varying histology and behavior. It is not surprising then that molecular features of triple-negative tumors are variable. Studies suggest that these tumors are not, in fact, receptor poor and express multiple drugable targets including HER1, HER3, HER4, c-kit, and c-met.^11-13 Certain variants may be more likely to overexpress EGFR or mesenchymal markers.^14,15 These findings suggest not only the opportunity to define new therapy for basaloid tumors but the need to carefully evaluate histology in trials of novel treatment strategies for this subgroup.

A unique feature of triple negative breast cancer appears to be enhanced sensitivity to chemotherapy agents.¹⁶ The triple-negative paradox described by Carey et al suggests that chemotherapy may be the most useful targeted therapy for this poor prognosis subgroup.⁵ However, the optimal chemotherapy regimen remains controversial.

Both preclinical and clinical data suggest that the triple-negative tumors are more likely to be BRCA1 deficient, either due to germline mutation in the case of BRCA1 carriers or by somatic changes, and hence are more sensitive to agents which induce double-strand breaks.¹⁷ This has led to the design of trials incorporating cisplatin for triple negative breast cancer and preliminary results of these trials suggest promising activity.¹⁸ However, clinical data do not support a unique sensitivity to agents which intercalate DNA as triple negative tumors also appear to benefit most both taxane- and anthracycline-based therapy.^19,20 Additional work is necessary to determine if optimal therapy for triple negative breast cancer should include a platinum or if we are simply observing enhanced sensitivity to antimitotic agents in tumors with a higher proliferative fraction. Future studies should be carefully designed to address these questions.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

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2. Sorlie TI, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001[Abstract/Free Full Text]

3. Rakha EA, Putti TC, Abd El-Rehim DM, et al: Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208:495-506, 2006[CrossRef][Medline]

4. Haffty BG, Yang Q, Reiss M, et al: Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24:5652-5657, 2006[Abstract/Free Full Text]

5. Carey LA, Dees EC, Sawyer LR, et al: The triple negative paradox: Primary tumor chemosensitivity of the basal-like breast cancer phenotype. Breast Cancer Res Treat 80:1023, 2004

6. Potemski P, Kusinska R, Watala C, et al: Prognostic relevance of basal cytokeratin expression in operable breast cancer. Oncology 69:478-485, 2005[CrossRef][Medline]

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8. Bonadona V, Dussart-Moser S, Voirin N, et al: Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review. Breast Cancer Res Treat 101:233-245, 2007[CrossRef][Medline]

9. Harris LN, You F, Schnitt SJ, et al: Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2 positive early breast cancer. Clinical Cancer Res 13:1198-1207, 2007[Abstract/Free Full Text]

10. Kusinska R, Potemski P, Jesionek-Kupnicka D, et al: Immunohistochemical identification of basal-type cytokeratins in invasive ductal breast carcinoma–relation with grade, stage, estrogen receptor and HER2. Pol J Pathol 56:107-110, 2005[Medline]

11. Livasy CA, Karaca G, Nanda R, et al: Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19:264-271, 2006[CrossRef][Medline]

12. Dolled-Filhart M, Ryden L, Cregger M, et al: Classification of breast cancer using genetic algorithms and tissue microarrays. Clin Cancer Res 1:6459-6468, 2006

13. Lengyel E, Prechtel D, Resau JH, et al: C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer 113:678-682, 2005[CrossRef][Medline]

14. Bossuyt V, Fadare 0, Martel M, et al: Remarkably high frequency of EGFR expression in breast carcinomas with squamous differentiation. International J Pathol 13:319-327, 2005

15. Dabbs DJ, Chivukula M, Carter G, et al: Basal phenotype of ductal carcinoma in situ: Recognition and immunohistologic profile. Mod Pathol 19:1506-1511, 2006[Medline]

16. Roman Rouzier, Charles M Perou, W: Fraser Symmans, et al: Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:S678-S685, 2005

17. Turner NC, Reis-Filho JS, Russell AM, et al: BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 2006 [e-pub ahead of print]

18. Garber JE, Richardson A, Harris LN, et al: Neo-adjuvant cisplatin (CDDP) in "triple-negative" breast cancer (BC). San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-17, 2006 (abstr 3074)

19. Jacquemier J, Penault-Llorca F, Mnif H, et al: Identification of a basal-like subtype and comparative effect of epirubicin-based chemotherapy and sequential epirubicin followed by docetaxel chemotherapy in the PACS 01 breast cancer trial: 33 markers studied on tissue-microarrays (TMA). J Clin Oncol 24:5s, 2006 (abstr 509)

20. Hayes DF, Thor A, Dressler L, Weaver D, et al: HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer: CALGB 9344. J Clin Oncol 24:5s, 2006 (abstr 510)

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