Efficacy and Safety of PD-1/PD-L1 Inhibitors in Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis

Background: Compared with other subtypes, triple-negative breast cancer (TNBC) is more aggressive and has a lower survival rate with chemotherapy being the only acknowledged systemic treatment option. Recently, PD-1/PD-L1 (programmed cell death-1 and programmed death-ligand 1) inhibitors have demonstrated survival benefits in locally advanced or metastatic TNBC patients. However, the effects of PD-1/PD-L1 inhibitors in neoadjuvant chemotherapy remain controversial. Methods: Extensive literature searches were conducted in the PubMed, Embase and Cochrane databases. A pooled odds ratio (OR) with 95% confidence intervals (CI) was analyzed. Results: Seven randomized controlled trials (N = 1707) were included. PD-1/PD-L1 inhibitor chemotherapy group showed pathological complete response (pCR) benefit of 59.0% vs. 40.4% (OR 1.98, 95% CI 1.38–2.82, p $<$ 0.001). Hematological adverse events were similar. There was no significant difference between the two groups in terms of anemia (OR 1.25, 95% CI 0.93–1.68, p = 0.14; I ${}^{2}$ = 0%, p = 0.99) or neutropenia (OR 1.00, 95% CI 0.82–1.21, p = 0.96; I ${}^{2}$ = 0%, p = 0.70). Conclusions: Adding PD-1/PD-L1 inhibitors to neoadjuvant chemotherapy can improve pCR rates in TNBC patients without increasing hematological toxicities. The data suggests that PD-1/PD-L1 inhibitors may be a viable option for patients with TNBC.

Keywords

PD-1/PD-L1 inhibitors

neoadjuvant therapy

pathological complete remission

triple negative breast cancer

1. Introduction

Breast cancer remains one of the most common malignant tumors worldwide. Triple-negative breast cancer (TNBC) is a special subtype characterized by non-expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2). At present, owing to the absence of approved therapeutic regimens, chemotherapy is the only accepted systemic treatment option for TNBC. In contrast with other subtypes, TNBC is associated with more aggressive tumors, higher mortality rate and lower survival rate. Accordingly, it is crucial to develop treatment plans that can alter this outcome.

Patients with breast cancer, especially TNBC, who attain pathological complete response (pCR) have greatly improved survival [1]. Therefore, seeking a higher pCR rate has become an important purpose of neoadjuvant therapy for TNBC. Recently, PD-1/PD-L1 (programmed cell death-1 and programmed death-ligand 1) inhibitors have demonstrated survival benefits in locally advanced or metastatic TNBC patients [2, 3]. As for early TNBC patients, several studies have been conducted to evaluate the impact of PD-1/PD-L1 inhibitors in addition to neoadjuvant chemotherapy. However, the results are contradictory [4, 5, 6, 7, 8, 9, 10].

We performed a systematic review and meta-analysis to clarify the effects of PD-1/PD-L1 inhibitors in the neoadjuvant setting for patients with TNBC.

2. Methods

2.1 Searching Strategy

An extensive literature search was performed in the PubMed, Embase and Cochrane databases from inception to November 14, 2022 without restriction to language. The following key words were used for the search: “PD 1”, “PD-1”, “PD-L1”, “PD L1”, “PD-1 Inhibitors”, “PD-L1 Inhibitors”, “Programmed Death-Ligand 1 Inhibitors”, “Programmed Cell Death Protein 1 Inhibitor”, “pembrolizumab”, “atezolizumab”, “durvalumab”, “Triple-negative Breast Cancer”, “ER Negative PR Negative HER2 Negative Breast Cancer”, and “Triple Negative Breast Neoplasms” When repeated studies were determined, the most detailed and recent articles were included.

2.2 Inclusion and Exclusion Criteria

Only those randomized controlled trials (RCTs) that compared the effects of PD-1/PD-L1 inhibitors during neoadjuvant chemotherapy including PD-1/PD-L1 inhibitors (the experimental group) with neoadjuvant chemotherapy alone (the control group) were considered qualified.

Eligible studies had to meet the following criteria: (1) RCTs included at least two treatment groups (PD-1/PD-L1 inhibitors plus chemotherapy and chemotherapy alone); (2) subjects were adult TNBC patients; and (3) pCR was reported as an outcome. Exclusion criteria were: (1) RCTs with incomplete data; (2) non-RCTs; and (3) metastatic or inflammatory breast cancer.

Two authors carried out the citation searches independently and identified eligible trials based on the aforementioned criteria. Cases of discrepancies were resolved through discussion with a third reviewer.

