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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1294-1295 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.0883
Potential Chemotherapy Options in the Triple Negative Subtype of Breast CancerHacettepe University Institute of Oncology, Department of Medical Oncology, Ankara, Turkey To the Editor: We read with great interest the study by Haffty et al1 in which they found no evidence that triple negative breast cancer patients are at higher risk for local relapse after conservative surgery and radiation. However, triple negative patients in their study showed poorer prognosis compared with the other subtypes. Multiple independent data sets have also revealed that the triple negative type carries a poor prognosis.2-4 It is not clear if the poor prognosis of triple negative breast cancer is due to poor therapy options or inherent aggressiveness. Given its triple negative receptor status (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2), triple negative breast cancers are not amenable to conventional targeted therapies for breast cancer, such as endocrine therapy or trastuzumab, leaving only chemotherapy in the therapeutic armamentarium. Until now there has been no specific treatment for breast cancer patients with triple negative breast cancer. Rouzier et al5 showed that the triple negative and human epidermal growth factor receptor 2-positive subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers. Another neoadjuvant study6 suggested that the clinical response to doxorubicin and cyclophosphamide was markedly higher among patients with triple negative tumors than among those with nontriple negative tumors. Pathologic complete response to neoadjuvant chemotherapy was higher in patients with triple negative tumors than in those with nontriple negative-like tumors. Unfortunately, in this study, 34% of triple negative patients did not receive chemotherapy, and among the patients who received adjuvant chemotherapy (66%) only 41% and 6% of them received anthracycline and taxanes as an adjuvant treatment, respectively. Therefore, lack of effective adjuvant treatment in this study may further lead to poorer prognosis. The authors also mentioned potential chemotherapeutic agents that may be effective in the management of triple negative breast cancer, such as epidermal growth factor receptor inhibitors. It is worth mentioning other possible agents that may be effective in this specific subgroup. BRCA1 pathway activity may be impaired in many triple negative breast cancers. BRCA1 functions in DNA repair and cell cycle checkpoint responses may result in sensitivity to DNA damaging agents, such as cisplatin, and resistance to spindle poisons.7 Recently Moyana et al8 reported that small heat-shock protein alpha-basic crystallin was commonly expressed in triple negative tumors and predicted poor survival in breast cancer patients independently of other prognostic markers. Alpha B crystallin overexpression also induced epidermal growth factor- and anchorage-independent growth, increased cell migration and invasion, and constitutively activated the mitogen-activated protein kinase/ERK (mitogen-activated extracellular signal regulated kinase/ERK) pathway. Therefore mitogen-activated extracellular signal regulated kinase inhibitors may be an effective therapy for triple negative breast tumors expressing alpha B crystallin. Recent study by Pinilla et al9 showed that caveolin-1 (CAV1) expression is associated with a triple negative phenotype in sporadic and hereditary breast cancer. ABI-007 (Abraxane; American BioScience Inc, Santa Monica, CA) is a novel, biologically interactive, nanometer-sized albumin-bound paclitaxel particle initially developed to avoid the toxicities associated with polyethylated castor oil. In their phase III study, Gradishar et al10 compared albumin-bound nanoparticle paclitaxel, ABI-007 with polyethylated castor oil-based paclitaxel in women with metastatic breast cancer. This study showed greater efficacy and a favorable safety profile of ABI-007 though no subgroup analysis of molecular phenotypes for differential efficacy of the treatment was performed. After the incorporation of ABI-007 with albumin in blood circulation, ABI-007 is preferentially transported from blood to tumor site in two ways. One way is through leaky junction of endothelial cells that are highly pronounced around the tumor tissue by induction of angiogenesis. The second way and perhaps more prominent way is acting through receptor-mediated transcytosis of this albumin-bound ABI-007.11 This second mechanism is mediated by CAV-1. Breast cancer patients with higher CAV-1 expression, as in the cases of breast cancer with triple negative phenotype, may show better efficacy with more favorable safety profile if they receive ABI-007. In conclusion, standard adjuvant chemotherapy seems to be less effective in breast cancer with triple negative type and new therapeutic approaches are indicated. Greater understanding of the pathologic and molecular characteristics of this phenotype may lead us to tailor the treatment for these patients. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Haffty BG, Yang Q, Reiss M, et al: Locoregional and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24:5652-5657, 2006 2. Sotiriou C, Neo SY, McShane LM, et al: Breast cancer classification and prognosis based on gene expression profiles from a population based study. Proc Natl Acad Sci U S A 100:10393-10398, 2003 3. Sorlie T, 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 4. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-8423, 2003 5. Rouzier R, Perou CM, Symmans WF, et al: Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678-5685, 2005 6. 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 7. Kennedy RD, Quinn JE, Mullan PB, et al: The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96:1659-1668, 2004 8. Moyano JV, Evans JR, Chen F, et al: Alpha B-crystallin is a novel oncoprotein that predicts poor clinical outcome inbreast cancer. J Clin Invest 116:261-270, 2006[CrossRef][Medline] 9. Pinilla SM, Honrado E, Hardisson D, et al: Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat 99:85-90, 2006[CrossRef][Medline] 10. Gradishar WJ, Tjulandin S, Davidson N, et al: Superior efficacy of albumin-bound paclitaxel, ABI-007, compared with polyethylated castor oil-based paclitaxel in women with metastatic breast cancer: Results of a phase III trial. J Clin Oncol 23:7794-7803, 2005 11. Desai N, Yao Z, Trieu V, et al: Evidence of greater antitumor activity of cremophor-free nanoparticle albumin-bound (nab) paclitaxel (Abraxane) compared to taxol: Role of a novel albumin transporter mechanism. Presented at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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