Yi et al. BMC Cancer 2010, 10:527 http://www.biomedcentral.com/1471-2407/10/527 Table 3 Multivariate Cox-regression analysis on metastatic OS Triple negativity HER2 positivity OS: overall survival, 95% CI: 95% confidence interval. P value 0.011 0.027 Hazard Ratio (HR) 2.03 1.86 95% CI 1.17 3.51 1.07 3.22 chemotherapy for TNBCs, irrespective of the che- motherapy regimen [31-33]. Despite the initial sensitivity to chemotherapy, several studies have shown that TNBCs carry a poor prognosis [11-13]. Our results also showed that TNBCs had poorer PFS and OS than non- TNBCs (Figure 1C). This finding suggests that despite the beneficial response to treatment, chemotherapy did not improve subsequent long-term survival of TNBC patients. Several studies support this paradoxical feature of high response, but poor long-term outcome [3,4,32-34]. Chemotherapy responsiveness is usually positively cor- related with good clinical outcomes resulting in long- term survival [35]. However, this chemosensitivity is insufficient to overcome biologic aggressiveness, and rapid tumor-growth characteristics of TNBCs. In fact, the TTD after AC chemotherapy in patients with TNBCs was much shorter than that for HR+ patients (median TTD, 15.9 months for TN, 13.2 months for HER2+, and 24.8 months for HR+; p = 0.0037). This finding suggests that another therapeutic strategy is needed to overcome the aggressive clinical behavior, prolong the survival time and improve the quality of life of TNBC patients. In contrast, a longer TTD after AC chemotherapy in patients with non-TNBCs, mainly of the HR+ subtype, may be due to the relatively slower tumor growth characteristics and additional benefit from hormonal therapies with subsequent easier disease control than for TNBCs. Thus, future treatment strate- gies should be developed based on the heterogeneity of the tumor. The consideration of such tumor heterogene- ity will make a valuable contribution to the design of individualized therapy. Dose intensification of conventional chemotherapeutic agents including doxorubicin may be beneficial to extend the therapeutic index [36]. However, most of the patients did not have durable responses. This suggests that doxorubicin resistance can easily occur in meta- static TNBC, perhaps due to prior exposure to doxoru- bicin or other chemotherapeutic agents in the adjuvant setting. Additionally, considering the poor correlation between chemosensitivity and long-term survival in patients with TNBCs, it is necessary to substantially pro- long the response duration. This is because once lack of response occurs, TNBCs appears to follow a more aggressive and fatal clinical course TNBCs have more Page 5 of 7 aggressive tumor biology as evidenced by a higher histo- logical grade and higher expression of Ki-67 than non- TNBCs. Recently, a few reports have suggested the potential use of these proliferation indexes as makers for complex tumor characteristics [33,37,38]. Impor- tantly, TNBCs are composed of heterogeneous disease entities, consisting of two or more subtypes [39,40]. The interpretation of our study may be limited, because it is a retrospective study. In addition, prior adjuvant therapy may affect on clinical outcomes in a metastatic setting. Despite these drawbacks, our study may have clinical impact in treating TNBC, for which therapeutic options are limited. The conventional treat- ments studies here need to be supplemented with new innovative therapeutic strategies based on an under- standing of the biologic differences and aggressiveness of TNBCs. As HER2 direct therapy in HER2 positive subtype, new innovative targets for TNBC need to be developed. Ongoing clinical trials may open the door to better treatment outcomes. These trials evaluating new drugs such as PARP1 inhibitors [40-42], EGFR tyrosine kinase inhibitors [43], and antiangiogenic agents for TNBCs in adjuvant and palliative settings. Conclusions TNBC had a comparable response rate to first-line AC chemotherapy compared to non-TNBC. Nonetheless, TNBC patients had shorter survival than non-TNBC patients. Innovative therapeutic strategies are needed to overcome the biologic aggressiveness of TNBCs. Acknowledgements Supported by a grant of the Korean Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412-CR01-0704-0001) Author details 1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon- dong Gangnam-gu, Seoul 135-710 Korea. 2Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 Korea. Authors’ contributions SYY carried out raw data and primary statistical analyses. JSA planned basic design of the study and coordination. JEU, DHL, and SHJ participated in data analysis and draft writing. HJJ, KHK, MHC, and MJP participated in clinical data collection and assisted statistical analysis. EYC and YLC carried out the immunohistochemical staining and evaluated the immunostaining. YHP participated in writing the manuscript and coordination. YHI organized and supervised the study. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Received: 1 October 2009 Accepted: 5 October 2010 Published: 5 October 2010 References 1. Dinh P, Sotiriou C, Piccart MJ: The evolution of treatment strategies: Aiming at the target. Breast 2007, 16(suppl 2):S10-S6.