2.3 Data Extraction

Two investigators independently extracted the following variables from each trial: (1) study information (author and year of publication); (2) trial design, including PD-1/PD-L1 inhibitor intervention, therapy regimens, number of patients in each arm and adverse events.

2.4 Risk of Bias Assessment

We evaluated the bias risk of eligible studies based on the guidelines in the Cochrane Reviewers’ Handbook. We assessed selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases. The risk of bias was divided into three levels: high, low, and unclear.

2.5 Publication Biases

We used a funnel plot to evaluate publication bias, which was created using the Egger and Begg tests in Stata 15.1 software (Stata, College Station, TX, USA). In addition, we conducted a t-test to determine the significance of the intercept, where a p-value of $<$ 0.05 was considered statistically significant.

2.6 Statistical Analysis

Review Manager (version 5.3.5; Cochrane Collaboration, Oxford, UK) was used for our meta-analysis. We used pooled odds ratios (ORs) with 95% confidence intervals (CIs) to calculate the binary variable. In addition, a Q statistical test based on chi square was conducted to evaluate the heterogeneity between studies. When the p-value in the Q-test was less than 0.10, a random effects model was used. For all other cases, a fixed effects model was performed. We used the classic forest map to present the results of the meta-analysis, with a statistical significance setting of p $<$ 0.05. We used sensitivity analysis to estimate the impact of individual studies on overall outcomes.

3. Result

3.1 Searching Result

We first identified 4804 records in the three databases for evaluation. Based on the inclusion and exclusion criteria utilized, 7 studies and 1707 patients were eligible for meta-analysis by examining the title, abstract, and full text of the records. The reference flow is shown in Fig. 1. The characteristics of these 7 studies are summarized in Table 1 (Ref. [4, 5, 6, 7, 8, 9, 10]).

Fig. 1.

Flow chart of the literature identify.

Table 1.Characteristics of qualified studies.

Study	Year	Country	PD-1/PD-L1 inhibitors	Treatment arms	Anemia		Neutropenia		Number of participants
Study	Year	Country	PD-1/PD-L1 inhibitors	Treatment arms	Experimental	Control	Experimental	Control	Experimental	Control
Ademuyiwa, Foluso O et al. [10]	2022	USA	atezolizumab	Carboplatin + paclitaxel vs. carboplatin + paclitaxel + atezolizumab	NA	NA	NA	NA	45	16
Gianni, L. et al. [9]	2022	Italy	atezolizumab	Carboplatin + nab-paclitaxel vs. carboplatin + nab-paclitaxel + atezolizumab	5	4	68	76	138	142
Loibl, S. et al. [8]	2019	Germany	durvalumab	Epirubicin + cyclophosphamide + nab-paclitaxel + placebo vs. nab-paclitaxel + epirubicin + cyclophosphamide + durvalumab	2	2	34	34	88	86
Mittendorf, E. A. et al. [7]	2020	USA	atezolizumab	Doxorubicin + cyclophosphamide + nab-paclitaxel + placebo vs. doxorubicin + cyclophosphamide + nab-paclitaxel + atezolizumab	14	12	38	36	165	168
Nanda, R. et al. [6]	2020	USA	pembrolizumab	Paclitaxel + doxorubicin + cyclophosphamide vs. pembrolizumab + paclitaxel	NA	NA	NA	NA	28	79
Pusztai, L. et al. [5]	2021	USA	durvalumab	Paclitaxel vs. durvalumab + olaparib + paclitaxel	NA	NA	NA	NA	20	130
Schmid, P. et al. [4]	2020	USA	pembrolizumab	Carboplatin + paclitaxel + placebo vs. carboplatin + paclitaxel + pembrolizumab	142	58	270	129	401	201

In total, 1707 patients were included in the final selected studies, of whom 885 were in the experimental group and 822 in the control group. Four studies reported hematological adverse events (anemia and neutropenia).

3.2 Quality Assessment

The bias risk of seven of the included studies was appraised using the Cochrane risk of bias tool. As shown in Fig. 2 (Ref. [4, 5, 6, 7, 8, 9, 10]), our results demonstrated that all studies randomly allocated patients to the appropriate treatment arms. All studies had registration information. Overall, these characteristics indicated a lower risk of design bias in the study (Fig. 3).

Fig. 2.

Quality assessment for risk of bias.

Fig. 3.

Graphs of risk of bias.

