Highlights
– Neoadjuvant immune checkpoint inhibitors (ICIs) added to chemotherapy increased pathologic complete response (pCR) rates in triple‑negative breast cancer (TNBC) irrespective of PD‑L1 status, with absolute pCR improvements of >10%.
– In hormone receptor–positive/ERBB2‑negative (HR+/ERBB2‑) disease, pCR benefit was confined to the PD‑L1–positive subgroup (absolute improvement +12.2%); no pCR benefit was observed in ERBB2‑positive tumors.
– In TNBC, addition of neoadjuvant ICI was associated with improved event‑free survival (EFS) both for patients achieving pCR (HR 0.65; 95% CI 0.42–1.00) and for those with residual disease (HR 0.77; 95% CI 0.61–0.98); corresponding 5‑year EFS estimates were 92.0% vs 88.0% with and without ICI in patients with pCR, and 63.3% vs 56.1% in those with residual disease.
– Grade ≥3 immune‑related adverse events (irAEs) occurred in 10.3% of patients during neoadjuvant ICI treatment.
Background and Clinical Burden
Early‑stage breast cancer comprises biologically heterogeneous tumors with different sensitivities to systemic therapy. Triple‑negative breast cancer (TNBC) carries a higher risk of early relapse and historically lower rates of pathologic complete response to chemotherapy alone. Achieving pCR after neoadjuvant therapy is strongly prognostic in TNBC and is used as an intermediate endpoint to guide adjuvant decisions and predict long‑term outcomes.
Immune checkpoint blockade has transformed treatment of several metastatic cancers. Multiple randomized trials have explored integrating ICIs into the (neo)adjuvant setting for early breast cancer, pairing PD‑1/PD‑L1 inhibitors with multiagent chemotherapy to enhance anti‑tumor immunity and increase pCR rates. However, trial results varied across subtypes and designs, creating uncertainty about which patients most benefit and whether neoadjuvant use translates into durable survival gains.
Study Design and Methods
This systematic review and meta‑analysis (Villacampa et al., JAMA Oncology 2024) identified randomized controlled trials (RCTs) up to December 10, 2023, that randomized patients with early breast cancer to ICI plus (neo)adjuvant chemotherapy versus chemotherapy alone. Nine RCTs were eligible, enrolling 5,114 patients across molecular subtypes: 2,097 TNBC, 1,924 HR+/ERBB2‑, and 1,115 ERBB2+ tumors.
The investigators performed two complementary analytical approaches: an extracted individual patient data (IPD) meta‑analysis and a trial‑level random‑effects meta‑analysis. Primary outcomes included pCR (ypT0/Tis ypN0), event‑free survival (EFS) stratified by pCR status, and safety (particularly grade ≥3 immune‑related adverse events). Hazard ratios were estimated using stratified Cox proportional hazards models.
Key Findings
Overall pCR Effects
Across included trials, adding neoadjuvant ICI to chemotherapy increased pCR rates in selected subgroups. Effects differed substantially by molecular phenotype.
Triple‑Negative Breast Cancer (TNBC)
– pCR: The meta‑analysis showed a clinically meaningful and statistically robust increase in pCR when ICIs were added to neoadjuvant chemotherapy in TNBC. The absolute improvement exceeded 10% and was observed regardless of tumor PD‑L1 expression.
– EFS: Importantly, neoadjuvant ICI was associated with improved EFS in TNBC both among patients who achieved pCR and among those with residual disease after surgery. For patients with pCR, the pooled hazard ratio for EFS was 0.65 (95% CI 0.42–1.00), translating to estimated 5‑year EFS of 92.0% with ICI versus 88.0% without ICI. For patients with residual disease, the hazard ratio was 0.77 (95% CI 0.61–0.98), with 5‑year EFS estimates of 63.3% vs 56.1%.
– Clinical interpretation: The survival benefit in both pCR and residual‑disease subgroups suggests that neoadjuvant ICI may alter disease course beyond simply increasing pCR rates. This supports the neoadjuvant strategy in appropriately selected early TNBC patients.
HR+/ERBB2‑ Tumors
– pCR: The addition of ICIs was associated with improved pCR only in the PD‑L1–positive (PD‑L1+) subset, with an absolute improvement of +12.2%. Most HR+/ERBB2‑ tumors are less immunogenic than TNBC, and the benefit was restricted to those with evidence of PD‑L1 expression.
– EFS: The meta‑analysis did not demonstrate consistent survival benefits across the overall HR+/ERBB2‑ population; benefits appear to be limited to biomarker‑defined subgroups and remain exploratory.
ERBB2‑Positive Tumors
– pCR and survival: No pCR benefit was observed with addition of ICIs to neoadjuvant chemotherapy in ERBB2+ tumors in the pooled analysis. The lack of benefit may reflect the dominant efficacy of HER2‑directed therapies in this subtype and lower incremental value of ICIs in that setting.
