New progress of Triple-negative breast cancer treatment research

Triple-negative breast cancer has a special biological characteristics and clinical and pathological features, occur in younger pre-menopausal women, breast cancer prognosis than other types of poor prognosis, is one of the hot research in recent years, this study of triple-negative breast cancer and treatment progress are discussed.
1 Overview
Triple-negative breast cancer (triple negative breast cancer, TNBC) is the estrogen and progesterone receptors (ER and PR) and HER-2 were negative breast cancer, breast cancer accounts for about 10% to 20.8%, a good in women under age 40, has a special biological behavior and clinical pathological features, clinical manifestations of an aggressive course of disease, high incidence of local recurrence and distant metastasis, poor prognosis than other types of breast cancer, endocrine therapy and targeted therapy invalid.
2 triple-negative breast cancer biology and clinical and pathological features
Triple-negative breast cancer biological characteristics of ductal carcinoma, histological grade and more grade Ⅲ, tumor invasion ability, the high risk of distant metastases, bone metastases compared with visceral metastasis probability is high, a higher incidence of brain metastases, 3 years for the transfer peak.
Yamamoto et al will triple negative breast divided into two types: basal cell-like and non basal-like type. By IHC analysis, CK5 / 6 and EGFR determination to distinguish basal-like type (express CK5 / 6 EGFR) and non-basal-like (did not express CK5 / 6 EGFR). In 39 cases of triple-negative operable breast cancer, 38.5% of basal cell-like type, 61.5% were non-basal-like type. Basal cell-like morphology, including the proportion of high proliferation, with central necrosis and push-type growth boundary. Triple-negative breast cancer is a basal-like subtype of breast cancer between the two is not entirely synonymous, not completely interchangeable.
Tohfe other analysis of 244 cases of breast cancer patients, 16% triple-negative breast cancer, this group of patients in the triple-negative breast cancer patients age, tumor size and number of lymph node metastasis of non-triple-negative breast cancer patients with no significant difference, but histological grade Ⅲ (72% VS28%) and nuclear grade Ⅲ grade (92% VS47%) was significantly higher than non-triple-negative breast cancer patients (P <0.01).
Haffty et al reported 482 cases of breast cancer in 117 cases of triple-negative breast cancer, 5-year survival of patients without lymph node metastasis and distant visceral metastasis rate, triple-negative breast cancer patients compared with non-negative breast cancer patients with three low (72 % and 85%, P <0.05; 94% and 99%, P = 0.05; 68% and 83%, P <0.05).
    Khan et al reported 282 cases of patients of African-American women, 30% triple-negative breast cancer patients, the median age was 57 years, histological Ⅲ / Ⅳ triple-negative breast cancer patients compared with non-high (32% VS20%, P <0.01); median follow-up of 5.5 years, Ⅰ stage breast cancer patients with triple-negative rate of local recurrence compared with non-triple-negative breast cancer patients with relatively high (25% VS10%, P <0.05); Ⅱ stage triple-negative breast cancer patients non-triple-negative breast cancer patients with local recurrence rates were 31% and 13% (P <0.05); Ⅲ period no significant difference; Ⅰ stage breast cancer and non-triple-negative breast cancer morbidity, the DFS was 4.7 years and 8.7 years; Ⅱ period, Ⅲ patients with no difference; Ⅱ stage triple-negative breast cancer and non-triple-negative breast cancer OS were 2.8 and 7 years (P = 0.01); so that the African-American women Ⅰ / Ⅱ stage breast yin cancer patients with a high recurrence rate and low survival characteristics.
Choi et al analyzed 348 cases of breast cancer, triple-negative breast cancer is 19.3%, 12.9% of HR-/HER-2 (+)-type, other ER (+), 5-year survival rates were 88.7%, 83.2%, 94 % (P <0.05), 5-year DFS of (79.7%, 75.1%, 87.4%, P <0.05), multivariate analysis results show that triple-negative breast cancer patients with poor prognosis.
