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Identifying subgroups deriving the most benefit from PD-1 checkpoint inhibition plus chemotherapy in advanced metastatic triple-negative breast cancer: a systematic review and meta-analysis

World Journal of Surgical Oncology volume 22, Article number: 346 (2024) Cite this article

Abstract

Background

The combination of immunotherapy and chemotherapy has demonstrated an enhancement in progression-free survival (PFS) for individuals with advanced and metastatic triple-negative breast cancer (TNBC) when compared to the use of chemotherapy alone. Nevertheless, the extent to which different subgroups of metastatic TNBC patients experience this benefit remains uncertain.

Objectives

Our objective was to conduct subgroup analyses to more precisely identify the factors influencing these outcomes.

Materials and methods

The PubMed database was searched until Dec 2023 for studies that compared PD-1 checkpoint inhibitors plus chemotherapy (ICT) with chemotherapy (CT) alone. The primary outcome of interest was progression-free survival (PFS). Review Manager (RevMan) version 5.4. was used for the data analysis.

Results

Four randomized controlled trials (RCTs) comprising 2468 advanced and metastatic TNBC were included in this systematic review and meta-analysis. PFS surge with combined therapy was observed in White (HR 0.80 [0.70, 0.91], p = 0.0007) and Asian ethnicities (HR 0.73 [0.58, 0.93], p = 0.01) but not in Blacks (HR 0.72 [0.42, 1.24], p = 0.24). Overall, patients with distant metastasis demonstrated to derive the PFS benefit from additional immunotherapy (HR 0.87 [0.77, 0.99], p = 0.03); however, metastasis to individual distant site was associated with failure to achieve any treatment difference (Bone: HR 0.79 [0.41, 1.52], p = 0.49; Lung: HR 0.85 [0.70, 1.04], p = 0.11; Liver: HR 0.80 [0.64, 1.01], p = 0.06). While number of metastases > 3 also showed to impact the PFS advantage (HR 0.89 [0.69, 1.16], p = 0.39). While patients, regardless of prior chemotherapy, experienced a notable enhancement in PFS with ICT (Overall: HR 0.79 [0.71, 0.88], p < 0.0001; Yes: HR 0.87 [0.76, 1.00], p = 0.05; No: HR 0.67 [0.56, 0.80], p < 0.00001), those previously exposed to chemotherapy exhibited a significantly smaller PFS advantage compared to those without prior chemotherapy, as evidenced by a significant subgroup difference (Test for subgroup difference: P = 0.02, I2 = 82.2%). Patients lacking PD-L1 expression also failed to achieve any additional benefit from immunotherapy (PD-L1-: HR 0.95 [0.81, 1.12]; p = 0.54; PD-L1+: HR 0.73 [0.64, 0.85], p < 0.0001). Age, ECOG status, and presentation with de novo metastasis/recurrent shown no impact on IT-associated PFS advantage.

Conclusions

Patient- and treatment- related factors such as ethnicity, distant metastases, number of metastases (> 3), previous exposure to chemotherapy and PD-L1 expression, seem to influence or restrict the advantage in progression-free survival associated with the addition of immunotherapy to chemotherapy, as opposed to chemotherapy alone, in patients with advanced and metastatic TNBC. Larger studies are warranted to validate these outcomes.

Introduction

Triple-negative breast cancer (TNBC) constitutes 15–20% of breast cancer occurrences and is linked to an unfavorable prognosis due to its aggressive characteristics, marked by the expression of highly proliferative, high-grade, and basal-like genes (approximately 55–81%), accompanied by the absence of specific targeted treatment options [1,2,3]. Treatment is challenging because it lacks expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and/or amplification or overexpression of human epidermal growth factor receptor 2 [HER2] [3]. Therefore, TNBC patients rely mainly on cytotoxic chemotherapy as the mainstay of treatment [1,2,3,4]. Despite a stronger response to chemotherapy among breast cancer (BC) subgroups, recurrence is higher in the first three years of treatment, which is associated with poor survival, a phenomenon termed the TNBC paradox [3,4,5]. Metastasis is the major cause of death in this subgroup, with a 5-year survival rate of < 30% in patients with metastatic TNBC (mTNBC) [2]. Therefore, alternative therapeutic approaches are required to improve patient outcomes.

