Triple-negative breast cancer (TNBC) refers to breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2), which tend to be poorly differentiated and mostly belong to the basal cell-like subtype (75-80%). TNBC is often associated with high expression of HER-1, c-Kit, P-cadherin and p53, and has many similarities with BRCA1-associated breast cancers. 80%-90% of BRCA1-associated breast cancers are triple-negative breast cancers, according to some studies. There is no significant correlation between prognosis and lymph node status and staging, with a peak of recurrence at 1-3 years, a peak of death at 5 years, and a high incidence of brain metastasis, and there is still a lack of treatment guidelines for this particular type of breast cancer.
TNBC, like HER-2 positive breast cancer, is more sensitive to paclitaxel and anthracycline chemotherapy than luminal subgroup and normal-like breast cancer. pCR is more likely to be achieved in patients with TNBC and patients who achieve pCR have a better prognosis, but the risk of recurrence and death in the first 3 years after surgery is higher for patients who do not achieve pCR, making the overall prognosis of TNBC still the worst. TNBC is often associated with inactivation of the BRCA1 pathway, which impairs DNA homologous recombination repair, and therefore TNBC may be more sensitive to drugs that can cause DNA interstrand cross-linking, such as platinum. Poly(adenosine diphosphate ribose polymerase-1) (PARP1) is a key enzyme for repairing DNA single-strand breaks, and BRCA1 gene-deficient TNBC cells are sensitive to PARP1 inhibitors. 2009 ASCO annual meeting reported a phase II study using gemcitabine/carboplatin (G/C) in combination with PARP-1 blocker BSI-201 for the treatment of TNBC, and the results showed that G/C C + BSI-201 group had a significantly higher objective remission rate than the G/C group and significantly longer median PFS (6.9 months versus 3.3 months) and median overall survival (9.2 months versus 5.7 months), and the combination of BSI-201 with G/C was safe and well tolerated by patients.
A study of neoadjuvant chemotherapy with ixabepilone for breast cancer showed a pCR rate of 26% in TNBC, higher than in other types of breast cancer. Other studies have shown improved progression-free survival with capecitabine for metastatic TNBC plus ixabepilone. Since the genetic instability of TNBC can cause many potential mechanisms of drug resistance, the use of multidrug combinations and sequential chemotherapy may be more effective in these patients, and Abraxane (a combination of paclitaxel and nanoalbumin particles) is more effective and has fewer side effects than conventional paclitaxel. In addition, TNBC expresses EGFR or stem cell factor receptor (C-Kit), etc., which are membrane tyrosine kinase receptors. some of the targeted drugs being tried are epirubicin, bevacizumab, eflornithine, troche,,, griseofulvin, dasatinib, lapatinib, etc., but most trials are still ongoing. 2009 ASCO meeting Nechushtan reported that epirubicin The preliminary results of the trial showed that the weekly regimen of paclitaxel and cetuximab was highly effective and well tolerated. dasatinib, an oral multikinase inhibitor, has been shown to be more sensitive to Basal-like breast cancer and to TNBC.
In conclusion, triple-negative breast cancer has unique clinicopathological and molecular features and a generally poor prognosis. Due to the lack of targeted treatment guidelines, an increasing number of clinical trials and targeted therapeutic agents are being investigated for this specific type of breast cancer, and we expect that the results of these clinical studies will improve the outcome and prognosis of triple-negative breast cancer.
Molecular pathological features and therapeutic response of triple negative breast cancer
Abstract
Triple negative breast cancer is a breast cancer that is negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. This type of breast cancer has special molecular expression characteristics, invasive behavior and metastatic pattern, and its poor prognosis, high rate of local recurrence and distant metastasis are among the hot topics of research in recent years. There is still a lack of treatment guidelines for this particular type of breast cancer, and some clinical trials are underway. In this paper, we summarize and analyze the molecular pathological characteristics, current treatment status and potential drug targets of triple-negative breast cancer.
Breast cancer is a highly heterogeneous group of malignant tumors with great variation in histomorphology, immunophenotype, biological behavior and therapeutic response. In recent years, with the development of molecular pathology and the application of gene microarray technology, researchers have found that certain gene expression profiles are closely associated with specific clinical features of breast cancer, thus providing a scientific basis for molecular pathological staging and individualized treatment of breast cancer. Triple negative breast cancer (triplenegativebreastcarcinoma (TNBC)) is defined as estrogen receptor (ER), progesteronereceptor (PR) and human epidermal growth factor receptor 2 ( humanepidermalgrowthfactorreceptor2(HER-2) negative breast cancers, which have similar characteristics, very high homozygosity, tend to be poorly differentiated, are mostly basal-like breast cancers, and are associated with breast cancer susceptibility gene 1 ( breastcancersusceptibilitygene1,BRCA1)-associated breast cancers have many similarities [1,2]. This type of breast cancer has a poor prognosis, a high rate of local recurrence and distant metastasis, and there is still a lack of treatment guidelines for this particular type of breast cancer, with some clinical trials underway. In this paper, we summarize and analyze the molecular pathological characteristics and current status of treatment, potential drug targets and future treatment trends of triple negative breast cancer.
