Immune checkpoint inhibitors plus neoadjuvant chemotherapy in early triple-negative breast cancer: a systematic review and meta-analysis

Xin, Yuanfang; Shen, Guoshuang; Zheng, Yong Hui; Guan, Yumei; Huo, Xingfa; Li, Jinming; Ren, Dengfeng; Zhao, Fuhua; Liu, Zhen; Li, Zitao; Zhao, Jiuda

doi:10.1186/s12885-021-08997-w

Cited by 21 publications

(18 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, Zhang et al group reported that PD-1/PD-L1 inhibitors in combination with chemotherapy improved pCR (OR 1.59, 95% CI 1.28 to 1.98), event-free survival (HR 0.66, 95% CI 0.48 to 0.91, p = 0.01), and overall survival (HR 0.72, 95% CI 0.52 to 0.99) in TNBC patients compared to chemotherapy alone [ 45 ]. Moreover, Li et al studied the pCR of ICIs in neoadjuvant setting in TNBC and reported that the OR significantly increased in their four included study meta-analysis (OR 2.14, 95% CI 1.37–3.35, P < 0.001) and a better event-free survival (HR 0.66, 95% CI 0.48 to 0.89, P = 0.007) [ 49 ], while similar values for pCR were reported by Rizzo et al (OR 1.95, 95% CI 1.27 to 2.99) and Xin et al (OR 1.91, 95% CI 1.32 to 2.78) [ 46 , 48 ]. Villacampa et al reported that patients with PD-L1-positive tumors had a significantly better PFS with ICIs (HR 0.67, 95% CI 0.58 to 0.79) and a trend towards better OS (HR 0.79, 95% CI 0.60 to 1.03), while no benefit was observed in patients with PD-L1-negative tumors [ 47 ].…”

Section: Discussionmentioning

confidence: 55%

Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials

et al. 2023

View full text Add to dashboard Cite

Background Triple-Negative Breast Cancer (TNBC) is a lethal subtype of breast cancer with limited treatment options. The purpose of this Network Meta-Analysis (NMA) is to compare the efficacy and safety of inhibitors of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in treating TNBC. Methods Our search strategy was used in six databases: PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature database, Embase, Scopus, and Web of Science up to November 2nd, 2022, as well as a thorough search in the most used trial registries. We included phase II and III randomized controlled trials that looked at the efficacy of PD-1/PD-L1 inhibitors in the treatment of TNBC and reported either Overall Survival (OS), Progression-Free Survival (PFS), or pathological Complete Response (pCR). The risk of bias was assessed utilizing Cochrane's risk of bias 2 tool, and the statistical analysis was performed using a frequentist contrast-based method for NMA by employing standard pairwise meta-analysis applying random effects model. Results 12 trials (5324 patients) were included in our NMA including seven phase III trials. Pembrolizumab in a neoadjuvant setting achieved a pooled OS of 0.82 (95% Confidence Interval (CI) 0.65 to 1.03), a PFS of 0.82 (95% CI 0.71 to 0.94) and a pCR 2.79 (95% CI 1.07 to 7.24) compared to Atezolizumab’s OS of 0.92 (95% CI 0.74 to 1.15), PFS of 0.82 (95% CI 0.69 to 0.97), and pCR of 1.94 (95% CI 0.86 to 4.37). Atezolizumab had less grade ≥ 3 adverse events (OR 1.48, 95% CI 0.90 to 2.42) than Pembrolizumab (OR 1.90, 95% CI 1.08 to 3.33) in the neoadjuvant setting. Conclusions PD-1/PD-L1 inhibitors exhibited varying efficacy in terms of OS, PFS, and pCR. They were associated with an increase in immune-related adverse effects. When used early in the course of TNBC, PD-1/PD-L1 inhibitors exert their maximum benefit. Durvalumab as a maintenance treatment instead of chemotherapy has shown promising outcomes. Future studies should focus on PD-L1 expression status and TNBC subtypes, since these factors may contribute to the design of individualized TNBC therapy regimens. Systematic review registration PROSPERO Identifier: CRD42022380712.

show abstract

Section: Discussionmentioning

confidence: 55%

Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials

et al. 2023

View full text Add to dashboard Cite

show abstract

“…These observations have been confirmed in two recent systematic reviews and meta-analyses. The first of these, which encompassed six randomized controlled trials focused on early TNBC (n=2142 patients), reported that NAC in combination with PD-1/PD-L1 inhibitors also resulted in improved pCR rates and event-free survival ( 29 ). The second included eight randomized controlled trials, encompassing 4901 patients with both early and metastatic TNBC (four trials in each category) ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3

et al. 2023

View full text Add to dashboard Cite

Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p<0.04-p<0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PD-L1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p<0.03 and p<0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC.

show abstract

“…Although ICB has made a difference in several cancer indications including melanoma, non-small cell lung cancer, Merkel cell carcinoma, head and neck cancer, and renal cell cancer amongst others, triple negative breast cancer (TNBC) has remained a clinical challenge until the recent FDA approval of pembrolizumab, an anti-PD-1 monoclonal antibody in combination with chemotherapy in early and late stage TNBC (7). Adjuvant chemotherapy, which frequently consists of DNA targeting agents, while necessary, can contribute additional acute toxicity and side effects to the immune-related toxicities inherent in the use of immune checkpoint inhibitors (8)(9)(10)(11)(12)(13)(14). These limitations can negatively impact the quality of life of patients during and after treatment and highlight the need for safer, less toxic anti-cancer agents that can be used in combination with ICB to improve patient outcomes.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of anti-tumor efficacy of immune checkpoint blockade by alpha-TEA

Redmond

Kasiewicz²,

Akporiaye³

2023

Front. Immunol.

View full text Add to dashboard Cite

Cancer immunotherapy such as anti-PD-1/anti-PD-L1 immune checkpoint blockade (ICB) can provide significant clinical benefit in patients with advanced malignancies. However, most patients eventually develop progressive disease, thus necessitating additional therapeutic options. We have developed a novel agent, a-TEA-LS, that selectively induces tumor cell death while sparing healthy tissues, leading to increased activation of tumor-reactive T cells and tumor regression. In the current study, we explored the impact of combined a-TEA-LS + ICB in orthotopic and spontaneously arising murine models of mammary carcinoma. We found that a-TEA-LS + ICB led to increased production of pro-inflammatory cytokines that were associated with a reduction in tumor growth and prolonged survival. Together, these data demonstrate the potential utility of a-TEA-LS + ICB for the treatment of breast cancer and provide the rationale for clinical translation of this novel approach.

show abstract

Immune checkpoint inhibitors plus neoadjuvant chemotherapy in early triple-negative breast cancer: a systematic review and meta-analysis

Cited by 21 publications

References 52 publications

Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials

Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials

Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3

Enhancement of anti-tumor efficacy of immune checkpoint blockade by alpha-TEA

Contact Info

Product

Resources

About