Discovery of the PD-1 (programmed cell death protein 1) receptor-ligand interaction pathway as the major tumor immune evasive mechanism has fashioned immunotherapy in the form of PD-1/PD-L1 inhibitors as an alternative and complementary option for cancer patients [6]. TNBC exhibits high infiltration of tumor-infiltrating lymphocytes (TILs) coupled with elevated PD-L1 expression, making it an ideal candidate for PD-1/PD-L1 inhibition [7,8,9]. In fact, both PD-1 inhibitors (pembrolizumab) and PD-L1 inhibitors (atezolizumab) as monotherapy have shown promising results in metastatic TNBC [10,11,12,13,14]. Unraveling the immunomodulatory effects of chemotherapy has encouraged the combination of these two therapies for complementary interplay, which has shown improved outcomes in several cancers, including breast cancer [15,16,17,18,19,20,21,22,23,24,25,26]. Recent clinical trials have led to approval of these agents in combination with chemotherapy for metastatic TNBC [10,11,12,13,14, 24,25,26,27]. There was significant improvement in the primary outcome (PFS) in the intention-to-treat (ITT) in three of the four major trials (IMPassion130, IMPassion131, KEYNOTE-355, and ALICE) [24,25,26,27]. The IMPAssion131 trial produced only marginally numerical improvement in PFS in ITT and PD-L1 + subgroups [26]. However, the other three trials showed improved PFS in PD-L1 + subgroup while the there was no difference in PFS for the treatment difference in PD-L1- patients.

Beyond PD-L1 expression serving as a marker for immunotherapy response, several factors such as age, race, and prior chemotherapy exposure have been identified as influencing the response to immunotherapy [10,11,12,13,14, 28, 29]. This study aims to investigate how patient- and treatment-related factors impact the responsiveness to immunotherapy in individuals with metastatic triple-negative breast cancer (mTNBC) through a comprehensive systematic review and meta-analysis.

Methods and materials

This systematic review and meta-analysis was performed following the updated version 2020 of PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines (Supplementary Table 1) [30]. The protocol for this study is registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) under registration number INPLASY202440097. The protocol can be accessed at https://inplasy.com/inplasy-2024-4-0097/.

Research strategy and study selection

PubMed was formally searched for several key terms until Dec 2023. The detailed key terms and research results are provided in Supplementary Table 2. Further potential studies were identified by screening the references of relevant articles. A stepwise procedure comprising retrieval, organization, and screening was followed by two reviewers (S.L. and B.F.) to select studies that met the eligibility criteria. Disagreements were resolved by consulting the corresponding author (M.K.).

Studies were evaluated for eligibility according to the following criteria: (1) Patients with advanced metastatic triple-negative breast cancer (TNBC) receiving chemotherapy with immune checkpoint inhibitors (ICIs); (2) Studies reported the comparison of subgroup for the primary outcome of interest (PFS); (3) Efficacy outcome (PFS) was reported in the form of hazard ratios and corresponding 95% confidence intervals; (4) Only randomized controlled trials (RCTs) were conducted with English-language restrictions.

The primary outcome of interest was comparison of progression-free survival in subgroups of the intention-to-treat (ITT) population, based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Data extraction

Data extraction was performed using the modified form “The Cochrane Collaboration Data Collection form for RCTs” obtained from the Cochrane website. The extracted data included the general characteristics of the included studies, participants, and the main outcomes. The general characteristics of the included studies included the first author, publication year, trial designation, national clinical trial (NCT) registration number, trial design, number and type of participants, treatment protocols, and median duration of follow-up. Participant information included age, race, menopausal status, ECOG (Eastern Cooperative Oncology Group) performance status, PD-L1 expression status, and use of previous chemotherapy. Furthermore, the outcomes of interest (progression-free survival, objective response rates, overall survival, and safety outcomes) for treatment differences were extracted from the papers.

Quality assessment

The Cochrane Collaboration Tool was used to assess the quality of the trials [31]. Assessments included sequence generation, allocation of sequence concealment, blinding of participants and personnel, blinding of outcomes and assessments, incomplete outcome data, selective outcome reporting, and other bias.