I. Molecular pathological features
The gene expression characteristics of breast cancer can be classified into five subtypes by cDNA microarray technology, namely, ductal type A (1uminalsubtypeA), ductal type B/C (1uminalsubtypeB/C), normalbreast-likesubtype, HER2over-expressionsubtype ( HER2over-expressionsubtype), and basal cell-like type (basa1-1ikesubtype) [3]. Among them, the basal-like type originates from ductal basal cells and is highly expressed in basal epithelial cell molecular markers, and is deficient in ER, PR and HER-2 expression. The majority of triple-negative breast cancers have the same gene expression profile as basal-like breast cancers, but according to gene profile expression analysis, the majority of TNBC are basal cell-like subtypes (75-80%), and other subtypes (lumiA, lumiB, Her-2 overexpression and normal mammary gland-like) are also included, and studies have shown that patients with TNBC expressing basal cytokeratin have significantly lower disease-free survival than Those who do not express basal cytokeratin have significantly lower disease-free survival than those who do not express basal cytokeratin, thus indicating that TNBC is a heterogeneous group. In many ways, there are still some differences in gene expression profiles and immunophenotypes between TNBC and basal-like breast cancer, and therefore the two cannot be fully equated yet.
Gene expression profiling of breast cancers using gene microarray technology is the most effective tool for identifying breast cancer subtypes, but because of the high cost of gene microarrays and the high quality of the specimens required, it is not possible to routinely apply them in clinical practice work. In this context, finding immunohistochemical markers that can replace genotypic analysis is one of the best ways. Nielsen et al. investigated immunohistochemical-based methods for the clinical detection of basal-like breast cancers. They first evaluated the immunohistochemical results of 21 basal-like cases identified by gene expression profiling and then analyzed the prognosis of 930 patients with long-term follow-up results using a tissue microarray approach, and found that combining ER and HER-2 negativity with CK5/6 and EGFR positivity was the best marker to identify basal-like gene expression [5]. Triple-negative breast cancers not only exhibit negative ER, PR and HER-2, but also are often associated with high expression of HER-1, c-Kit, P-cadherin and p53, while negative expression of androgen receptor and E-cadherin. In addition, TNBC is often accompanied by mutations in the BRCA1 gene, and the pathway mediated by BRCA1 plays an important role in the pathogenesis of TNBC [6].BRCA1 as a multifunctional protein can play a tumor suppressive role in a variety of biological pathways, and both mutations in the BRCA1 gene and gene sequence changes in BRCA1 function-related proteins can affect the tumor suppressive function of BRCA1, leading to breast cancer occurrence [7]. Some studies have shown that 80%-90% of BRCA1-associated breast cancers are triple-negative breast cancers, and BRCA1 has become one of the targets for therapeutic research.
II. Current status and trends in treatment
Although this type of breast cancer has a high overall response rate and pathological remission rate to chemotherapy, the overall clinical prognosis of patients is still the poorest. Therefore, in recent years, many exploratory studies have been conducted on this subgroup in clinical treatment.
1.Chemotherapeutic drugs
(1) Anthracyclines
Liedtke et al. reported the follow-up results of 255 triple-negative breast cancer patients who received neoadjuvant chemotherapy with anthracycline-containing drugs at M. D. Anderson Cancer Center in the U.S. The results showed that compared with non-TNBC patients, TNBC patients were more likely to obtain pCR, and patients who obtained pCR had a better prognosis. However, for TNBC patients with residual lesions, there is a higher risk of recurrence and death in the first 3 years after surgery [8]. Another study from Carey reported that 107 breast cancers given AC (adriamycin + cyclophosphamide) as neoadjuvant chemotherapy resulted in clinical remission rates of 70% and 85% for the HER-2+/ER- and TNBC subgroups, respectively, which were significantly higher than the 47% for the 1uminal subgroup, and pathological complete remission rates of 36% and 27%, respectively, and only 7% for the ER+ subgroup. However, their distant metastasis-free survival and overall survival were significantly shorter than that of the luminal subgroup [9]. A retrospective study showed that patients with BRCA1 and BRCA2-associated breast cancer are extremely sensitive to neoadjuvant chemotherapy with the regimen of adriamycin + cyclophosphamide.
