Immunotherapy in Breast Cancer: Current Status and Future Directions

The paper reviews the evolving role of immuno-oncology in breast cancer (BC), historically viewed as poorly immunogenic compared with melanoma and lung cancer. BC subtypes differ immunologically: TNBC and HER2+ generally have higher tumor mutational burden and tumor-infiltrating lymphocytes than HR+/HER2−. ICIs, particularly anti–PD-(L)1 agents, have changed the TNBC treatment paradigm, improving outcomes in metastatic first-line therapy for PD-L1–positive disease and in the neoadjuvant setting. The review outlines current evidence, strategies to enhance benefit, and key challenges including biomarker selection and toxicity management.

- Metastatic TNBC: ICI monotherapy in unselected or pretreated patients yields limited activity (ORR ~5–20%, mPFS 1–2 months) with outcomes influenced by prior lines and PD-L1 status. Combination of ICIs with chemotherapy in first-line PD-L1–positive TNBC improves outcomes (KEYNOTE-355; IMpassion130), while IMpassion131 (paclitaxel-based) was negative, likely due to factors including steroid premedication and prior taxanes. - Strategies to overcome resistance: address tumor-intrinsic (antigen loss, mutations) and microenvironmental mechanisms (TAMs, Tregs, MDSCs, inhibitory cytokines). Combinations under study include novel checkpoints (LAG3, TIM3), targeted agents (anti-angiogenics, PARPi), ADCs (e.g., T-DXd, ladiratuzumab vedotin) with ICIs, and locoregional approaches (RT, ablation) to boost antigen release and abscopal immune effects. CAR-T cells are being explored in TNBC (target selection and on-target/off-tumor risks are key challenges). - Early-stage TNBC: Multiple randomized neoadjuvant trials show that adding ICIs increases pCR and improves survival. A meta-analysis of five trials demonstrated a significant pCR advantage; KEYNOTE-522 improved 3-year EFS regardless of PD-L1. GeparNuevo did not meet pCR primary endpoint but showed survival benefit, suggesting pCR is not the sole driver of ICI benefit. - Post-neoadjuvant setting: Need to define roles of adjuvant pembrolizumab continuation and how to integrate capecitabine or olaparib in patients with residual disease; trials are ongoing (including ADC+ICI escalation strategies). - HR+/HER2− BC: Immunologically colder with low TILs; ICI monotherapy or chemo-ICI combinations in unselected endocrine-resistant disease show limited benefit overall. Signals of activity emerge in selected contexts (e.g., PD-L1–positive cohorts, CD274 amplification, early-stage high-risk subsets in I-SPY2; PARPi+ICI in gBRCA-mutated disease). ADC+ICI combinations are under evaluation. - HER2+ BC: Rationale from TILs/PD-L1 prevalence and immune-mediated mechanisms of trastuzumab. PANACEA showed limited activity (ORR 15%) confined to PD-L1–positive tumors. IMpassion050 (neoadjuvant) failed to improve pCR and had unfavorable risk–benefit. KATE2 (T-DM1±atezolizumab) was negative in ITT but suggested PFS benefit in PD-L1–positive subgroup; confirmatory trials (KATE3, ASTEFANIA) are ongoing.

Narrative, non-systematic review synthesizing clinical trial data (phase I–III), translational insights on tumor immune microenvironment and resistance mechanisms, and ongoing trial landscapes across BC subtypes (TNBC, HR+/HER2−, HER2+). The review integrates efficacy, safety, and biomarker findings from published studies and conference reports to outline current standards, investigational combinations, and clinical gaps. No formal systematic search or meta-analytic methods are described.