Measurement of treatment effect and data synthesis

Hazard ratios (HRs) and their corresponding 95% confidence intervals (CI) were extracted for progression-free survival. Natural logarithm of the HRs [ln(HRs)] were taken and standard errors were calculated for individual outcomes according to the following formula: SE=(LN (Upper 95% CI)-LN (Lower 95% CI))/ (2*1.96); where LN stands for natural logarithm. Review Manager (RevMan) version 5.4 was used to pool HRs using the inverse variance statistical method [31, 32]. Heterogeneity was assessed using Chi2 test and I2 value and graded as low (I2 = 25%), moderate (I2 = 50%), or high (I2 = 75%) according to the I2 values [33]. A fixed-effects analysis model was adopted unless the heterogeneity exceeded 50% (I2\(\ge\)50%). In this case, a random-effects analysis model was used. The significance level was set at p < 0.05.

Results

The initial database search identified 1814 published studies. Scrutiny for duplicity, relevance, and eligibility resulted in the final selection of four randomized, placebo-controlled, double-blind, phase III/IIb trials (RCTs) involving 2468 patients with advanced metastatic triple-negative breast cancer (mTNBC) patients [24,25,26,27]. The research strategy and study selection process are shown in Fig. 1. The general characteristics of the included studies are summarized in Table 1. Overall, 1488 participants received a PD-1 or PD-L1 inhibitor plus chemotherapy (CT), constituting the immunotherapy (IT) plus CT (ICT) cohort of this systematic review. A total of 980 participants who were only administered CT comprised the CT alone cohort. Participants in the three RCTs (n = 1593) received atezolizumab (a PD-L1 inhibitor), while pembrolizumab (a PD-1 inhibitor) was administered in one RCT (n = 847). About 74% of the participants were White (1772/2468), followed by Asian (25.5% [613/980]). Performance status as per ECOG estimation was 0 in 60% (1471/2468) patients. PD-L1 expression was positive in 54% (1328/2648) of the participants. In studies involving pembrolizumab, PD-L1 expression was evaluated using the PD-L1 IHC 22C3 pharmDx assay, which measured PD-L1 expression on both tumor cells and immune cells, resulting in what is termed as the combined positive score (CPS) [25]. RCTs investigating atezolizumab utilized the VENTANA PD-L1 (SP142) assay, which assessed PD-L1 expression solely on immune cells (IC) [24, 26, 27]. This approach was adopted based on findings from a phase I trial, which demonstrated a notable improvement associated with PD-L1 expression on immune cells rather than tumor cells (TC) [34]. Majority of the patients were presented with de novo metastasis (59% [1074/1817]), of which the lung was the predominant metastatic site 54% (982/1817). And, about 59% (1449/2468) of the participants had previously received chemotherapy. The previous (neo)adjuvant chemotherapy with curative intent was administered at least ≥12 months before randomization (6 months in case of KEYNOTE-355). Other baseline information of participants are highlighted in Table 2.

Fig. 1
figure 1

PRISMA flow diagram of research strategy and study selection

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Table 1 General characteristics of the included randomized controlled trials
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Table 2 Baseline characteristics of patients
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Progression free survival (PFS) was reported as the primary endpoint in all four RCTs involving 2468 advanced metastatic TNBC patients [24,25,26,27]. Individually, each trial showed significant improvement in the PFS from combined therapy except IMPassion131 trial which only showed marginal numerical benefit (KEYNOTE-355: HR 0.82 [0.69, 0.97], p = not tested; IMPassion130: 0.80 [0.69, 0.92], p = 0.0025; IMPAssion131: HR 0.86 [0.70, 1.05], p = not tested; ALICE: 0.56 [0.33, 0.95], p = 0.033). Overall survival (OS) was reported in three studies, with slightly contrasting outcomes (IMPassion130: 0.84 [0.69, 1.02], p = 0.08; IMPAssion131: HR 1.12 [0.88, 1.43], p = not tested; ALICE: 0.75 [0.43, 1.30], p = not tested) [24, 26, 27]. The IMPassion130 and ALICE trials reported slightly improved OS; however, the recently concluded IMPasssion131 trial revealed no such advantage with the addition of IT [24, 26, 27].

