Purpose: Immunotherapies targeting PD-1/L1 enhance pathologic
complete response (pCR) rates when added to standard neoadjuvant
chemotherapy (NAC) regimens in early-stage triple-negative, and
possibly high-risk estrogen receptor–positive breast cancer. However,
immunotherapyhas been associatedwith significant toxicity, andmost
patients treated with NAC do not require immunotherapy to achieve
pCR. Biomarkers discerning patients benefitting from the addition of
immunotherapy fromthosewhowould achieve pCRtoNACalone are
clearly needed. In this study,we tested the ability ofMHC-II expression
on tumor cells, to predict immunotherapy-specific benefit in the
neoadjuvant breast cancer setting.
Patients and Methods: This was a retrospective tissue-based
analysis of 3 cohorts of patients with breast cancer: (i) primary
nonimmunotherapy-treated breast cancers (n ¼ 381), (ii) triplenegative
breast cancers (TNBC) treated with durvalumab and
standard NAC (n ¼ 48), and (iii) HER2-negative patients treated
with standard NAC (n¼87) or NAC and pembrolizumab (n¼66).
Results:HLA-DRpositivity on≥5% of tumor cells, definedapriori,
was observed in 10% and 15% of primary non-immunotherapy–
treated hormone receptor–positive and triple-negative breast cancers,
respectively. Quantitative assessment of MHC-II on tumor cells was
predictive of durvalumabþ NAC and pembrolizumabþ NAC (ROC
AUC, 0.71; P ¼ 0.01 and AUC, 0.73; P ¼ 0.001, respectively), but not
NAC alone (AUC, 0.5; P ¼ 0.99).
Conclusions: Tumor-specific MHC-II has a strong candidacy as
a specific biomarker of anti–PD-1/L1 immunotherapy benefit when
added to standard NAC in HER2-negative breast cancer. Combined
with previous studies in melanoma, MHC-II has the potential to be a
pan-cancer biomarker. Validation is warranted in existing and
future phase II/III clinical trials in this setting.

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