Immune Subtyping Identifies Patients With Hormone Receptor-Positive Early-Stage Breast Cancer Who Respond to Neoadjuvant Immunotherapy (IO): Results From Five IO Arms of the I-SPY2 Trial

Abstract

Purpose: Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+HER2-) patients from five IO arms.

Methods: A total of 204 HR+HER2- (MammaPrint high-risk) patients from five IO arms (anti-PD-1, anti-PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti-PD-1/toll-like receptor 9 dual-IO combination, and anti-PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint- (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%).

Results: Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2- patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint-, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint-. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5).

Conclusion: Using an accurate selection strategy, HR+HER2- patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2- patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

Trial registration: ClinicalTrials.gov NCT01042379.

FIG 1.

Trial design and data. (A) I-SPY2 trial schematic, (B) patients per arm in this analysis, (C) development of the IO response prediction clinical biomarker ImPrint. AC, doxorubicin/cyclophosphamide; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IDE, investigational device exemption; IO, immunotherapy; LAG3, lymphocyte activation gene 3; MP, MammaPrint; pCR, pathologic complete response; RPS, response predictive subtypes.

FIG 2.

Prevalence and performance of ImPrint for HR+HER2–. (A) Sankey diagram showing prevalence of ImPrint+ versus ImPrint– in HR+HER2– in I-SPY2. (B-D) pCR bar plots in unselected HR+HER2– (B) versus in ImPrint– (C) and ImPrint+ (D) in the IO arm used as a training set (pembro). (E -G) pCR bar plots in unselected HR+HER2– (E) versus in ImPrint– (F) and ImPrint+ (G) in the four IO arms used as independent validation sets (durvalumab/olaparib, pembrolizumab/SD101, cemiplimab, and cemiplimab/LAG3). HR+HER2–, hormone receptor–positive and human epidermal growth factor receptor 2–negative; IO, immunotherapy; LAG3, lymphocyte activation gene 3; pCR, pathologic complete response.

FIG 3.

ImPrint performance variations by IO arm and comparison with control. (A) Bar plots showing pCR rates by arm in ImPrint– and ImPrint+ subsets. (B) pCR rate bar plots in all five IO arms together versus control in ImPrint– and ImPrint+ subsets. IO, immunotherapy; LAG3, lymphocyte activation gene 3; pCR, pathologic complete response.

FIG 4.

Prevalence and IO response prediction performance of tumor grade, MP1/MP2 and ER-low. (A) Sankey diagram showing prevalence of tumor grade I, II, and II tumors in HR+HER2– in I-SPY2. (B) pCR rate bar plots in all five IO arms together versus control within grade I/II and grade III subsets. (C) Sankey diagram showing prevalence of MP1 versus MP2 class tumors. (D) pCR rate bar plots in all five IO arms together versus control within MP1 and MP2. (E) Sankey diagram showing prevalence of ER-low (ER ≤ 10%) versus other (ER > 10%) tumors. (F) pCR rate bar plots in all five IO arms together versus control within ER-low and ER > 10% tumors. ER, estrogen receptor; HR+HER2–, hormone receptor–positive and human epidermal growth factor receptor 2–negative; IO, immunotherapy; MP1, MammaPrint High 1 risk; MP2, MammaPrint (ultra) High2 risk; pCR, pathologic complete response.

FIG A1.

Tumor clinical and molecular features associated with ImPrint status in the HR+HER2– subset in I-SPY2. (A-D) Mosaic plots showing the distribution of tumor grade (A), MP1/2 class (B), tumor stage (C), and % ER+ cells (D) in ImPrint– versus ImPrint+ subsets (P values from Fisher's exact tests). (E) Box plot showing tumor LD by MR in ImPrint– versus ImPrint+ subsets (P value from a t test). Boxes show median and 25th-75th IQR. Whiskers denote largest/smallest values within 1.5× the IQR. ER, estrogen receptor; HR+HER2–, hormone receptor–positive and human epidermal growth factor receptor 2–negative; LD, longest diameter; MP1, MammaPrint High 1 risk; MP2, MammaPrint (ultra) High2 risk; MR, magnetic resonance (imaging).

FIG A2.

Tumor grade III and MP2 as a predictor of pCR for IO in HR+HER2–. (A and B) Bar plot showing pCR rates in tumor grade III versus grade I/II in the combined five IO arms (A) and within each IO arm (B). (C and D) Bar plot showing pCR rates in MP1/2 class in the combined five IO arms (C) and within each IO arm (D). (E) Tables showing tumor grade versus response (top) and MP1/2 class versus response (bottom) (data for [A] and [D]). (F) Mosaic plot showing pCR as a function of PD-L1-positivity in the pembrolizumab arm by mIF analysis (PD-L1+: %PD-L1+ tumor cells >1%). HR+HER2–, hormone receptor–positive and human epidermal growth factor receptor 2–negative; IO, immunotherapy; LAG3, lymphocyte activation gene 3; mIF, multiplex immunofluorescence; MP1, MammaPrint High 1 risk; MP2, MammaPrint (ultra) High2 risk; pCR, pathologic complete response.