(2) Paclitaxel
Clinical studies have shown that TNBC, like HER-2+ breast cancer, is more sensitive to paclitaxel and anthracycline chemotherapy than normal-like breast cancer in preoperative chemotherapy, and Rouzier found that after preoperative chemotherapy with paclitaxel sequential FAC in 82 breast cancers, the pathological remission rate was 45% for both, while luminalA/B and normal-like were only 7% and 0%, respectively [10]. A phase III clinical trial of postoperative adjuvant chemotherapy for operable high-risk breast cancer showed the efficacy of paclitaxel in triple-negative breast cancer, but the sequential dosing regimen may be one of the reasons for its better efficacy. The results of the phase III clinical study showed that a new paclitaxel formulation, Abraxane (a combination of paclitaxel and nanoalbumin particles), has higher efficacy and fewer side effects than conventional paclitaxel, and its mechanism of action modulates the transcytosis of vascular endothelial cells in part by specifically binding to gp60 and caveolin-1, which is often highly expressed in triple-negative breast cancer. Therefore Abraxane may be more effective against this subgroup [11].
(3) Platinum
In vitro studies have shown that BRCA1-associated breast cancers are extremely sensitive to drugs that cause interstrand cross-linking such as alkylating agents, mitomycin C, and platinum, and to drugs that cause DNA double-strand breaks such as etoposide and bleomycin, but resistant to antimitotic spindle drugs such as paclitaxel and vincristine.Isakoff reported that ΔNp63α and TAp73 are highly Leong’s study confirmed that TNBC breast cancer cells expressing both ΔNp63α and TAp73 are highly sensitive to the chemotherapeutic agent cisplatin, that TAp73 induces the pro-apoptotic protein Bcl-2 family molecules and promotes apoptosis, and that ΔNp63α and TAp73 can DDP can dissociate the △Np63α-TAp73 protein complex, so that TAp73 can continue to function as an apoptotic gene and promote apoptosis in tumor cells [13]. 14.3% were SD and only 28.6% were PD [14].
(4) Others
Rugo et al. randomized 1973 patients with metastatic breast cancer who were pre-treated with AT regimen into capecitabine plus ixabepilone group and capecitabine only group. In both groups of TNBC patients, improved progression-free survival was found in the plus isapirone treatment group, which showed a trend toward improved overall survival but did not produce a statistically significant improvement in overall survival [15].
Because the genetic instability of this type of breast cancer can result in many potential mechanisms of drug resistance, the use of multidrug combinations and sequential chemotherapy may be more effective in this group of patients, and the better regimens are currently considered to be AC sequential paclitaxel, CEF sequential doxorubicin, adriamycin sequential doxorubicin and CMF, and paclitaxel plus carboplatin.
The WSGAM01 randomized trial study compared breast cancer patients with >9 positive lymph nodes treated with a two-cycle intensive EC regimen sequenced with a two-cycle high-dose chemotherapy regimen (epi-adriamycin 90 mg/m2 + cyclophosphamide 3 g/m2 + cetepe 400 mg/m2) with a four-cycle dose-intensive EC regimen sequenced with a three-cycle CMF regimen, and showed that young triple-negative breast cancer Nunes et al. reported 24 patients with triple-negative breast cancer receiving neoadjuvant chemotherapy with AC-T regimen with a median age of 53 years and a median follow-up of 15 months, which showed 20% pCR, 33% cCR, and 50% PR, thus concluding that AC-T regimen is an effective treatment for triple-negative breast cancer neoadjuvant chemotherapy [16]. Hatzis et al. distinguished 229 stage I-III breast cancers according to molecular phenotype into ER-/HER-2- (n=97) and ER+/HER-2- (n=132) types, all of which received neoadjuvant chemotherapy with T/FAC regimen with pCR or minimal residual In ER-/HER-2-type 47% and ER+/HER-2-type 17% [17]. Chang et al. reported 60 cases of stage II and III breast cancer treated with surgery after 4 cycles of neoadjuvant chemotherapy with doxorubicin and carboplatin in 58 cases and 14 pCR Ten of the cases were triple-negative breast cancer, and patients with triple-negative breast cancer had a higher pCR rate compared to HR+/HER2C or HER2+ patients [18].Chia et al. studied 14 patients with recurrent metastatic triple-negative breast cancer, four of whom received prior adjuvant chemotherapy with paclitaxel-containing regimens and six with prior adjuvant chemotherapy with anthracycline-containing regimens. These patients were treated with TC regimens (paclitaxel 80 mg/m2 and carboplatin AUC2D1, D8, D15 weekly regimen or paclitaxel 175 mg/m2 and carboplatin AUC5D1 three-week regimen). The results suggest that the TC regimen has a high efficiency (57%) in patients with recurrent metastatic triple-negative breast cancer and still presents better results in patients with previous paclitaxel [19].