Risk of bias assessments

Quality assessment was performed using The Cochrane Collaboration Tool. All included RCTs were double-blinded [24,25,26,27]. A detailed assessment is provided in Supplementary Figure S1.

Meta-analysis of factors of concern

Baseline patient- and treatment-related characteristics were evaluated for association with efficacy derived from ICT, such as age, race, ECOG status, PD-L1 expression, metastatic information and prior exposure to chemotherapy.

Age

The efficacy of ICT in comparison to CT alone was analyzed for the effect of age in three RCTs involving 2400 mTNBC patients. Both age subgroups at cutoff 65 derived significant benefit from the combination therapy (< 65: HR 0.83 [0.73, 0.94], p = 0.004; ≥65: 0.71 [0.57, 0.89], p = 0.003) (Fig. 2). Further subdivision of age < 65 subgroup into age = 18–40 and age = 40–64 years only showed marginally better numerical improvement in the PFS for younger age subgroup as compared to older subgroup (18–40: HR 0.54 [0.23, 1.30], p = 0.17; 40–64: 0.87 [0.74, 1.03], p = 0.10). Importantly, the latter analysis involved only two studies which included IMPassion131 which has produced negative results.

Fig. 2
figure 2

Forest plot of meta-analysis of progression-free survival (PFS) based on age subgroups between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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Ethnicity

Racial comparison for the treatment difference was reported in three RCTs involving 2400 mTNBC patients. White race (HR 0.80 [0.70, 0.91], p = 0.0007), which was the predominant subgroup (70%), and Asian participants (HR 0.73 [0.58, 0.93], p = 0.01) showed a significant association with the combined approach, whereas African-American race only derived numerically better PFS with ICT than CT alone (HR 0.72 [0.42, 1.24], p = 0.24) (Fig. 3).

Fig. 3
figure 3

Forest plot of meta-analysis of progression-free survival (PFS) based on racial subgroups between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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ECOG

All the 4 RCTs involving 2468 advanced and mTNBC patients reported comparison for ECOG subgroups. Both ECOG subgroups (ECOG 0, 1) derived significant benefit from the combination therapy (ECOG 0: HR 0.79 [0.69, 0.90], p = 0.0005; ECOG 1: 0.80 [0.71, 0.91], p = 0.0006) (Fig. 4).

Fig. 4
figure 4

Forest plot of meta-analysis of progression-free survival (PFS) based on ECOG performance status between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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Presence of metastasis

In the first step, we estimated the survival advantage derived by de novo metastatic patients versus others which was reported in 3 RCTs (n = 1817). There was no difference (p = 0.87) in patients presenting with de novo metastasis versus patients progressing on treatment (de novo metastasis: HR 0.78 [0.68, 0.90], p = 0.0004; No: 0.80 [0.67, 0.95], p = 0.01) (Fig. 5).

Fig. 5
figure 5

Forest plot of meta-analysis of progression-free survival (PFS) based on based on presence of de novo metastasis between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors. The PFS data for recurrent mTNBC patients in KEYNOTE-355 study was reported based on recurrence within 12 months (KEYNOTE-355) and beyond 12 months (KEYNOTE-355*). KEYNOTE-355 study reported the recurrent mTNBC patients based on 12 months

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Comparison of distant metastasis was reported for bone, lung and liver metastasis in more than a single study and hence were incorporated into meta-analysis. Individually, metastasis to each distant site was associated with lack of net-benefit of immunotherapy addition (Bone: HR 0.79 [0.41, 1.52], p = 0.49; Lung: HR 0.85 [0.70, 1.04], p = 0.11; Liver: HR 0.80 [0.64, 1.01], p = 0.06) (Fig. 6). However, there was no significant difference between the subgroups across each comparison due similar trend towards better survival in both subgroups (Bone: p = 0.79; Lung: p = 0.21; Liver: p = 0.88). Moreover, we combine the results from all the metastatic sites which showed a net benefit of immunotherapy addition (HR 0.87 [0.77, 0.99], p = 0.03) as shown in Fig. 7.

