Treatment for Triple-Negative Breast Cancer: An Umbrella Review of Meta-Analyses

Introduction

Breast cancer is the most common malignant tumor among female individuals. The incidence of breast cancer has increased year by year in recent years. According to the latest statistics, new cases of breast cancer account for nearly 30% of all new tumors in female individuals.¹ Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative on immunohistochemical examination for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2.² TNBC accounts for 15–20% of all breast cancers³ and more than 50% of metastatic breast cancers. The main clinicopathological manifestations of TNBC are high-grade invasive ductal carcinoma and regional necrosis,⁴ as well as myeloid carcinoma. Compared patients with other subtypes of breast cancer, patients with TNBC are younger, have a larger tumor size, and have more frequent lymph node involvement.⁵ Moreover, the disease stage in TNBC is typically later,⁶ the risk of postoperative recurrence is higher, and metastasis is more likely.

Because TNBC has special pathological and biological characteristics, its clinical treatment is difficult. In recent years, the treatment of TNBC has become a focus of tumor research. Many meta-analyses of TNBC treatment have also been published; however, these studies still lack systematic evidence summary and evaluation. Therefore, this study aims to further analyze and evaluate meta-analyses of TNBC treatment to provide more reliable evidence for clinical applications and facilitate the formulation of more effective treatment schemes.

Materials and Methods

Retrieval Strategy

We searched for relevant literature in the PubMed, EMBASE, and Cochrane Library databases as of June 30, 2021. The search terms included “TNBC” or “triple negative breast cancer” or “triple negative breast tumors”, combined with “systematic review or meta-analysis.”

Inclusion Criteria

We included studies that examined patients of any age with TNBC of any disease course; studies that used surgery, chemotherapy (CT), radiotherapy, targeted therapy, immunotherapy, zoledronic acid, GnRH analogs, or their combination as interventions; studies that included overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS), progression-free survival (PFS), event-free survival (EFS), local relapse-free survival (LFS), pathological complete response (PCR), objective response rate (ORR), disease recurrence rate, local recurrence rate, and distant metastasis rate; and studies that were meta-analyses.

Exclusion Criteria

If any of the following conditions were met, the study was excluded from this review: incomplete data, no outcome index literature, only summary text can be obtained, and duplicate publications or those with the same intervention measures.

Literature Screening

Two people independently screened the literature. First, they excluded the studies that obviously did not meet the inclusion criteria after reading the titles and abstracts of all the initially identified studies. The full text of studies passing the initial screening was examined and strictly compared with inclusion and exclusion criteria. Any disagreement about study inclusion was settled by a third evaluator.

Data Extraction

Two people independently extracted data and compared their findings. Extracted data included: title, publication date, author’s name, published journal, disease stage, intervention plan, comparison, number of patients, number of studies, OS, RFS, DFS, PFS, LFS, EFS, ORR, PCR, local recurrence rate, distant metastasis rate, etc.

Evidence Evaluation

Evidence evaluation was based on the joint World Health Organization–United Nations Food and Agriculture Organization expert consultation⁷ (Table 1). The reliability of evidence was mainly assessed according to the study design (meta-analysis of prospective studies or respective studies), sample number, heterogeneity (I²), and effect size. The evidence was classified as (a) convincing, (b) highly suggestive, (c) suggestive, or (d) weak.

Table 1 Criteria Used to Rate the Level of Evidence for the Treatment of Triple-Negative Breast Cancer

Results

Search Results and General Characteristics of Included Literature

According to the search strategy, a total of 784 studies were screened out. After reading the full text according to the protocol, 28 studies (10 meta-analyses of observational studies and 20 meta-analyses of interventional studies) including seven treatment methods (surgical treatment, 2 studies; CT, 16 studies; radiotherapy, 1 study; targeted therapy, 6 studies; immunotherapy, 1 study; zoledronic acid, 1 study; and GnRH analog, 1 study) were included in this study. The literature screening process is shown in Figure 1. The basic characteristics and results of the included studies are shown in Table 2.