2. Targeted drug therapy
Although neither ER/PR nor HER-2 are expressed in TNBC breast cancers, they express EGFR (HER-1) or stem cell factor receptor (C-Kit), etc., both membrane tyrosine kinase (tyrosinekinase) receptors that mediate MAP kinase and AKT signaling pathways, respectively. Some of the targeted drugs currently being tried are cetuximab (Erbitux, Erbitux), bevacizumab (bevacizumab), Avastingefitinib (Iressa, Eressa), erlotinib (Tarceva, Troche), imatinib (Gleevec, Gleevec), and dasatinib (BMS-354825), and lapatinib (lapatinib, Tyk-erb), with most trials still ongoing.
Corkery has reported the results of an in vitro study of three ER/PR/HER-2 triple-negative breast cancer cell lines and found that the IC50 of gefitinib was lower than that of erlotinib, while cetuximab had essentially no effect [20]. carey et al. suggested that since the proliferation of triple-negative breast cancer is dependent on EGFR/HER1, cetuximab in combination with carboplatin may be more effective in triple-negative breast cancer. A total of 102 metastatic triple-negative breast cancers were enrolled in the TBCRC001 trial, of which 83% were previously treated with anthracyclines and 64% with paclitaxel, and were treated in 2 groups: group C (31 cases) with cetuximab alone and group C+P (71 cases) with cetuximab combined with carboplatin. The results showed that group C:PR 6%, SD 4% and group C+P:PR 18%, SD 9% [21]. At the 2009 ASCO meeting Nechushtan reported cetuximab in combination with paclitaxel for the treatment of patients with stage I/II TNBC, and preliminary trial results showed a high efficiency (11/12) and better tolerability of the weekly regimen of paclitaxel with cetuximab [22].
Poly(adenosine diphosphate ribose polymerase-1) (PARP1) is a key enzyme for cell proliferation and DNA repair, and BRCA1 gene-deficient triple-negative breast cancer (TNBC) cells are sensitive to PARP1 inhibitors.The 2009 ASCO Annual Meeting reported a phase II multicenter randomized open trial study using gemcitabine/carboplatin (G/C) in combination with PARP-1 blocker BSI-201 for the treatment of TNBC. center randomized open trial study in which patients were randomized to either the G/C group or the G/C+BSI-201 group, showed that the G/C+BSI-201 group had significantly higher objective remission rates (48% versus 16%) and clinical benefit rates (CR+PR+SD ≥ 6 months, 62% versus 21%), median PFS (6.9 months versus 3.3 months) and median overall survival (OS, 9.2 months versus 5.7 months) were also significantly prolonged, while it could be observed that BSI-201 was safe in combination with G/C and was well tolerated by patients [23].
Dasatinib is an oral multi-kinase inhibitor that inhibits kinases including BCR-ABL, SRC family kinases, c-KIT, and PDGFR. an in vitro study by Huang et al. found that 11 of 12 breast cancer cell lines were effective against dasatinib [24]. finn et al. reported a phase II clinical trial using dasatinib for TNBC clinical trial, in which a pre-test confirmed that Dasatinib inhibited tumor cell proliferation and metastatic activity and that gene expression profiles indicated that Basal-like breast cancers may be sensitive to Dasatinib treatment. The trial found Dasatinib to have monotherapy activity against TNBC with a clinical effectiveness of 9.3% by treating 43 patients with progressive TNBC with Dasatinib [25].
The BEATRICE trial is comparing the efficacy of standard chemotherapy regimens and standard chemotherapy + bevacizumab regimens as adjuvant therapy for early-stage triple-negative breast cancer. the N0537 trial is comparing the efficacy of gemcitabine monotherapy and gemcitabine + aflibercept (VEGFTrap) regimens for the treatment of triple-negative breast cancer that has failed anthracycline and/or paclitaxel therapy. The NCT00472693 trial is a non-randomized, open phase II clinical study of bevacizumab in combination with paclitaxel (abraxane) as second-line therapy for the treatment of receptor triple-negative metastatic breast cancer. A non-randomized, open, single-center clinical phase II study of trospium (Tarceva) plus chemotherapy as neoadjuvant chemotherapy for triple-negative primary breast cancer (NCT00491816) is also underway.
In conclusion, along with the promotion and adoption of molecular pathology and genotyping of breast cancer, increasing attention is being paid to triple-negative breast cancer, which has its own unique clinicopathological and molecular features and generally poor prognosis for patients. Due to the lack of targeted treatment guidelines, more and more clinical trials and targeted therapeutic agents for this particular type of breast cancer are being investigated, and we expect the results of these clinical studies to improve the outcome and prognosis of triple-negative breast cancer.