Introduction

Breast Cancer (BC) has been growing in its incidence in the past years. “In 2020, there were 2.3 million women diagnosed with BC and 685,000 deaths globally” [1]. BC affects women in a major proportion. There are three types of BC: the first type expresses hormone receptors estrogen receptor (ER+) or Progesterone Receptor (PR+). The second type expresses Human Epidermal Receptor 2 (HER 2+) and the last one is the Triple Negative Breast Cancer (TNBC) (ER-, PR-, HER2-) [2]. TNBC has six subtypes, two Basal Like (BL1 and BL2), a Mesenchymal (M), Mesenchymal Steam-Like (MSL), Immunomodulatory (IM) and Luminal Androgen Receptor (LAR) [3] (Figure 1).

The factors that influence BC activation are not clearly described, however the most common subtype is hormone receptor positive with 60% of the documented cases, while HER2 positive has an incidence of 20% and TNBC as only 10-20%, which has the worst prognosis for the patient [2].

Patients with BC have a big number of treatments, depending on the type of BC that they present. The pharmacotherapeutic approach can be based on the BC molecular characteristics with the objective of improving the specificity and prognosis of the patient [2].

Many treatments are approved by the US Food and Drug Administration (FDA), but for TNBC there are a few that are accepted, and others are in different investigation stages, one of the reasons is the unspecificity of chemotherapy. Scientists have researched different ways to attack TNBC, and one way to treat this condition is immunotherapy, in conjunction with chemotherapy [3].

TNBC treatment

Previously, the only treatment option for TNBC was surgery, radiotherapy, and chemotherapy. Nevertheless, these therapeutic approaches did not recognize the difference between cancer cells and normal cells, so they performed their effects on both and caused unnecessary adverse effects in the patient associated with their low specificity [4].

Traditional adjuvant or neoadjuvant chemotherapy for the treatment of TNBC is based on the administration of anthracyclines with cyclophosphamide, and some regimens include taxanes [5]. These schemes achieve a favorable response in approximately 40% of cases, while the use of platinum reaches 50% but has high toxicity.

In recent years, much research has been carried out with the objective of increasing the selectivity and effectiveness of treatment, as well as reducing damage to the patient. Based on research and reports, immunotherapy was developed [6].

Immune response

Our body has a natural way to protect ourselves from tumor cells, the responsible of this labor are T cells. They require two signals to attack damaged cells, the first is to recognize an antigen, then this is followed by CD28 costimulation.

Recent investigations suggest that some types of BC are immunogenically active and that some breast tumors have a sub-stantial lymphocytic infiltrate [7]. The first attempt to modify the immune response in the research of a new treatment was blocking Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4), this is a checkpoint in the cytotoxic T-lymphocyte response. Other T-cell checkpoints that modulate inhibitory signaling are programmed cell Death Protein 1 (PD-1), mucin-domain containing 3 (TIM-3) and Lymphocyte-Activation Gene-3 (LAG-3).

In recent years, many scientists have focused their investigations on the PD1/ Programmed Death Ligand 1 (PD-L1) pathway [8].

PD-1 and PD-L1 in cancer immunotherapy

Immune evasion is an adaptive mechanism developed by tumor cells that allows them to escape the immune system and consequently promote their survival and metastatic spreading [9], which results in a poor prognosis for the patient.

Recent studies have showed that tumor cells can express high levels of immune inhibitory signaling proteins as PD-L1, a transmembrane glycoprotein encoded by the Cd274 gen located on chromosome 9 in humans [10].

PD-L1 interacts with PD-1 and generates a negative costimulation of T cell activation and reduce the cytokine expression such as INF-ϒ, TNF-α and IL-2, which plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response [11].

In the tumor microenvironment, the binding of PD-1/PD-L1 causes the activation of an evasion mechanism of the immune system because it induces phosphorylation of tyrosine residues in the cytoplasm, decreasing the induction of apoptosis of tumor cells, inhibits secretion of granular enzymes, perforins and IFN-γ, IL-2 and TNF-α [3].

Discovery of this negative regulation pathway of T cell activation provides a new opportunity for clinical application in diverse advanced cancers, especially in patients with TNBC, with agonists and antagonists of PD-1. The use of antibody-based PD-1 and PD-L1 inhibitors in clinical studies have shown durable tumor remissions in patients with TNBC [12].