Table 2 Main Characteristics and Results of the Eligible Studies

Figure 1 Flow chart of literature screening included in this study.

Breast-Conserving Surgery Plus Radiotherapy versus Simple Mastectomy

Patients with TNBC with small tumor volume are more likely to choose breast-conserving surgery than simple mastectomy. After breast conserving surgery plus radiotherapy, the local recurrence rate, distant metastasis rate, and all-cause mortality of patients were significantly reduced.⁸ The local control rate in patients with TNBC after breast conserving surgery plus radiotherapy was similar to that of patients with non TNBC.⁹

CT versus Non-CT

Adjuvant CT combined with surgery reduced the risk of recurrence in patients (pT1abN0M0),^10,11 and the OS was improved (HR = 0.72, 95% CI: 0.53–0.99);¹⁰ however, further analysis suggested that only T1b patients (rather than T1a) truly benefited from adjuvant CT.^10,11

Neoadjuvant CT versus Adjuvant CT

Compared with adjuvant CT, neoadjuvant CT (NACT) led to no significant improvement in OS or DFS in patients with TNBC. However, when PCR was achieved after NACT, the OS and DFS were significantly improved. The OS was lower when there were residual lesions after neoadjuvant therapy (HR = 1.18, 95% CI: 1.09–1.28).¹²

Compared with patients with non TNBC, patients with TNBC had higher PCR rates after NACT (OR = 3.10, 95% CI: 2.51–3.82), and DFS and OS were significantly improved in patients with PCR. The PCR rate in patients with TNBC with high Ki-67 expression was higher than that in patients with low Ki-67 expression (OR = 9.87, 95% CI: 3.53–27.62).¹³

Platinum Chemotherapy

Platinum-based NACT significantly improved the PCR rate in patients with TNBC patients (OR = 2.12, 95% CI: 1.64–2.73) compared with non-platinum-based NACT¹⁴. There was no significant difference in ORR between platinum-containing and platinum-free NACT (RR = 1.11, 95% CI: 0.96, 1.29),¹⁵ and there was no significant improvement in long-term survival.¹⁶ Compared with non platinum containing chemotherapy, Platinum-based CT significantly increased ORR (OR = 2.34, 95% CI: 1.66–3.28) in patients with metastatic TNBC¹⁷ and slightly improved OS and PFS in patients with metastatic TNBC.¹⁸ Compared with patients with non TNBC, the PCR rate of patients with TNBC was significantly better after NACT (OR = 2.89, 95% CI: 1.28–6.53). There was no significant difference in PFS between patients with advanced or metastatic TNBC and non TNBC after platinum therapy.¹⁹ For patients with TNBC with BRCA mutation, platinum-containing neoadjuvant therapy did not significantly improve the PCR rate.^20,21

Capecitabine Chemotherapy

Adding capecitabine to the CT regimen can significantly improve DFS and OS in patients with early TNBC.^22–24 However, in the subgroup analysis of DFS, patients treated with adjuvant CT containing capecitabine benefited significantly, while patients with NACT did not improve.²² In patients with metastatic TNBC, there was no significant benefit in OS and PFS in patients treated with capecitabine CT. There was no significant improvement in OS in patients treated with capecitabine alone (HR = 1.19, 95% CI: 0.98–1.45).²⁵

Radiotherapy

For patients with TNBC, whether they underwent breast conserving surgery or mastectomy, adjuvant radiotherapy significantly reduced the risk of local recurrence. However, it was not relevant in terms of overall survival. Nevertheless, patients with early-stage disease and young patients may benefit from it.²⁶

Targeted Therapy

NACT with bevacizumab improved the PCR rate in patients with TNBC (RR = 1.30, 95% CI: 1.16–1.45).²⁷ In patients with locally progressive TNBC, DFS was also significantly improved after bevacizumab treatment (HR = 0.88, 95% CI: 0.78–0.98).²⁸ CT containing bevacizumab can significantly improve PFS.²⁹ OS was improved in patients with metastatic TNBC, but the result was not statistically significant (HR = 0.96, 95% CI: 0.79–1.16).³⁰

