Triple-negative breast cancer refers to breast cancer with negative estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her-2). This type of breast cancer accounts for 10.0%-20.8% of all pathological types of breast cancer and has special biological behavior and clinicopathological features, with poorer prognosis than other types.
Epidemiology
Triple negative breast cancer is a subtype of breast cancer based on cell morphology and cell surface receptors, which has been clinically developed using gene microarray technology. Carey et al. showed that the incidence of triple-negative breast cancer in African-American women under 50 years of age is even 39%, compared to 16% in white women and 14% in postmenopausal African-American women.
Clinical and molecular pathological features
Triple-negative breast cancer presents clinically as an aggressive disease process. Several clinical studies have shown that this type of breast cancer has a higher risk of distant metastases, with a higher incidence of visceral metastases than bone metastases and a higher incidence of brain metastases. Although Dent et al. showed that the risk of distant metastases in triple-negative breast cancer peaks at 3 years and may decrease thereafter, the prognosis is still poor and the risk of death is high.
Kandel et al. showed that the median tumor size of triple-negative breast cancer was 2 cm, and 50% had lymph node metastases. Analysis of the pathological features revealed that the histological grade of these breast cancers was mostly grade 3, with a high proportion of proliferation, positive expression of c-kit, p53, epidermal growth factor receptor (EGFR), and positive basal cell markers cytokeratin (CK) 5/6 and 17.
Some clinical features of triple-negative breast cancer are directly or indirectly derived from basal-like breast cancer. However, triple-negative breast cancer is a subtype of basal-like breast cancer, and the two are not completely synonymous or interchangeable.
BRCA1-associated breast cancer also has some of the phenotypic and molecular pathological features described above, and most scholars believe that there may be a correlation between it and triple-negative breast cancer. The BRCA1 gene has become one of the targets of research, and studies have been initiated to address this target.
Treatment
There are no specific treatment guidelines for triple-negative breast cancer, so the treatment is generally standard for breast cancer. A number of targeted prospective clinical trials based on molecular pathological abnormalities are currently underway, so most of the information is from retrospective studies or trial subgroup analyses.
1. Chemotherapy
Chemotherapy is more effective in triple negative breast cancer than in other types of breast cancer, but its prognosis remains poor if only conventional standard treatment is given.
Adjuvant chemotherapy
The PACS 01 trial is a phase III randomized clinical trial comparing the efficacy of a six-cycle FEC [fluorouracil + epirubicin + cyclophosphamide] regimen with a three-cycle FEC regimen followed by three cycles of docetaxel in patients with lymph node positive breast cancer. At the 2006 American Society of Clinical Oncology (ASCO) annual meeting, investigators reported better metastasis-free survival (P=0.05) and overall survival (OS) rates (P=0.005) in patients with basal-like breast cancer in the sequential treatment arm of the trial. Thus, although basal-like breast cancer has a poor prognosis, it responds better to sequential docetaxel chemotherapy with FEC.
At the 2007 ASCO Annual Meeting, investigators reported the results of a phase III clinical trial of postoperative adjuvant chemotherapy for operable high-risk breast cancer. Patients were divided into two groups, one with an AC regimen (doxorubicin + cyclophosphamide) followed by paclitaxel (175 mg/m2, repeated every 3 weeks for 4 cycles) and the other with an AP regimen (doxorubicin + paclitaxel) followed by paclitaxel (80 mg/m2, repeated once a week for 12 cycles). At 5 years of follow-up, it was found that while the disease-free survival (DFS) advantage in the AP sequential paclitaxel group at 3 years had disappeared at 5 years compared with the AC sequential paclitaxel group (80% versus 81%, P=0.38), the OS advantage at 3 years persisted at 5 years (90% versus 87%, P=0.04). Further analysis showed that this advantage was even more pronounced for triple-negative breast cancer (87% versus 79%, P=0.037).
These results suggest that paclitaxel has some efficacy in triple-negative breast cancer, but sequential dosing may also be a reason for its better efficacy. Since the results were obtained from subgroup or retrospective analyses of the trials, they cannot be directly applied to clinical practice and need to be confirmed by prospective studies.
Neoadjuvant chemotherapy
Carey et al. used the AC regimen to treat 107 patients with locally advanced breast cancer with neoadjuvant chemotherapy and found that the clinical efficacy rate was 70% for Her-2-positive/ER-negative breast cancer, 85% for basal-like breast cancer, and only 47% for luminal breast cancer (ER-positive) (P<0.0001), and the pathological complete remission (pCR ) rates were 36%, 27%, and 7%, respectively (P=0.01), but the rates of metastasis-free survival (P=0.04) and OS (P=0.02) were lower in the former two than in the latter, and poorer survival was significantly associated with higher recurrence in those with residual lesions (P=0.003).
It is suggested that poorer OS may be related to the presence of local residual lesions, i.e., failure to achieve pCR, and therefore neoadjuvant chemotherapy should still be aimed at achieving pCR to ultimately improve survival.
Platinum-based drugs Since the BRCA1 gene is associated with DNA double-strand break repair, and platinum-based drugs can cross-link with the DNA double-strand, leading to DNA double-strand breaks, preventing DNA replication, transcription and ultimately cell death, platinum-based drugs may be more effective in triple-negative breast cancer.
A non-randomized phase II clinical trial by Garber et al. enrolled 28 patients with triple-negative breast cancer in neoadjuvant chemotherapy with cisplatin alone. The results showed that the overall effective rate was 50%, complete remission rate was 14%, partial remission rate was 36%, stable disease rate was 18%, 11% disease progression, and pCR rate was 21%, among which two patients with BRCA1 mutation achieved pCR, and age was significantly associated with pCR (P<0.04).