    Dent and other relatively non-triple-negative breast cancer and triple-negative breast cancer patients with clinical symptoms, natural history and prognosis of the disease. 1601 cases, 108 cases of patients with triple-negative breast cancer, accounting for 11.2%, 49% after chemotherapy, non-triple-negative breast cancer patients with 1421 cases, accounting for 88.9%, 26% after chemotherapy. The median follow-up of 8.1 years. Triple-negative breast cancer patients and non-triple-negative breast cancer patients, the median age, histological grade Ⅲ, T <2.0cm, lymph node involvement, respectively, for the (53 years and 57.7 years, P <0.01; 66% and 28%, P <0.01; 36.5% and 62.7%, P <0.01; 54.6% and 45.6%, P <0.05). Triple-negative breast cancer tumor size, lymph node involvement and the relationship between the small (T <1.0cm: 56% LN + VS T ≥ 2.5cm: 50% LN +), non-triple-negative breast cancer patients with lymph node involvement and tumor size (T < 1.0cm: 19% LN + VS T ≥ 2.5cm: 60% LN +). Local recurrence rates were similar in both groups, but the triple-negative breast cancer, distant metastasis rate of 2.6 times the non-triple-negative breast cancer (95% CI, 2.0 ~ 3.5; P <0.01), time to recurrence was 2.6 years and 5 years (P <0.01), triple-negative breast cancer recurrence within three years of the peak, then decline rapidly, distant metastasis rate of 34%; non-triple-negative breast cancer, distant metastasis rate was 24%. Triple-negative breast cancer, non-triple-negative breast cancer death risk 3.2 times, (95% CI, 2.3 ~ 4.5; P <0.01), mortality rates were 42% and 28% (P <0.01), the median relapse to death time was 9 months and 20 months (P <0.05).
    Palmieri et al reported the factors that predict brain metastasis: lymph node-positive, histological grade Ⅲ, ER (-), EGFR (+), HER-2 (+) CK5 / 6 (+), BRCAL (+), young and lung metastasis .
    Hines, etc. compared 118 cases of brain metastases in patients with triple-negative breast cancer patients with non-triple-negative breast cancer prognosis, time to distant metastasis, metastasis to brain metastasis occurs time to time of death and brain metastases diagnosis to the time of death were 15 months (0 to 54) and 24 months (0 ~ 263) (HR1.81, 95% CI, 1.08 ~ 3.02, P <0.05), 3 months (0 to 70) and 11 months (0 - 175) (HR1.70, 95% CI, 1.02 ~ 2.83, P <0.05), 7 months (0-70) and 7 months (0 ~ 111) (HR1.78, 95% CI, 0.98 ~ 3.24, P> 0.05) 26 months (3 to 109) and 49 months (4 ~ 302) (HR2.44, 95% CI, 1.34 ~ 4.45, P <0.01).
3 triple-negative breast cancer treatment progress
Triple-negative breast cancer patients because of endocrine therapy or targeted therapy (trastuzumab) therapy, there is no treatment guidelines for triple-negative breast cancer, so the normal routine standard of care treatment for.
    3.1 neoadjuvant chemotherapy
Carey and other use of AC in the treatment of 107 patients with locally advanced patients with neoadjuvant chemotherapy, and found that HER-2 + / ER-breast cancer patients with clinical efficiency of 70%, higher basal-like breast cancer, up to 85%, while the Luminal Breast cancer is only 47% (P <0.01); pCR rate of the three were 36%, 27%, 7% (P = 0.01). However, the higher initial sensitivity to chemotherapy did not translate into a higher survival, the first two of distant metastasis-free survival and overall survival than those in which low (P = 0.04 and 0.02); poor survival and residual lesions of the high recurrence rate was significantly associated (P <0.05). Studies suggest that basal-like and HER-2 + / ER-breast cancer, anthracycline-containing neoadjuvant chemotherapy for breast cancer have higher efficiency than the Luminal. Rouzier and other studies have shown that basal-like breast cancers and HER-2 high-expressing breast cancer patients compared with patients with luminal-type breast cancer and nornal-like type of paclitaxel and anthracycline-containing neoadjuvant chemotherapy better. Corelia Liedtke and other experiments on the triple-negative breast cancer patients, the triple-negative patients compared with non-triple-negative breast cancer patients have a higher pathologic complete remission rate (22% vs11%; P <0.05) of triple-negative breast cancer pathologic complete response patients can receive non-triple-negative breast cancer patients with similar survival rates. Neoadjuvant chemotherapy in cancer patients still remains in patients with triple-negative breast cancer patients compared with non-triple-negative breast cancer prognosis is significantly worse survival (P <0.01), especially in the first three years of treatment performance was particularly notable. Chang, etc. study of 60 cases Ⅱ, Ⅲ breast cancer after four cycles of neoadjuvant paclitaxel and carboplatin chemotherapy, of which 58 patients underwent surgery, 14 cases of pCR cases, 10 cases triple-negative breast cancer, compared with HR + / HER2-type or HER2 +, triple-negative breast cancer patients with a higher pCR rate.
