No standard first-line treatment exists for patients with metastatic triple-negative breast cancer (mTNBC). In this single-arm, phase II study (NCT00601159), we evaluated the efficacy and tolerability of cisplatin and gemcitabine (GP) as the first-line therapy in mTNBC. Eligible women were those who had measurable disease with no prior chemotherapy for mTNBC. All patients received 21-day-cycle of cisplatin 25 mg/m 2 on days 1-3 and gemcitabine 1,000 mg/m 2 on days 1 and 8. Treatment was continued until disease progression, unacceptable toxicity or up to 8 cycles. BRCA1/2 mutation status and immunohistochemical basal markers were included in the correlative studies. Sixty-four patients with the median age of 49 years were enrolled. Thirty patients (46.9%) had 1 year from diagnosis to recurrence. The median progression free survival (PFS) was 7.2 months (95%CI, 5.6-8.9 months) and overall survival (OS) was 19.1 months (95%CI, 12.4-25.8 months) with median follow-up 42 months. Patients received treatment for a median of six cycles. The overall response rate was 62.5%. The most common grades 3/4 toxicities were neutropenia (42.2%), thrombocytopenia (29.7%), anemia (18.8%) and nausea/vomiting (15.6%).No specific BRCA1/2 mutation carriers were identified. The efficacy of responses and basal-like subtype were independent favorable factors for PFS and OS, respectively. We conclude that the combination of GP has significant activity and a favorable safety profile as the first-line chemotherapy in mTNBC patients, in particular patients with basal-like subtype. The promising role of this combination as the front-line treatment for mTNBC continued to be evaluated in our ongoing phase III trial (CBCSG006).Triple-negative breast cancer (TNBC), 12-20% of all breast cancers, does not express the estrogen receptor (ER), progesterone receptor and the gene amplification of human epidermal growth factor receptor 2 (HER2).

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Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16INK4a and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up-regulated in the luminal-A of IDC (P<0.008). Triple-negative breast cancers were characterized by a correlation of p53 overexpression with a high level of p16 expression. Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction. Taken together, the present study suggest that p16 expression in luminal-A breast cancers is associated with their progression from DCIS to IDC, and both p53 and p16 expressions are important for the development of triple-negative breast cancers in DCIS and IDC.

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