The study concluded that neoadjuvant chemotherapy with cisplatin has comparable efficacy in triple-negative breast cancer, and its pCR rate is similar to that of other trials of combination chemotherapy, thus warranting further study.
High-dose chemotherapy
The use of high-dose chemotherapy (HDC) in the treatment of breast cancer has been inconclusive, but many investigators are still studying HDC in specific subtypes of breast cancer. Several retrospective studies have shown that cyclophosphamide and cetapide based HDC has shown some effectiveness in the treatment of triple negative breast cancer.
Rodenhuis et al. retrospectively analyzed a study comparing the efficacy of a 5-cycle FEC regimen with a 4-cycle FEC regimen sequenced with 1 cycle of HDC (cyclophosphamide 6 g/m2, cetapide 480 mg/m2, carboplatin 1600 mg/m2) in the treatment of Her-2 negative breast cancer and found that Her-2 negative patients benefited from HDC while positive patients did not. Further analysis of this study at the 2006 ASCO Annual Meeting found that the efficacy of HDC in triple-negative breast cancer patients was comparable to that of Her-2 negative, hormone receptor-positive patients treated with endocrine therapy but not HDC.
The WSG AM 01 trial divided breast cancer patients with more than 9 lymph nodes into two groups, one receiving 2 cycles of intensive EC (epirubicin + cyclophosphamide) regimen followed by 2 cycles of HDC (epirubicin 90 mg/m2, cyclophosphamide 3 g/m2, cetapide 400 mg/m2), and the other receiving 4 cycles of the same EC regimen followed by 3 cycles of intensive CMF ( The other group received 4 cycles of the same EC regimen followed by 3 cycles of intensive CMF (cyclophosphamide + methotrexate + fluorouracil) regimen. The results showed that the greatest benefit from HDC was in young patients with triple-negative breast cancer.
Therefore, for Her-2 negative breast cancer, HDC is still one of the directions of clinical research. According to the current study results and related data, HDC based on alkylating agents is effective in the treatment of triple negative breast cancer, and it is worth to carry out more studies.
2.Targeted therapy
EGFR overexpression is one of the characteristics of triple-negative breast cancer, and the percentage can reach 54%.
The synergistic effect of cetuximab and paclitaxel was found in human breast cancer animal models, and Gholam et al. used the combination of the two in patients with triple-negative breast cancer with cutaneous metastases who had received multiple regimens of chemotherapy, with significant efficacy and good patient tolerance. Because of the specific role of platinum in triple-negative breast cancer, clinical trials are currently underway using cetuximab alone in combination with carboplatin or cisplatin in advanced triple-negative breast cancer, and clinical trials are about to begin to evaluate the efficacy of erlotinib in combination with chemotherapy in the neoadjuvant treatment of breast cancer.
Dasatinib is an orally administered small molecule multi-targeted tyrosine kinase inhibitor. Some preclinical studies have shown that triple-negative breast cancer cells are sensitive to dasatinib, and clinical trials have been conducted to use it in advanced triple-negative breast cancer.
3. Radiotherapy
As an oncogene, BRCA1 collaborates with various genes during DNA replication to maintain genomic stability, and BRCA1 deficiency can lead to abnormalities in the DNA synthesis (S phase) detection site and late DNA synthesis (G2 phase) – division (M phase) transition.
Haffty et al. analyzed 442 patients with breast cancer and 100 of them with triple-negative breast cancer to see the difference in local area recurrence and distant metastasis. All patients underwent breast-conserving surgery and radiotherapy. As of September 2005, the median follow-up period was 7 years, with 50 breast recurrences, 10 lymph node recurrences, 68 distant recurrences, and 62 deaths among the 442 patients. Compared with other types of breast cancer, the OS rate (67% versus 75%, P=0.096), survival without distant metastasis (61% versus 75%, P=0.002), specific survival (67% versus 78%, P=0.03) and survival without lymph node metastasis (93% versus 99%, P=0.021) of triple-negative breast cancer were poor. However, there was no difference in the local control rate between triple-negative breast cancer and other types (83% for both).
Thus, the local recurrence rate of triple-negative breast cancer did not increase significantly after breast-conserving surgery and radiotherapy, demonstrating its sensitivity to radiation, suggesting that radiotherapy has a role in local control and that some new treatment strategies should be developed to reduce the chance of distant metastasis.
Prognostic indicators
In a retrospective analysis of 1944 patients with invasive breast cancer, Rakha et al. found that tumor size, lymph node and androgen receptor status were the most useful prognostic markers in 16.3% of triple-negative breast cancers. Nielsen et al. showed that overexpression of Her-1 was associated with poor survival regardless of lymph node status and tumor size, while c-kit expression was also increased, but no correlation with prognosis was found.
Conclusion
Triple-negative breast cancer has special biological characteristics, pathological features and clinical course. It has positive basal cell markers such as CK5/6 and 17, positive EGFR expression, high proliferation ratio and poor differentiation, and has more similar features to basal-like breast cancer and BRCA1-associated breast cancer. This subtype of breast cancer is still sensitive to radiotherapy, but its prognosis is poor after conventional standard treatment. Because of the abnormal BRCA1 gene, high EGFR expression and other signaling pathways in this tumor, studies have been conducted to target these targets, and we expect the results of these clinical studies to improve the prognosis of triple-negative breast cancer.