    3.2 Adjuvant chemotherapy
2007 ASCO meeting reported a high risk for breast cancer may be surgery postoperative adjuvant chemotherapy Ⅲ clinical results. After the experiment divided into two groups, one group AC (60/600mg/m2), 21d for a period, a total of four cycles of sequential treatment given after paclitaxel 175mg/m2, 21d for a period of 4 weeks, another group AP50/200mg/m2, every 3 weeks for 4 cycles) therapy given after sequential paclitaxel (80mg/m2), repeated weekly for 12 weeks, after chemotherapy, endocrine receptor-positive patients receiving treatment. 5-year follow-up found, AC-Taxol 3 weeks group, although the AP-paclitaxel (weekly) 3-year disease-free survival advantage at 5 years is gone (80% vs81%), but the 3-year overall survival advantage when 5 years still exists (87% vs90%, P <0.05). Further analysis, the triple-negative breast cancer patients with more obvious advantages (79% vs87%, P <0.05), these results show for the triple-negative breast cancer patients with paclitaxel have a certain effect, but also a sequential method of treatment delivery to obtain good therapeutic reasons. Burnell, and so analysis of NCIC CTG MA.21 test reports into the group of 2104 cases were 16,123 cases of determination of ER, PR HER2, including triple-negative breast cancer patients was 551 cases, 30.4 months follow-up of patients after 261 cases of recurrence, the COX model analysis, the 3-year RFS was 80.5% triple-negative breast cancer patients, all have measured ER, PR, HER2 patients 86.5% (P <0.01), were not measured for the 87.7% (P <0.01). Multivariate analysis showed that triple-negative breast cancer was significantly lower RFS. Recurrence could not be due to too little analysis of various options on the impact of triple-negative breast cancer.
    3.3 Radiotherapy
BRCA1 germline mutations in breast cancer patients, 90% triple-negative breast cancer. Haffy other on the 442 cases in 100 cases of breast cancer, triple negative breast cancer patients were analyzed to observe the local recurrence and distant metastasis difference. All patients underwent excision of breast-conserving surgery and treatment. As of mid-September 2005, median follow-up 7 years, 442 patients, 50 cases of breast recurrence, 10 cases of lymph node recurrence, 68 cases of distant recurrence, 62 patients died. Compared with other types of breast cancer, triple-negative breast cancer patients with poor overall survival (67% VS75%), distant metastasis-free survival is poor (61% VS75%, P <0.05), specific survival rate is poor (67% VS78%, P <0.05), without lymph node metastasis-free survival is poor (93% VS99%, P <0.05). However, local control rate, triple-negative breast cancer and other types of no difference (83% VS 83%). So that the triple-negative breast cancer patients with tumor resection in breast-conserving surgery and radiotherapy the local recurrence rate and no special increase, triple-negative breast cancer patients demonstrated the sensitivity to radiation, that radiation therapy for local control has some effect .
    3.4 Targeted therapy
    Three lack of ER-negative breast cancer and HER-2 signaling pathway abnormal proliferation of cells driven role in promoting proliferation of these tumor cell proliferation of the specific mechanism is not entirely clear. EGFR overexpression is a feature of triple-negative breast cancer, up to 54%. Animal models of human breast cancer found that cetuximab and paclitaxel have synergistic effect, Gholam so will their combination for triple-negative breast cancer receiving multi-process treatment of skin metastases achieved remarkable results. As the platinum drugs in the special role of triple-negative breast cancer, EGFR antibodies currently used cetuximab monotherapy with carboplatin or cisplatin treatment of advanced triple-negative breast cancer clinical trials are ongoing, and evaluation Eluo Imatinib combined with chemotherapy in the neoadjuvant treatment of breast cancer treatment clinical trials will soon begin.
Dasatinib is an oral small molecule multi-target kinase inhibitor, while the role of the src and abl protein, has been approved by the FDA for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Part of the pre-clinical experiments showed that the dasatinib sensitivity of triple-negative breast cancer cells. In order to prove its efficacy, has launched its for advanced triple-negative breast cancer clinical trials.
PARP1 is a DNA damage and repair mechanisms - a recovery path in the base quiche a key component. Lack this pathway, DNA single-strand breaks can lead to double-strand breaks, this damage cells in the absence of BRCA1 is not repaired. In vitro experiments have shown that inhibition of PARP1 deletion or mutation of BRCA1 can induce selective apoptosis of cells. PARP1 inhibitors are in early clinical development stage, the three-negative breast cancer may be a promising therapeutic approach.
4 prognosis and outlook
    Triple-negative breast cancer is a high risk of breast cancer, the overall prognosis is poor, and other types of breast cancer prognostic factors are different. Triple-negative breast cancer has a special biological characteristics, pathological characteristics and clinical course. The basal cell markers (CK5 / 6 and 17, etc.), EGFR expression was positive and so, with a high proportion of proliferation, differentiation and poor characteristics, and basal-like breast cancer and BRCA1-related breast cancer have many similar characteristics. BRCA1 gene and because of this unusual tumor, EGFR overexpression, and other signal transduction pathway abnormalities, has launched a study related to the treatment of these targets, we look forward to these studies give the triple-negative breast cancer greater hope to improve the prognosis of triple-negative breast cancer.

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