The lack of expression of three vital markers in triple-negative breast cancer relies mainly on chemotherapy and has a worse prognosis. To find further classification and potential targets of TNBC, more attention has been focused on TNBC. In this research, in order to guide further exploration of TNBC, we initially evaluated TNBC research tendency in the past 20 years in large amounts, covering nearly all publications from the first appearance of TNBC definition to the latest research.
1. Publication tendency and region contribution of TNBC publications
With the development of breast cancer target exploration, HR and HER2 have become essential biomarkers for the classification and treatment of breast cancer. After endocrine therapy in HR+ breast cancer and anti-HER2 treatment appeared in the late 1900s and brought significant benefits to breast cancer treatment (7, 8), scientists and clinical doctors started to notice the subtype of breast cancer with neither HR expression nor HER2 amplification. After 2007, the number of publications about TNBC started to increase (9). To date, the number of TNBC publications has reached nearly 3000 per year and is still increasing. Generally, the RRI of TNBC in all publications and breast cancer has increased continuously over the past 20 years, indicating that TNBC has become an area of focus in breast cancer research. TNBC studies covered various countries, among which the USA published the most studies with the highest H index, which indicates its significant contribution to TNBC studies. Although China is the country with the highest increasing speed and the second highest publication number of TNBC publications, the citation and H-index are relatively lower than those of the top 10 countries. Thus, China should improve the quality of publications to make research more efficient. The increasing speed of research in China is possibly due to the increasing incidence of breast cancer, at a rate higher than the global rate (10), and the greater support from the Chinese government for breast cancer research (11). Nevertheless, Chinese research still needs to develop quality, including more population in the regular national cancer registries, and promote long-term follow-up of breast cancer cohorts.
2. Focus of TNBC publications in different periods reflects the development of TNBC management
According to the publication focus of TNBC in the past 20 years, TNBC research can be divided into three phases. Before 2015, TNBC studies mainly focused on regulating treatments, including effective chemotherapy. As the main effective treatment for TNBC at that time, various publications focused on a suitable combination of different chemotherapy regimens for adjuvant chemotherapy, neoadjuvant chemotherapy, or chemotherapy for metastatic TNBC. Platinum, taxane, carboplatin, anthracycline, cyclophosphamide, and fluorouracil are the key cytotoxic regimens mentioned in various publications. To date, these chemotherapies play an essential role in TNBC treatment. However, these chemotherapy strategies are usually administered to other subtypes of breast cancer. Thus, TNBC specific treatment strategies are still lacking. It was not until recently that randomized controlled trials (RCTs) on TNBC-specific chemotherapy have been reported. At that time, the chemotherapy response of different regimens in TNBC has been mentioned in publications as well. The GEICAM/2003-11_CIBOMA/2004-01 trial published in January 2020 revealed that adding capecitabine in (neo)adjuvant chemotherapy significantly increased DFS in patients with early TNBC(12). The PATTERN trial(13) published in September 2020 mentioned paclitaxel-plus-carboplatin as an efficient choice for adjuvant chemotherapy compared with CEF-T (cyclophosphamide, epirubicin, and fluorouracil followed by docetaxel). Furthermore, platinum-based neoadjuvant chemotherapy showed a significant response in TNBC (14, 15) which is one of the most cited publications (Table 1). The phase II GeparSixto trial (16) reported in 2014 showed a significantly higher response rate after adding carboplatin in taxane, anthracycline, and bevacizumab combination in TNBC patients. Phase III clinical trials, CBCSG010, published in June 2020 indicated that capecitabine, epirubicin, and cyclophosphamide can improve prognosis without additional side effects compared with three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide in adjuvant chemotherapy for TNBC (17). Nevertheless, it should be noted that RCTs, especially phase III clinical trials, take a long time, from designing to reporting results. There may be a delay in the publication of clinical trials and focus on the day.