Fig. 6
figure 6

Forest plot of meta-analysis of progression-free survival (PFS) based on based on presence of (A) bone, (B) lung, and (C) liver metastasis between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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Fig. 7
figure 7

Forest plot of meta-analysis of progression-free survival (PFS) based on based on presence of distant metastasis between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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Number of metastasis

Significant improvement was maintained regardless of the number of metastatic sites divided into 0–3 (HR, 0.78 [0.69, 0.89]; p = 0.0002) and ≥ 3 metastatic sites (HR, 0.80 [0.67, 0.96]; p = 0.02) (Fig. 8). However, strictly adhering to patients with greater than 3 (> 3) metastatic sites after excluding KEYNOTE-355, the PFS advantage was lost with the combined approach (HR, 0.89 [0.69, 1.16]; p = 0.39).

Fig. 8
figure 8

Forest plot of meta-analysis of progression-free survival (PFS) based on based on number of metastatic sites between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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Prior exposure to chemotherapy

Prior exposure to chemotherapy appeared to dampen the response to combination therapy (Yes: HR 0.87 [0.76, 1.00], p = 0.05; No: 0.67 [0.56, 0.80], p < 0.00001) (Fig. 9A). Although, both subgroups derived significant improvement in PFS, test for subgroups difference was significant (p = 0.02) due the huge difference in the outcomes between the subgroups (I2 = 82.2%). This trend was not associated with prior use of taxane (Fig. 9B).

Fig. 9
figure 9

Forest plot of meta-analysis of progression-free survival (PFS) based on based on exposure to previous (A) chemotherapy and (B) taxane chemotherapy between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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PD-L1 expression

Patients deficient in PD-L1 expression failed to achieve an additional IT-derived PFS advantage (HR 0.95 [0.81, 1.12]; p = 0.54) (Fig. 10). There was significant difference between the subgroups (p = 0.02; I2 = 83%).

Fig. 10
figure 10

Forest plot of meta-analysis of progression-free survival (PFS) based on PD-L1 expression between patients receiving immunotherapy plus chemotherapy (ICT) and CT alone. Immunotherapy mainly consisted of PD-1/PD-L1 inhibitors

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Publication bias

No publication bias was observed in the outcomes as illustrated in Fig. 11.

Fig. 11
figure 11

Funnel plot of publication bias assessment in progression-free survival (PFS) analysis for (A) age; (B) ethnicity; (C) ECOG status; (D) de novo metastasis; (E) bone metastasis; (F) lung metastasis; (G) liver metastasis; (H) distant metastasis; (I) number of metastasis; (J) prior use of chemotherapy; (K) prior use of taxane; (L) PD-L1 expression

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Discussion

Immunotherapy, in the form of PD-1 checkpoint inhibition, has been extensively explored and compared to chemotherapy. Earlier trials evaluating pembrolizumab (PD-1 inhibitor) and atezolizumab (PD-L1 inhibitor) as monotherapy or in combination with chemotherapy have shown the safety and anticancer activity of these agents in the treatment of previously treated/untreated, locally advanced, and metastatic triple-negative breast cancer (mTNBC) [10,11,12,13,14]. Its efficacy is more evident in patients with higher PD-L1 expression [13]. However, no improvement in OS has been reported compared to chemotherapy [35]. The combination of these agents and chemotherapy was eventually tested against CT alone in a number of trials in early stage TNBC (neoadjuvant setting) and advanced mTNBC [19,20,21,22,23,24,25,26,27]. Individually, all included trials showed similar consistent improvements in PFS as the main outcome for the entire (ITT) population [24,25,26,27]. Moreover, pool results of previously published meta-analyses have shown significant improvement in the PFS for the advanced and mTNBC with the combination therapy [36,37,38]. Overall survival results are contradictory among the three RCTs [24,25,26,27].