- Metastatic TNBC, ICI monotherapy: ORR ~5–20%; mPFS ~1–2 months; outcomes worse with more prior lines; PD-L1 expression correlates with benefit. - Metastatic TNBC, first-line chemo-ICI: - KEYNOTE-355 (pembrolizumab+chemo): In PD-L1 CPS≥10, mOS 23 vs 16 months (HR 0.73; 95% CI 0.55–0.95; p=0.0185); mPFS 10 vs 6 months; established new standard for PD-L1–positive disease. - IMpassion130 (atezolizumab+nab-paclitaxel): ITT OS not statistically significant; exploratory PD-L1+ analysis suggested mOS 25.4 vs 17.9 months (HR 0.67; 95% CI 0.53–0.86). - IMpassion131 (atezolizumab+paclitaxel): Negative for PFS benefit in PD-L1–positive population. - Early TNBC, neoadjuvant chemo-ICI: - Meta-analysis of 5 trials (n=1496): higher pCR with ICI addition (OR 1.72; 95% CI 1.22–2.42). - KEYNOTE-522: 3-year EFS 84.5% vs 76.8%, benefit regardless of PD-L1; pCR increase ~7.5%. - Safety of 5-drug regimens: grade≥3 TRAEs ~77% vs 73%; immune-mediated grade≥3 ~13% vs 1%. - ADC+ICI combinations in TNBC: Early-phase ORRs promising (ladiratuzumab vedotin+pembrolizumab ORR ~54%; T-DXd+durvalumab ORR ~67%) with manageable safety to warrant further study. - Targeted therapies with ICIs in TNBC: MEK inhibitor (cobimetinib) and HDAC inhibitor (entinostat) combinations failed in unselected populations; PARPi+ICI (TOPACIO, MEDIOLA) showed activity similar to PARPi monotherapy. - Special metastatic TNBC populations: Maintenance durvalumab in SAFIR02-BREAST IMMUNO was negative overall but improved OS in an exploratory TNBC subgroup; efficacy of ICIs in early relapsing metastatic disease (DFI ≤12 months) under investigation in IMpassion132. - Early TNBC, novel combinations: Anti-VEGF TKIs with ICIs under evaluation; neoadjuvant sacituzumab govitecan+pembrolizumab showed ORR ~30% in phase II NeoSTAR; RT+ICI (PEARL) yielded pCR ~56% with reduced chemotherapy intensity. - Post-neoadjuvant TNBC: Need to define ICI continuation and integration with capecitabine/olaparib; trials ongoing including ADC±ICI escalation after residual disease. - HR+/HER2− BC: - Metastatic: ICI mono or chemo-ICI in unselected endocrine-resistant disease has low efficacy (ORR 0–3%; mPFS <3 months); PD-L1–selected cohorts show modest ORR (~12%). Maintenance durvalumab was negative overall; exploratory CD274 amplification associated with prolonged survival in a few cases. - Early: I-SPY2 showed pCR improvement with pembrolizumab+NACT (30% vs 13%). Durvalumab+olaparib+NACT improved estimated pCR (overall and selectively in MammaPrint MP2: 64% vs 22%). CDK4/6i+ICI combinations faced safety issues. - HER2+ BC: - PANACEA (trastuzumab+pembrolizumab): ORR 15%, activity confined to PD-L1–positive; higher TILs associated with better outcomes. - IMpassion050 (neoadjuvant): No pCR benefit; unfavorable risk–benefit; EFS benefit cannot be excluded; APTneo will address EFS. - KATE2 (T-DM1±atezolizumab): Primary PFS negative in ITT; PD-L1+ subgroup mPFS 8.5 vs 4.1 months (HR 0.60; 95% CI 0.32–1.11); no OS difference. Confirmatory trials (KATE3; ASTEFANIA) ongoing. - Biomarkers and endpoints: PD-L1 assays are heterogeneous; TILs prognostic and predictive in some contexts; ctDNA dynamics correlate with recurrence risk after NACT; need composite endpoints (e.g., residual cancer burden, ctDNA clearance) beyond pCR to capture ICI effects.

The evidence establishes ICIs as integral to TNBC management upfront: in metastatic disease for PD-L1–positive tumors combined with chemotherapy, and in early-stage disease in the neoadjuvant setting, where survival benefits exceed what pCR gains alone would predict. Negative trials underscore the importance of context: chemo backbone, steroid exposure, prior therapies, and patient selection materially influence outcomes. To expand benefit and overcome resistance, rational combinations are required—targeting immune checkpoints beyond PD-1/PD-L1, modulating the TME (e.g., TAMs), integrating ADCs and PARP inhibitors, and leveraging locoregional therapies to enhance immunogenicity. Outside TNBC, HR+/HER2− and HER2+ subtypes show limited but context-dependent signals, particularly in early high-risk disease and PD-L1–positive HER2+ subsets, supporting continued exploration with precise biomarker-driven strategies. Broadly, heterogeneity in PD-L1 testing and the imperfect surrogacy of pCR necessitate better biomarkers (e.g., TILs, ctDNA, immunograms) and validated composite endpoints to guide escalation/de-escalation and accelerate development.

ICIs have reshaped the TNBC treatment landscape, improving OS in PD-L1–positive metastatic first-line therapy and EFS in early-stage neoadjuvant regimens. Maximizing and extending benefit requires refined biomarkers to select responders and rational combinations—particularly ADC+ICI escalation—balanced against toxicity. For HR+/HER2− and HER2+ BC, early settings and selected biomarker-defined subgroups offer the most promise, while CAR-T cells and therapeutic vaccines represent innovative avenues. Future progress will depend on standardizing biomarker assays, integrating dynamic measures like ctDNA, and validating composite surrogate endpoints aligned with the kinetics of immunotherapy.

- The review is narrative and not based on a systematic search; potential selection bias of included studies. - Heterogeneity across trials in PD-L1 assays, thresholds, and scoring (CPS vs IC) complicates cross-study comparisons and patient selection. - Limited evidence for ICI efficacy in early-relapsing metastatic TNBC (DFI ≤12 months) and for retreatment after prior ICI exposure in early-stage settings. - Optimal chemotherapy backbone with ICIs (role of platinum, dose-dense AC) remains uncertain; stage I TNBC not addressed in pivotal trials. - Safety and long-term outcomes of ADC+ICI combinations need further definition; on-target/off-tumor risks for CAR-T in solid tumors persist. - pCR is an imperfect trial-level surrogate for EFS/OS in the ICI era; need for validated composite endpoints (RCB, ctDNA clearance, immune biomarkers).