Wolf Denise M, Yau Christina, Campbell Michael, Glas Annuska, Barcaru Andrei, Mittempergher Lorenza, Kuilman Midas, Brown-Swigart Lamorna, Hirst Gillian, Basu Amrita, Magbanua Mark, Sayaman Rosalyn, Huppert Laura, Delson Amy, Symmans W Fraser, Borowsky Alexander, Pohlmann Paula, Rugo Hope, Clark Amy, Yee Douglas, DeMichele Angela, Perlmutter Jane, Petricoin Emmanuel F, Chien Jo, Stringer-Reasor Erica, Shatsky Rebecca, Liu Minetta, Han Hyo, Soliman Hatem, Isaacs Claudine, Nanda Rita, Hylton Nola, Pusztai Lajos, Esserman Laura, van 't Veer Laura
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA.
Department of Surgery, University of California San Francisco, San Francisco, CA.
JCO Precis Oncol. 2025 Jun;9:e2400776. doi: 10.1200/PO-24-00776. Epub 2025 Jun 17.
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.
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%).
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).
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.
新辅助免疫疗法（IO）已成为早期三阴性乳腺癌（TNBC）的标准治疗方法，但尚未用于其他亚型。我们之前开发了一种基于临床级mRNA的免疫分类器（ImPrint），用于预测对IO的反应，该分类器目前在I-SPY2.2中作为反应预测亚型的一部分使用。我们报告了ImPrint在来自五个IO治疗组的激素受体阳性和人表皮生长因子受体2阴性（HR+HER2-）患者中的表现。
本分析纳入了来自五个IO治疗组（抗PD-1、抗PD-L1/聚[ADP-核糖]聚合酶抑制剂联合治疗、抗PD-1/ toll样受体9双重IO联合治疗以及抗PD-1±淋巴细胞激活基因3双重IO联合治疗）的204例HR+HER2-（MammaPrint高风险）患者和来自单纯化疗对照组的191例患者。使用治疗前的mRNA将患者分为ImPrint+（可能敏感）和ImPrint-（可能耐药）。对ImPrint预测含IO治疗组病理完全缓解（pCR）的性能进行了表征，并与肿瘤分级（III级）、MammaPrint（超）高风险2（MP2）和雌激素受体（ER）低表达（ER≤10%）进行了比较。
总体而言，五个IO治疗组的pCR率为33%。26%的HR+HER2-患者为ImPrint+，ImPrint+患者接受IO治疗的pCR率为75%，而ImPrint-患者为17%，在一个双重IO治疗组中pCR率最高>90%。在对照组中，ImPrint+患者的pCR率为33%，ImPrint-患者为8%。肿瘤分级（III级）、MP2和ER低表达患者接受IO治疗的pCR率分别为45%、56%和63%，与ImPrint相比，pCR优势比更低（OR<7.5）（OR=14.5）。
通过准确的选择策略，HR+HER2-患者可以实现与TNBC和HER2+患者最佳新辅助治疗相似的pCR率（即pCR率>65%-70%）。ImPrint是一种获得美国食品药品监督管理局研究性器械豁免（IDE）批准的检测方法，可能代表了一种识别HR+HER2-患者进行IO治疗的方法，这种方法能在可能的获益与严重免疫相关不良事件风险之间实现最佳平衡。