Poly (ADP-ribose) polymerase inhibitors (PARPis) can improve PFS in patients with advanced TNBC (OR = 0.39, 95% CI: 0.24–0.63).³¹ Moreover, patients with BRCA1/2 mutations and patients who have not received platinum therapy can benefit more from PARPis therapy.³¹ Sorafenib plus CT can improve PFS in patients with metastatic TNBC (HR = 0.69, 95% CI: 0.49–0.98).³²

Immunotherapy

Adding a programmed death ligand 1 (PD-L1) inhibitor to NACT can improve the PCR rate in patients with early PD-L1-positive TNBC (summary OR = 1.65, 95% CI: 1.06–2.57).³³

Other Therapies

For patients with premenopausal TNBC, treatment with NACT plus zoledronic acid non-significantly increased the PCR rate (OR = 1.92, 95% CI: 0.67–5.47).³⁴

Compared with other anti-tumor drugs and placebo, GnRH analog based treatment non-significantly improved OS in patients with TNBC (HR = 0.94, 95% CI: 0.52–1.71). PFS was also not improved.³⁵

Evidence Rating

The results of evidence evaluation showed that platinum-containing NACT improved PCR rate, platinum-containing CT improved ORR and OS for patients with metastatic disease, capecitabine-containing adjuvant CT improved DFS and OS; bevacizumab-containing NACT improved PCR rate, and programmed death 1 (PD-1)/PD-L1 blockade-containing NACT improved PCR rate. Probable evidence showed that NACT improved PCR rate for patients with high Ki67 expression. There was suggestive evidence that breast-conserving therapy reduced local recurrence and distant metastasis and improved OS; CT reduced the disease recurrence rate and improved OS for patients with pT1abN0M0 TNBC; NACT improved DFS and OS; platinum-containing CT improved PFS for metastatic disease, platinum-containing NACT improved PCR rate for patients with BRCA mutation; capecitabine-containing regimens improved OS and PFS for patients with metastatic disease; radiotherapy reduced local recurrence and improved OS; bevacizumab-containing CT improved PFS for patients with metastatic disease; and GnRH analogs improved OS. However, other evidence is limited (Table 3).

Table 3 Evidence from Studies of Treatment for TNBC

Discussion

TNBC has special pathological and biological characteristics. It is a disease with poor prognosis. At present, surgery combined with conventional CT cannot meet the survival needs of patients. Patients with TNBC have clinical characteristics such as young onset age and large tumor volume. NACT improves the opportunities for surgical resection and breast conserving surgery³⁶ and reduces the scope of surgery. It is also a frequently selected scheme clinically. The main end point of treatment is to achieve PCR. At present, anthracycline combined with taxane is commonly used clinically; however, long-term use can lead to drug resistance. Studies have shown that adding platinum³⁷ or capecitabine,³⁸ to the above CT regimen can benefit patients with TNBC. Other studies have suggested that targeted therapeutic drugs, such as PARPis,³⁹ bevacizumab,⁴⁰ sorafenib⁴¹ and PD-L1 inhibitors⁴² also have certain curative effects on patients with TNBC. However, the clinical stages most benefitting from these treatments and the specific benefits of patients need to be further studied.

A comparative analysis of interventional methods for TNBC was summarized in this umbrella evaluation. It was found that platinum, bevacizumab, and immunotherapy improved PCR rate in neoadjuvant therapy; platinum improved ORR and OS in metastatic TNBC; and capecitabine improved DFS and OS as part of adjuvant therapy.