In the PD-L1 + subgroup analysis, the PFS obtained in the IMPassion131 (HR 0.82 [0.60, 1.12], p = 0.20) and ALICE (HR 0.65 [0.27, 1.54], p = 0.33) trials was insignificant for treatment differences compared with the other two trials that showed significant improvement (KEYNOTE-355: HR 0.74 [0.61, 0.90], p = 0.0014; IMPassion130: 0.64 [0.47, 0.87], p < 0.001) [24,25,26,27]. Nonetheless, a previous meta-analysis has demonstrated a significant net-benefit in PFS for PD-L1 + TNBC patients involving these four studies [36]. Our study also endorses these results as the combined therapy was able to provide significant improvement in PFS in the PD-L1 + subgroup by pooling the subgroup comparison involving PD-L1 expression subgroups. Although different PD-L1 expression assays were used, PD-L1 expression in tumor and/or immune cells (> 1%) was significantly associated with IT-derived improvement in PFS, suggesting a strong predictive value of PD-L1 expression in patients with mTNBC. In contrast, PD-L1 expression in early stage TNBC patients has failed to show any predictive value when assessed using pathological complete response (pCR) [39]. Long-term outcome parameters, such as event-free survival (EFS) and PFS, may represent an appropriate choice for assessing the benefit of immunotherapy, as immune responses may persist for longer periods of time with memory responses. Nonetheless, the results of a meta-analysis revealed a higher ORR and 1-year PFS for PD-L1 + metastatic breast cancer patients than for those with PD-L1-negative tumors (ORR: OR 1.44 [1.09, 1.91], p = 0.01; 1-year PFS: OR 1.55 [1.02–2.36], p = 0.04) [40]. However, TNBC is characterized by a higher recurrence rate than other subtypes; therefore, further investigations are required to establish PD-L1 expression biomarker ability in patients with TNBC.

The utilization of chemotherapy in the neoadjuvant or adjuvant setting emerged as another significant factor influencing the response to immunotherapy. Our analysis indicates that individuals with a history of prior chemotherapy derive relatively diminished benefits compared to those without such a history. Previous research has consistently demonstrated an adverse effect of the number of prior lines of therapy on the response to PD-1/PD-L1 inhibition. These studies encompassed trials involving pembrolizumab/atezolizumab monotherapy in patients with triple-negative breast cancer (TNBC) and other malignancies like lung cancer [10,11,12,13,14, 41].

The association between ethnicity and the benefit from immune checkpoint inhibition has long been investigated in the context of several other cancers. Consistent with our analysis, a retrospective review of 207 lung (n = 174) and head & neck cancer (n = 33) patients who had received either combination therapy or ICI monotherapy between 2015 and 2020 also showed a higher ORR in non-Hispanic Whites (n = 45%) as compared to Blacks (n = 38%) and Hispanic (n = 18%) (ORR: W 38.7%, B 32.5%, H 27.0%) [28]. However, one can notice that the order of ORR correlates with number of participants in each racial category. The number of Black participants in our study also merely constituted the 7% which also have impact on the lack of treatment difference in this category. On the other hand, there was no difference in IT-derived benefits in Whites and Asians in our study which also coincides with the results of a meta-analysis pooling outcomes from 19 prospective clinical trials involving various cancers [42]. Their study reported a significant improvement in PFS and OS for immunotherapy (PD-1/PD-L1 inhibition) against control/chemotherapy in both Asian and non-Asians. Benefits were reported for the overall population, as well as individually for each cancer type, including lung cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, and breast cancer. Hence, the lack of a PFS advantage in African-American participants need further investigations.

In this group of studies, 59% of the patients were presented with de novo metastasis, which also showed an association with deriving a numerically better improvement in PFS compared to recurrent patients. Conventionally, breast cancer patients with de novo metastasis have shown a better 5-year disease specific survival (DSS) as compared to recurrent metastatic breast cancer patients (44% versus 21%) [43]. Moreover, the presence of distant metastases at each individual site (bone, lung and liver) dampen the benefit derived from immunotherapy addition. Previously, only metastasis to liver has been confirmed in a meta-analysis to reduce the prospects of additional immunotherapy [44]. Nonetheless, patients with distant metastasis collectively were able to derive significant PFS advantage associated with adding immunotherapy, which may suggest limitation of individual analysis and hence such outcomes are to be interpreted with caution. Moreover, number of > 3 metastases demonstrated to impact the PFS advantage. Other factors like age, ECOG status fail to show any association with treatment difference. Further investigations are necessary to elucidate the specific implications of these findings.

