1. Origin of the concept and cognitive process
In 2000, Perou and Sorlie et al. from Stanford University analyzed the gene expression characteristics of 65 surgically resected specimens from 42 breast cancer patients by cDNA microarray technology and classified breast cancer into 5 subtypes: ductal A, ductal B, HER2 overexpression, basal-likephenotype (BP) and normal breast. The treatment and prognosis of these subtypes are distinctly different. Immunohistochemical markers are now a good clinical alternative to genotypic analysis. Currently, it is considered that ER, PR and HER2 negative (TNBC) can replace basal-like breast cancer, and the authors themselves agree to add CK5/6 and EGFR positivity to further clarify the diagnosis.
2. Clinicopathological characteristics
TNBC breast cancer accounts for 10%-17% of all breast cancers and is commonly seen in younger (<50 years) premenopausal African, African American, Hispanic and BRCA1 mutation carriers women. The rate of TNBC reported in Korea is 14.7% and in Japan is 15%. More complete data are not yet reported in China. TNBC is characterized by an aggressive clinical presentation and has a poor overall survival and disease-free survival compared to other types. Since there is no access to endocrine and targeted HER-2 therapy, chemotherapy is the only primary treatment and the prognosis is worse than other types. Several studies have shown that TNBC has a higher rate of visceral (lung, liver, brain) metastasis and a very low rate of bone metastasis than non-TNBC.
The most effective and accurate technique for the identification of TNBC is gene microarray, but due to its high requirements and high price, its routine application is not possible, so immunohistochemistry is the most commonly used tool in practice.
MRI shows that the vast majority (97%) are mass-type lesions exhibiting typical malignant enhancing kinetic features.PET-CT examination of TNBC breast cancer reveals enhanced uptake of FDG.
3. Treatment choice
A standard dose of anthracycline-based chemotherapy regimen followed by surgery does not improve the poor prognosis of patients, probably because P53 variants are common in TN breast cancer, and P53 variants abnormalities lead to anthracycline resistance.
The largest clinical study to date was done by Liedtke et al. in which neoadjuvant chemotherapy was given to 1118 early-stage breast cancers to investigate the responsiveness and OS of triple-negative breast cancers. although a high pCR rate was found in the TNBC group, the overall survival rate was lower than that of non-TNBC. interestingly, patients who achieved pCR with preoperative chemotherapy had a higher survival rate, regardless of receptor status. Compared to those with residual tumor after chemotherapy, TNBC has a lower survival rate than non-TNBC patients, and the lower survival rate is associated with chemoresistance in more than 50% of TNBC.
TNBC breast cancers are often associated with BRCA1 mutations, and a major role of BRCA1 is to participate in the repair of duplex DNA breaks, and BRCA1 deficiency leads to the absence of such repair function. the correlation between TNBC and BRCA1 mutations in DNA damage repair mechanisms shows its sensitivity to DNA-damaging platinum drugs. Preclinical experiments have confirmed that high expression of p63,p73 (p53-related transcription factor) in TNBC patients is associated with sensitivity to platinum-based chemotherapy.
(1) New drugs
ABI-007 (nano-paclitaxel) is a new paclitaxel albumin using human blood albumin as drug carrier and stabilizer, which can improve the therapeutic effect of paclitaxel and increase the drug uptake inside the tumor without increasing the drug concentration in normal tissues and increasing the anti-tumor activity. Caveolin-1, often highly expressed in TNBC, plays an important role in cytokinesis and cytokine signaling in cancer cells, and ABI-007 is designed to inhibit tumor cell proliferation through a membrane transduction mechanism.
Rugo reported that in patients with anthracycline- and paclitaxel-resistant TNBC, the new microtubule stabilizer ixabepilone combined with capecitabine significantly improved PFS (4.1 vs. 2.1 months) and ORR (27% vs. 9%) compared with capecitabine alone. In neoadjuvant chemotherapy, a group of TNBC achieved a pCR rate of 26% with isapirone.
(2) High-dose chemotherapy (HDC)
(3) Sequential chemotherapy
(4) Radiotherapy
The OS rate, survival without distant metastasis, specific survival and survival without lymph node metastasis were poor in triple-negative breast cancer, but there was no difference between triple-negative breast cancer and other types in terms of local control rate (both 83%). It indicates that radiotherapy has a role in local control and some new treatment strategies should be developed to reduce the chance of distant metastasis.
(5) Targeted therapy and related studies
Endocrine therapy and trastuzumab-targeted therapy for TNBC are ineffective, but some TNBC breast cancers highly express EGFR, c-Kit, CK5/6, P-cadherin, p53, and these patients are expected to benefit from targeted therapies for related conditions.
①Targeting EGFR
②Targeting DNA damage repair mechanism
③Tyrosine kinase inhibitors
Sunitinib inhibits more than 80 tyrosine kinases and multiple growth factor receptors, such as targeting PDGFR, VEGFR, CSF1, C2kit and Flt3 proteins. Sunitinib is effective in inhibiting the growth of tumor cells in which tyrosine kinase regulation is dysregulated. Experimental tumor models have confirmed that sunitinib has the effect of inhibiting tumor cell growth, degeneration and metastasis. Yu Zhiyong of Shandong Cancer Hospital carried out sunitinib-based combination chemotherapy so far on 6 cases of triple-negative breast cancer, one of which was a patient with liver metastasis. 1 case of hormone receptor-positive and Her-2 negative, advanced, recurrently recurrent metastasis, all of whom had failed treatment with docetaxel, anthracycline, vincristine, gemcitabine, etc., achieved 100% clinical benefit with sunitinib combination chemotherapy.
④Vascular endothelial growth inhibitors
⑤Other
Heat shock protein (Hsp90) inhibitor PU-H71, Cetuximab (Erbitux, Erbitux), gefitinib (Iressa, Eressa), erlotinib (Tarceva, Troche), imatinib (Gleevec, Gleevec) dasatinib (BMS- 354825), lapatinib (lapatinib, Tyk-erb)
4. Conclusion
Along with the promotion and adoption of molecular pathology and genotyping of breast cancer, triple-negative breast cancers are receiving increasing attention, which have their own unique clinicopathological and molecular biological features and generally poor prognosis for patients. Due to the lack of targeted treatment guidelines, clinical trials and targeted therapy drug selection for this particular type of breast cancer face new opportunities and challenges. We expect that the results of these clinical studies will improve the outcome and prognosis of triple negative breast cancer.