3.3 Pathological Complete Response Rates

Overall, including all the seven studies, 854 of 1707 (50.0%) patients achieved a pCR after neoadjuvant treatment, 522 of 885 (59.0%) patients in the PD-1/PD-L1 inhibitor chemotherapy group and 332 of 822 (40.4%) patients in the control group. As shown in Fig. 4 (Ref. [4, 5, 6, 7, 8, 9, 10]), a significant statistical difference was observed (OR 1.98, 95% CI 1.38–2.82, p $<$ 0.001). Due to the high heterogeneity of the study (I ${}^{2}$ = 58%, p = 0.03), a random effects model was used for evaluation.

Fig. 4.

Odds ratio for pathological complete response of experimental versus control.

3.4 Grade

\geq

3 Hematological Adverse Events

Anemia. As shown in Fig. 5 (Ref. [4, 7, 8, 9]), four RCTs reported the incidence of grade $\geq$ 3 anemia. Overall, 239 of 1953 patients (12.2%) developed grade $\geq$ 3 anemia, of whom 163 of 1175 (13.9%) in the PD-1/PD-L1 inhibitors group and 76 of 778 (9.8%) in the control group (OR 1.25, 95% CI 0.93–1.68, p = 0.14; I ${}^{2}$ = 0%, p = 0.99).

Fig. 5.

Odds ratio for grade $\geq$ 3 anemia of experimental versus control.

Neutropenia. As shown in Fig. 6 (Ref. [4, 7, 8, 9]), four RCTs reported the incidence of grade $\geq$ 3 neutropenia. Overall, 685 of 1953 patients (35.1%) developed grade $\geq$ 3 neutropenia, of whom 410 of 1175 (34.9%) in the PD-1/PD-L1 inhibitors group and 275 of 778 (35.3%) in the control group (OR 1.00, 95% CI 0.82–1.21, p = 0.96; I ${}^{2}$ = 0%, p = 0.70).

Fig. 6.

Odds ratio for grade $\geq$ 3 neutropenia of experimental versus control.

3.5 Sensitivity Analysis

The sensitivity analysis was conducted by excluding each study one by one. The result showed the stability of pooled OR estimates (Fig. 7, Ref. [4, 5, 6, 7, 8, 9, 10]).

Fig. 7.

Forest plot for sensitivity analysis (random effects model with 95% confidence interval).

3.6 Publication Bias

As shown in Fig. 8, we did not detect any publication bias in the funnel plot (Begg’s test, p = 0.293).

Fig. 8.

Funnel plots for publication bias.

4. Discussion

To assess the role of PD-1/PD-L1 inhibitors in the neoadjuvant setting for patients with TNBC, we conducted a systematic review and meta-analysis of PD-1/PD-L1 inhibitor co-treatment during chemotherapy. Our meta-analysis revealed that the inclusion of PD-1/PD-L1 inhibitors to neoadjuvant chemotherapy regimens significantly increased the pCR rate without raising hematological toxicities.

Chemotherapy elicits cancer cell death and generates signals to prompt dendritic cells to stimulate the presentation of tumor antigens to T cells, which is a pathway to activate the immune system against cancer [11]. PD-L1 expression on tumor cells and its binding to PD-1 on activated T cells inhibits T cell proliferation, survival, cytokine production, and other effector functions, ultimately inhibiting anti-tumor immune responses [12, 13]. These considerations have led to the hypothesis that TNBC may be particularly susceptible to PD-1/PD-L1 inhibitors. The results of several studies in related fields support this opinion [14, 15, 16]. Similarly, the current meta-analysis showed that TNBC patients would benefit from the addition of PD-1/PD-L1 inhibitors. A significant absolute 18.6% increased pCR rate was observed with the use of PD-1/PD-L1 inhibitors-based neoadjuvant chemotherapy (OR 1.98, 95% CI 1.38–2.82, p $<$ 0.001).

Chemotherapy is plagued with a series of hematological side effects, such as anemia and neutropenia. Hematological adverse events, especially those graded $\geq$ 3, not only seriously affect the quality of life of patients, but also reduce the tolerance of patients to interventions, leading to treatment delay or even interruption, which may prolong overall treatment time and compromise patient survival [17, 18]. In this study, our results revealed that the incidence of anemia and neutropenia above grade 3 was 13.9% and 34.9% in the experimental group, respectively, while it was 9.8% and 35.3% in the control group. There was no significant difference between the two groups in terms of anemia (OR 1.25, 95% CI 0.93–1.68, p = 0.14; I ${}^{2}$ = 0%, p = 0.99) or neutropenia (OR 1.00, 95% CI 0.82–1.21, p = 0.96; I ${}^{2}$ = 0%, p = 0.70).