Results of IMPassion131 trial significantly differs from that of other trails which warrants further discussion. In contrast to the IMPassion131 trial, the KEYNOTE-355 trial had evaluated PD-1 inhibitor with a wide range of chemotherapy backbones that comprised paclitaxel, nab-paclitaxel, and gemcitabine/carboplatin [24, 25]. PD-L1 expression assay also differed in the latter [25]. In comparison with IMPassion130, the IMPassion131 trial not only showed a contrasting outcome in PFS in PD-L1 + patients but also revealed an insignificant OS in ITT and PD-L1 + populations [24, 26]. IMPassion130 showed clinically meaningful improvement in OS in both subgroups (ITT: HR 0.86 [0.72, 1.02], p = 0.078; PD-L1+: HR 0.71 [0.54, 0.94]), while OS was not reported in KEYOTE-355. Despite broad similarities in the baseline characteristics of patients in IMPassion130 and IMPassion131, apparent differences between these two trials included the evaluation of nab-paclitaxel (compared to paclitaxel), fewer Asian participants (18% versus 29%), and a higher proportion of patients with de novo metastatic disease (37% versus 31%) in the IMPassion130 trial [24, 26]. Two of these three differences (Asian participants and de novo metastasis) were revealed to impact IT-derived PFS in our study. Differences in chemotherapy backbone (paclitaxel versus nab-paclitaxel) may not have any effect on the outcome as revealed from the assessment in the KEYOTE-355 trial (ITT: HR 0.69 [0.51 to 0.93] versus HR 0.57 [0.35 to 0.93]) and notable similarity demonstrated in median PFS (and hazard ratios) in the ITT control arms of IMPassion131 (5.6 months with paclitaxel alone) and IMPassion130 (5.5 months with nab-paclitaxel alone) [24,25,26]. The only obvious and debated argument for the failure of the IMPassion131 trial is the allowance of concomitant steroid use (8–10 mg dexamethasone or equivalent for at least the first two infusions) [26, 45]. Previously, dexamethasone, with its immunosuppressive activity, has been linked to dampening the anti-tumor activity of checkpoint inhibitors and anti-cancer vaccines [46, 47].

Despite the moderate number of participants, our study was limited by the small number of participants selected for inclusion. Certain dissimilarities were observed in these studies with respect to the type of agent (PD-1 or PD-L1 inhibitor), chemotherapy backbone, PD-L1 expression assessment assay, and ethnicity [48]. These differences may have led to heterogeneity in the pooled analyses. A study assessing the concordance of tumor and immune cell staining with different PD-L1 tests have reported lower concordance for IC and reduced TC PD-L1 staining/concordance for SP142 vs. SP263 [49]. However, the impact of this lower concordance on the ability of PD-L1 expression to predict outcomes in large cohorts of patients from randomized controlled trials (RCTs) remains largely unresolved. Nonetheless, each study individually reported positive outcomes for PD-L1 expression, resulting in low heterogeneity in the primary outcome for PD-L1-positive patients (I2 = 0%) and minimal heterogeneity for PD-L1-negative patients (I2 = 27%). Therefore, significant heterogeneity in our results due to different IHC assays is highly unlikely.

Conclusions

In summary, our study uncovered limitations in the progression-free survival (PFS) benefits linked to PD-1/PD-L1 checkpoint inhibitors among patients with advanced and metastatic triple-negative breast cancer (TNBC). The supplementary immunotherapy did not yield a substantial PFS advantage for Black individuals, those with more than 3 metastases, and those without PD-L1 expression. Furthermore, the PFS benefit was restricted in patients with distant metastases and a history of chemotherapy exposure. Larger-scale studies are necessary to validate these findings.

Data availability

Not applicable.

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  1. Shengfa Lin and Bihe Fu contributed equally to this work.

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  1. Department of Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510168, People’s Republic of China

    Shengfa Lin & Bihe Fu

  2. Department of Radiation Oncology, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou, Guangdong, 510095, People’s Republic of China

    Muhammad Khan

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Lin, S., Fu, B. & Khan, M. Identifying subgroups deriving the most benefit from PD-1 checkpoint inhibition plus chemotherapy in advanced metastatic triple-negative breast cancer: a systematic review and meta-analysis. World J Surg Onc 22, 346 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-024-03424-3

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World Journal of Surgical Oncology

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