Monotherapy or combination therapy as adjuvants or neoadjuvants represents a promising clinical alternative for the treatment of TNBC due to the remarkable clinical response in these patients. Nevertheless, these new strategies also are limited by the social and economic accessibility of the patients, as well as immune-related toxicity, innate and acquired drug resistance [12].

Immunotherapy is an ideal option for the treatment of TNBC, because it allows selective inhibition of specific immune check-points, such as the documented expression of PD-L1 in tumor or immune cells that allows it to evade the immune system [13].

Atezolizumab

Atezolizumab is a monoclonal antibody that blocks PD-L1 on tumor cells or tumor infiltrating immune cells. Atezolizumab, Tecentriq, Genentech Inc., on March 8, 2019, the Food & Drug Administration (FDA) granted accelerated approval in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 > 1%. This approval was based on a phase 3 study, IMpassion130 (NCT02425891), multicenter, double-blind, placebo-controlled study, with 902 participants randomized 1:1 in two-arm, for evaluated the efficacy, safety, and pharmacokinetics. The status of the study is completed on August 31, 2021. Clinical benefit was observed in patients who were treated with atezolizumab and nab-paclitaxel demonstrated improved Overall Survival (OS) and Progression-Free Survival (PFS) in both the Intention-To Treat (ITT) population and the subgroup of PD-L1 positive population [14]. The data of the second prespecified interim OS analysis showed that are consistent with the first interim OS analysis where although median OS in the ITT population was longer with Atezolizumab plus nab-paclitaxel than with placebo plus nab-paclitaxel, the significance boundary was not crossed. However, the magnitude of OS benefit with atezolizumab in PD-L1 positive patients remained clinically meaningful, with an increase of 7 months in median OS with atezolizumab plus nab-paclitaxel treatment. The updated PFS results in PD-L1 positive population showed an improvement of 2.2 months with atezolizumab plus nab-paclitaxel compared with placebo group [15].

IMpassion031 (NCT03197935), is a global phase 3, double blind, placebo-controlled study, with 333 participants randomized 1:1 in two arms, for evaluated the efficacy and safety of atezolizumab or placebo in combination with neoadjuvant chemotherapy with nab-paclitaxel followed by doxorubicin plus cyclophosphamide for the treatment of early-stage TNBC. Atezolizumab with chemotherapy demonstrated improved pathological complete response (pCR) in the ITT population in patients with early TNBC including patients with PD-L1 negative [16].

IMpassion131 (NCT03125902), multicenter, phase 3, double blind, placebo-controlled study, with 651 participants randomized 2:1 to receive atezolizumab or placebo plus paclitaxel in patients with previously untreated inoperable locally advanced or metastatic TNBC. This study was designed to evaluate the efficacy and safety of atezolizumab in combination with paclitaxel compared with placebo plus paclitaxel. The data of the primary PFS analysis showed that adding atezolizumab to paclitaxel did not show statistically significant improvement in investigator-assessed PFS in the PD-L1 positive population. Final OS results was 22.1 months in the atezolizumab plus paclitaxel group versus 28.3 months in the placebo plus paclitaxel group [17]. Do to treatment with atezolizumab combined with paclitaxel did not significantly reduce the risk of cancer progression and death, on September 8, 2020, the FDA alerted to health care professionals should not replace paclitaxel protein-bound with paclitaxel in clinical practice when use in combination with atezolizumab [18].

Pembrolizumab

Pembrolizumab, Keytruda manufactured by Merck Sharp & Dome Corp., is a monoclonal antibody that binds to the PD-1 receptor found on T cells and blocks its interaction with PD-L1 and PD-L2. On November 13, 2020, the FDA granted accelerated approval to pembrolizumab in patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 combined positive score (CPS) > 10 [19]. This approval was based on KEYNOTE-355 (NCT02819518) a phase 3, double-blind, multicenter, placebo-controlled study, with 847 participants, in part 2, randomized 2:1 in two-arm, for evaluated the efficacy and safety of pembrolizumab or placebo plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin). The data showed that pembrolizumab plus chemotherapy clinically meaningful improvement in OS and PFS, in participants with CPS > 10 [20].

On July 26, 2021, FDA approved pembrolizumab for high-risk, early-stage TNBC in combination with chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery [21]. This approval was based on KEYNOTE-522 (NCT03036488) a phase 3, double-blind, multicenter, placebo-controlled study, with 1174 participants randomized 2:1 in two arms. In the first interim analysis, in first 602 participants randomly, neo-adjuvant pembrolizumab in combination with chemotherapy followed by adjuvant pembrolizumab improved in pCR (64.8% versus 51.2%) compared with the neoadjuvant placebo in combination with chemotherapy followed by placebo after surgery [22].