Platinum compounds, as a DNA crosslinking agent, cross connect with DNA after entering tumor cells, interfere with tumor cell DNA replication, lead to tumor cell DNA double strand break, and play an anti-tumor role. Studies have shown that platinum-containing CT can be used as an option for anthracycline and taxus resistant patients.³⁷ Its advantages in improving the PCR rate of patients with TNBC as part of neoadjuvant therapy and improving long-term survival in patients with metastatic disease have also been confirmed in some other relevant studies.^{15–17,43–45}

Capecitabine, as an oral drug for fluorouracil, has often been used in metastatic breast cancer or after anthracycline or taxane treatment.⁴⁶ Some studies suggest that capecitabine can benefit patients with TNBC treated with anthracycline combined with taxane.³⁸ This review showed that it has certain benefits in improving the long-term survival of early-stage patients, especially as an adjuvant treatment. Jiang et al also drew a similar conclusion in their studies.⁴⁷

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor receptor (VEGF). It can bind to VEGF-A, block VEGF, and lose its biological activity. In the studies of Ma et al, it was also found that adding bevacizumab to NACT regimens can improve the PCR rate of patients.⁴⁸

Immunotherapy may play an anticancer role by activating T cell autoimmunity in human body. PD-1 and PD-L1 are co-inhibitory molecules expressed on the surface of a variety of tumor cells. PD-1, as a key cell surface receptor, triggers the activation of inhibitory pathways by binding with its ligand, PD-L1, thereby inhibiting the T-cell response.⁴⁹ PD-(L)1 blockade can block the immune escape of tumor cells mediated by PD-1 and PD-L1. Monoclonal antibodies against PD-1/PD-L1 immune checkpoints have become a new tumor treatment strategy. The current analysis results suggest that such an approach has certain advantages in the neoadjuvant treatment of PD-L1-positive TNBC.

Other interventions, such as breast-conserving surgery, radiotherapy, zoledronic acid, GnRH inhibitors, targeted drugs such as sorafenib and PARPis, have also achieved some favorable results. However, due to the retrospective design or small sample size of some studies, the results of some studies have obvious heterogeneity and other problems, the level of evidence in this analysis is low. Therefore, further research is needed.

In recent years, we have a deeper understanding of the typing and molecular biological characteristics of different subtypes of TNBC. Lehmann et al⁵⁰ divided TNBC into six subtypes including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. However, Jiang et al⁵¹ divided TNBC into four transcriptome-based subtypes: luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Putative therapeutic targets or biomarkers were identified among each subtype; the comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC. Compared with the European and American patients, premenopausal African American women with breast cancer have higher morbidity and mortality of TNBC.⁵² On the one hand, the reason is that their proportion of receiving surgery and chemotherapy is relatively low; on the other hand, factors such as tumor microenvironment or tumor biological characteristics also play an important role.⁵³ The study found that,^54,55 African American TNBC women are more likely to resist chemotherapy after neoadjuvant chemotherapy than white women, resulting in a lower pathological complete remission rate. Studies have shown that different molecular subtypes, genomic structure and cellular microenvironment may lead to different response and prognosis of TNBC to chemotherapy.^56,57 However, there were not the relevant meta-analysis literatures regarding treatment comparison for different molecular subtypes and races of TNBC.

At present, precision therapy is formulated based on TNBC molecular typing, and better outcomes have been achieved in some studies.^58,59 In the future, more efforts should be devoted to the in-depth exploration of precise treatment based on molecular typing, and more reliable meta-analysis articles are also expected, which is conducive to the individualized treatment of TNBC patients.

Conclusion

TNBC is a heterogeneous disease with poor prognosis. In this study, we comprehensively reviewed the meta-analysis literature of various treatment methods of TNBC and defined the evidence level of each comparison to determine the reliability of the analyses. The results showed that only some analyses of platinum, capecitabine, bevacizumab, and immune checkpoint inhibitors were supported by convincing evidence. Many studies are low-level evidence, because there are various adverse factors in these studies, including retrospective, small sample size, short follow-up time, and other biases. However, we did not find out the relevant meta-analysis literatures regarding different molecular subtypes and races of TNBC treatment. Therefore, more rigorous and detailed researches on the treatment of TNBC are needed in the future to obtain more reliable clinical evidence.