Several limitations in our meta-analysis exist. First, non-hematologic adverse reactions to the lungs, endocrine system, and nervous system are important factors that influence treatment decisions and have not been evaluated in our study. Second, due to the lack of long-term follow-up in these studies, whether the increased pCR rates with the addition of PD-1/PD-L1 inhibitors would improve long-term outcomes, such as disease-free survival (DFS) and overall survival (OS), remains unknown. Third, the number of included patients was not very large. Fourth, the detection bias (blinding of outcome assessment) of the included studies was unclear. Fifth, different chemotherapy regimens in the study may affect the interpretation of the results. Hence, future research should focus more on the design of RCTs, such as sufficient sample size and strict blinding to guarantee counterbalance between intervention groups, as well as evaluating other side effects and long-term efficacy.

5. Conclusions

Our results demonstrated that adding PD-1/PD-L1 inhibitors to neoadjuvant chemotherapy could improve pCR rates in TNBC patients without increasing hematological toxicities. Nevertheless, further high-quality RCTs are needed to support any definitive recommendations for the routine use of PD-1/PD-L1 inhibitors in clinical practice.

Availability of Data and Materials

All data generated or analyzed during this study are included in this published article.

Author Contributions

ZYL designed the study. YF and XZC conducted the selection of relevant studies and data extraction separately. ZZ evaluated the quality of each study independently. SSR and XZC performed the statistical analysis. ZZ and SSR drafted the manuscript. ZYL contributed to the interpretation of the results and critically checked the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Material

PRISMA checklist.dot

References

[1]

Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014; 384: 164–172.

| Google Scholar

[2]

Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020; 396: 1817–1828.

| Google Scholar

[3]

Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. Oncology. 2020; 21: 44–59.

| Google Scholar

[4]

Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. The New England Journal of Medicine. 2020; 382: 810–821.

| Google Scholar

[5]

Pusztai L, Yau C, Wolf DM, Han HS, Du L, Wallace AM, et al. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Cancer Cell. 2021; 39: 989–998.e5.

| Google Scholar

[6]

Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial. JAMA Oncology. 2020; 6: 676–684.

| Google Scholar

[7]

Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020; 396: 1090–1100.

| Google Scholar

[8]

Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer JU, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Annals of Oncology. 2019; 30: 1279–1288.

| Google Scholar

[9]

Gianni L, Huang CS, Egle D, Bermejo B, Zamagni C, Thill M, et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Annals of Oncology. 2022; 33: 534–543.

| Google Scholar

[10]

Ademuyiwa FO, Gao F, Street CR, Chen I, Northfelt DW, Wesolowski R, et al. A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel with or without atezolizumab in triple negative breast cancer (TNBC) - NCI 10013. NPJ Breast Cancer. 2022; 8: 134.

| Google Scholar

[11]

Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annual Review of Immunology. 2013; 31: 51–72.

| Google Scholar

[12]

Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. Journal for Immunotherapy of Cancer. 2018; 6: 8.

| Google Scholar

[13]

Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Molecular Cancer. 2019; 18: 10.

| Google Scholar

[14]

Wang Y, Liu Y, Zhu S, Bi X. 170P Phase II study of camrelizumab plus chemotherapy as neoadjuvant therapy in patients with early triple-negative breast cancer. Annals of Oncology. 2022; 33: S616.

| Google Scholar

[15]

Zhang M, Song J, Yang H, Jin F, Zheng A. Efficacy and safety of PD-1/PD-L1 inhibitors in triple-negative breast cancer: a systematic review and meta-analysis. Acta Oncologica. 2022; 61: 1105–1115.

| Google Scholar

[16]

Pandy JGP, Ordinario MVC, Alcantara MJE, Li RK. 194P Neoadjuvant immunotherapy plus chemotherapy in early triple-negative breast cancer: a meta-analysis of randomized controlled trials. Annals of Oncology. 2020; 31: S320.

| Google Scholar

[17]

Li ZY, Zhang Z, Cao XZ, Feng Y, Ren SS. Platinum-based neoadjuvant chemotherapy for triple-negative breast cancer: a systematic review and meta-analysis. The Journal of International Medical Research. 2020; 48: 300060520964340.

| Google Scholar

[18]

Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast cancer. Lancet. 2021; 397: 1750–1769.

| Google Scholar

Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Clin. Exp. Obstet. Gynecol. Print ISSN 0390-6663 Electronic ISSN 2709-0094