Adjuvant ICI Use
– The pooled analysis suggested no numerical improvement in EFS when ICIs were used only in the adjuvant setting after surgery (hazard ratios >1 across examined strata). This finding underscores that timing of ICI exposure (neoadjuvant vs adjuvant) likely matters and that the majority of benefit was accrued when ICIs were delivered before surgery with concurrent chemotherapy.
Safety
– Immune‑related toxicity during the neoadjuvant phase was notable but generally manageable: grade ≥3 immune‑related adverse events occurred in 10.3% of patients receiving ICIs. Common severe events reported in trials include hepatitis, colitis, endocrinopathies (hypophysitis, thyroiditis), and less frequently pneumonitis. Treatment discontinuation, corticosteroid requirement, and rare permanent sequelae must be weighed against potential benefits.
Expert Commentary and Interpretation
Biological plausibility: TNBC tends to have higher tumor‑infiltrating lymphocytes, higher genomic instability, and greater neoantigen load relative to HR+ disease, offering mechanistic rationale for improved responses to ICI. The observation that neoadjuvant ICI improved EFS even among patients achieving pCR may reflect improved systemic immune surveillance or eradication of micrometastatic disease through priming of adaptive immunity during tumor antigen exposure in the neoadjuvant setting.
Biomarker considerations: PD‑L1 expression emerged as an important enrichment biomarker in HR+/ERBB2‑ disease but was not required for benefit in TNBC in this meta‑analysis. However, PD‑L1 assays and cutoffs varied between trials, limiting direct comparability. Additional biomarkers under investigation include stromal tumor‑infiltrating lymphocytes (sTILs), tumor mutational burden, gene expression immune signatures, and circulating immune markers; these may help refine patient selection.
Timing implications: The differential results between neoadjuvant and adjuvant use suggest that tumor antigen presence during neoadjuvant ICI exposure may be necessary to induce robust and durable anti‑tumor immunity. Trials that administered continued adjuvant ICI after neoadjuvant exposure complicate interpretation; pooled analyses like this help but cannot fully substitute for head‑to‑head randomized comparisons of timing strategies.
Limitations of the meta‑analysis and primary trials: Heterogeneity across trials is a major caveat. Differences include type of ICI (PD‑1 vs PD‑L1), chemotherapy backbone (anthracycline/taxane variations), use of adjuvant ICI, PD‑L1 assay and threshold, surgical timing, definitions of EFS and follow‑up duration, and geographical differences. Some survival analyses remain immature. While an IPD extraction strengthens the analysis, aggregated trial‑level heterogeneity limits granularity for subgroup and interaction testing. Moreover, absolute survival gains, while meaningful, must be balanced against immunotoxicity, quality of life, and financial costs.
Clinical practice implications: For clinicians managing early TNBC, these pooled data reinforce current guideline shifts toward integrating neoadjuvant pembrolizumab with multiagent chemotherapy for high‑risk disease in many settings, recognizing the need for careful patient selection, baseline counseling for irAEs, and coordination for perioperative management. For HR+/ERBB2‑ patients, PD‑L1 testing may be informative if considering experimental ICI strategies, but routine use is not yet supported outside trials. ERBB2+ disease should continue to prioritize HER2‑directed neoadjuvant regimens.
Conclusion and Research Priorities
This meta‑analysis synthesizes randomized evidence demonstrating that adding ICIs to neoadjuvant chemotherapy improves pCR and EFS in TNBC and increases pCR in PD‑L1+ HR+/ERBB2‑ tumors, with a manageable but meaningful rate of serious immune toxicity. No benefit was shown for ERBB2+ tumors or for ICI given only in the adjuvant setting in the pooled datasets.
Key next steps for the field include:
– Prospective biomarker‑driven refinement to identify patients with the highest likelihood of benefit while sparing others from toxicity and cost.
– Longer follow‑up to confirm overall survival benefits and to characterize late immunologic toxicities and quality‑of‑life outcomes.
– Comparative studies to define optimal ICI agent, chemotherapy backbone, and duration, and to establish whether patients with residual disease after neoadjuvant ICI require additional adjuvant immunomodulation.
– Health‑economic evaluations to quantify cost‑effectiveness and inform guideline and payer decisions.
Funding, ClinicalTrials.gov, and Conflicts
Funding sources and trial registrations are reported within the primary trials and the cited systematic review. Individual RCTs included in the meta‑analysis were sponsored by a mix of academic groups and industry partners; readers should consult original trial reports for details, ClinicalTrials.gov identifiers, and disclosed conflicts of interest.
References
1. Villacampa G, Navarro V, Matikas A, et al. Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta‑Analysis. JAMA Oncol. 2024 Oct 1;10(10):1331‑1341. doi:10.1001/jamaoncol.2024.3456 IF: 20.1 Q1 .
(For detailed trial‑level data and trial identifiers, consult the primary RCT publications cited within the JAMA Oncology meta‑analysis.)