Ongoing clinical trials

Because patients with TNBC have high relapse rate and upon relapse the median overall survival is less than a year, treatment for the TNBC is the most challenging in comparison with breast cancer expressing hormone receptor or human epidermal receptor 2 [23]. Based on the available clinical evidence and the recent approvals for atezolizumab and pembrolizumab in TNBC, in Figure 2 we can observe the clinical trials that are proving atezolizumab or pembrolizumab as a treatment in conjunction with other interventions, in the last eight years. On the other hand, there are many clinical trials evaluating PD-1/PD-L1 inhibitors to continue the investigation of other Immune Checkpoint Inhibitor (ICI) in combination with chemotherapy, vaccines, or even other immunomodulatory drugs. Here, we summarize the ongoing and recruiting clinical trials based on PD-1/PD-L1 inhibitors combined with chemotherapy or with other therapeutic agents that are registered in ClinicalTrials.gov [24]. We excluded clinical trials with not yet recruiting, completed, terminated, withdrawn, and unknown recruitment status. Table 1 includes some characteristics of the clinical trials for anti-PD-1 and anti-PD-L1 antibodies.

Avelumab, toripalimab, nivolumab, sintilimab, spartalizumab, tislelizumab, cemiplimab and durvalumab are antibody PD-1/PD-L1 inhibitors that we found with registered clinical trials. Each of these antibodies is being evaluated in combination with chemotherapy-based regimen but also with other drugs that have different therapeutic targets. We found studies in different clinical phases of development, most of them are in phase I and phase II. The studies for avelumab, toripalimab and durvalumab in advanced clinical phases are described below.

The clinical trial phase III for avelumab as adjuvant or post-neoadjuvant treatment for high-risk TNBC (NCT02926196), is an open label study with 474 patients who have completed treatment with curative intent including surgery followed by adjuvant chemotherapy (stratum A) or including neoadjuvant chemotherapy followed by surgery further adjuvant chemotherapy (stratum B). Treatment with avelumab will be given for 1 year. The primary outcome measure is Disease Free Survival (DFS) and the secondary outcome measure is overall survival up to 5 years after randomization. The study started on June 2016 and the estimated date to complete the study is June 2023.

The clinical trial phase III (NCT04085276), multicenter, double-blind study with 531 participants for evaluate toripalimab or placebo with nab-paclitaxel for first/second line treatment of metastatic or recurrent TNBC. The primary outcome measure is PFS up to approximately 61 months from first patient in. The study started on December 21, 2018, and the estimated date to complete the study is on December 31, 2024.

The clinical trial phase III (NCT05629585), is a multicenter, open label, 3-arm study with 1075 participants for evaluate the efficacy and safety of datopotamab deruxtecan with or without durvalumab versus investigator´s choice of therapy (capecitabine, pembrolizumab) in participants with stage I to III TNBC. The primary outcome measure is invasive Disease-Free Survival (iDFS); it will be determined based on disease recurrence per investigator assessment based on all available clinical assessments. The study started on November 28, 2022, and the estimated date to complete the study is on March 27, 2030.

Undoubtedly, the findings and results of these studies will provide further insight into the benefit that PD-1/PD-L1 inhibitors can have when combined with different drugs. On the other hand, it is important to highlight that in the most ongoing clinical trials in patients with TNBC, the therapies such as platinum, capecitabine, gemcitabine, anthracycline, and taxane-based regimens combined with PD-1/PD-L1 inhibitors the activity in patients with TNBC has been demonstrated.

Table 1: Baseline characteristics and demographics.

Conclusion

TNBC is a disease that represents a therapeutic challenge due to its highly invasive nature, the non-expression of receptors that leads to a low response to conventional therapy, and the expression of PD-L1 that contributes to evading the immune system.

Immunotherapy based on the use of immune point control antibodies such as atezolizumab and pembrolizumab, allows to regulate T cell regulatory mechanisms, blocking PD-1/PD-L1 has represented an unprecedented advance in the treatment of TNBC as shown in clinical studies that enhance the antitumor immune response, increase Overall Survival (OS) and Progression-Free Sur- vival (PFS) in patients.

In addition, there are still many clinical trials in the research phase, with the objective of discovering new combinations of treatments, reducing adverse effects, and increasing specificity, resulting in a more economical and safer intervention for the patient.

Conflict of interest: Authors declare no conflict of interest.

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