To 2016–2017, publications about TNBC focused more on genomic and drug resistance mechanisms for existing treatments. During this period, BRCA mutation and identification of PARP inhibitors in TNBC led to a peak in studying target in terms of DNA damage and DNA repair and many other topics at the cell level, such as apoptosis and pathways. In 2009, The New England Journal of Medicine published a phase I study indicating that monotherapy with the PARP inhibitor olaparib has antitumor function and fewer side effects compared with standard therapy in human cancer, including breast cancer with germline BRCA mutation (18). Later, in 2011, a phase II study published in the Lancet Oncology (19) confirmed the safety and tolerability of olaparib in advanced TNBC patients without BRCA1/2 mutations. Although this study did not observe efficacy in these patients without BRCA1/2 mutations, it was still one of the most cited publications (Table 1) that led to further phase III clinical trials. In the same year, another PARP inhibitor, iniparib, also underwent phase II clinical trials (20) with high citation counts (Table 1), showing that iniparib combined with chemotherapy can improve the prognosis of metastatic TNBC patients. However, the phase III study of iniparib (21) published in 2014, did not meet the prespecified criteria of primary endpoints. It was not until 2017 that the phase III OlympiAD study (22) on olaparib laid the foundation for PARP inhibitor therapy in advanced HER2- breast cancer with germline BRCA mutation. Despite clinical trials on PARP inhibitors in TNBC, many RCTs on chemotherapy have also analyzed different responses to treatment in different gene mutation groups, which is another reflection of the importance of genomic evaluation in TNBC. For example, the INFORM trial published by the Journal of Clinical Oncology in May 2020 found a similar response to single-agent cisplatin and doxorubicin combined with cyclophosphamide (AC) in neoadjuvant chemotherapy of TNBC with BRCA mutation (23). Moreover, many studies have explored the regulation of the BRCA/HDR pathway in order to identify potential targets for TNBC (24) (Table 1).
After 2018, the immune response in TNBC gradually attracted more attention, showing topics such as tumor infiltrating lymphocytes (TILs), programmed cell death ligand 1 (PDL1), immune checkpoint, and macrophages. Moreover, the appearance of nanoparticles in TNBC also indicates that new materials combined with existing regimens, such as nab-paclitaxel, may provide new opportunities for improving TNBC treatment (25, 26). In this period, TNBC treatment targeting the immune checkpoint was the most focused topic. In 2014, a highly cited publication focused on PDL1 in TNBC (27). Subsequently, many clinical trials and related researches on anti PD1/PDL1 therapy in TNBC have been conducted. In most cited publications, two clinical trials on anti PD1/PDL1 therapy in TNBC published in 2018 reached the top 10 cited. One of two publications is KEYNOTE-012 (28), a phase Ib clinical trial of pembrolizumab, a PD1 inhibitor in TNBC. KEYNOTE-012 shows that pembrolizumab has sufficient tolerance for advanced TNBC. Another phase III clinical trial revealed the efficacy of the anti PDL1 regimen of atezolizumab and nab-paclitaxel therapy in advanced TNBC (29). In 2019, atezolizumab combined with nab-paclitaxel was successfully approved by the FDA for PDL1 positive unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) (30). Nevertheless, atezolizumab combined with nab-paclitaxel did not show improved prognosis in mTNBC according to the IMpassion130 trial (31). However, researchers still noticed the benefit of this combination in mTNBC with PD-L1 positivity. Given that atezolizumab and nab-paclitaxel showed efficacy in neoadjuvant chemotherapy of TNBC (32), targeting immune checkpoints still has potential for further exploration in TNBC.
In terms of immune treatment biomarkers, tumor infiltrating lymphocytes (TILs), on which PD1 is mainly expressed, is another highly focused topic in terms of immune topic in recent years. TILs have been found to be associated with both prognosis and response to neoadjuvant chemotherapy in TNBC (33-35). Further research is needed to confirm the role of TILs in TNBC.
Despite TNBC targets and treatment strategies listed above, there are more novel potential TNBC targets such as ERK, AKT, autophagy, lncRNA, and EGFR, some of which have targeted regimens and are undergoing clinical trials. Cetuximab, an anti-EGFR antibody together with carboplatin, was evaluated in stage IV TNBC and failed to observe any benefit (36).
Publication focus in TNBC reflects the tendency of more individual and variable diagnosis methods and treatment strategies for TNBC. It is expected that more effective strategies targeting TNBC will appear in the future and will improve prognosis of TNBC patients.