Huppert L A, Wolf D, Yau C, Brown-Swigart L, Hirst G L, Isaacs C, Pusztai L, Pohlmann P R, DeMichele A, Shatsky R, Yee D, Thomas A, Nanda R, Perlmutter J, Heditsian D, Hylton N, Symmans F, Van't Veer L J, Esserman L, Rugo H S
Department of Medicine, University of California San Francisco, San Francisco, USA.
Department of Laboratory Medicine, University of California San Francisco, San Francisco, USA.
Ann Oncol. 2025 Feb;36(2):172-184. doi: 10.1016/j.annonc.2024.10.018. Epub 2024 Oct 28.
Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer (EBC) is a heterogenous disease. Identification of better clinical and molecular biomarkers is essential to guide optimal therapy for each patient.
We analyzed rates of pathologic complete response (pCR) and distant recurrence-free survival (DRFS) for patients with HR+/HER2-negative EBC in eight neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage estrogen receptor (ER) positivity, ER/progesterone receptor status, MammaPrint (MP)-High1 (0 to -0.57) versus MP-High2 (<-0.57), BluePrint (BP)-Luminal-type versus BP-Basal-type, and ImPrint immune signature. We quantified the clinical/molecular heterogeneity, assessed overlap among these biomarkers, and evaluated associations with pCR and DRFS.
Three hundred and seventy-nine patients with HR+/HER2-negative EBC were included in this analysis, with an observed pCR rate of 17% across treatment arms. pCR rates were higher in patients with stage II versus III disease (21% versus 9%, P = 0.0013), ductal versus lobular histology (19% versus 11%, P = 0.049), lower %ER positivity (≤66% versus >66%) (35% versus 9%, P = 3.4E-09), MP-High2 versus MP-High1 disease (31% versus 11%, P = 1.1E-05), BP-Basal-type versus BP-Luminal-type disease (34% versus 10%, P = 1.62E-07), and ImPrint-positive versus -negative disease (38% versus 10%, P = 1.64E-09). Patients with lower %ER were more likely to have MP-High2 and BP-Basal-type disease. At a median follow-up of 4.8 years, patients who achieved pCR had excellent outcomes irrespective of clinical/molecular features. Among patients who did not achieve pCR, DRFS events were more frequent in patients with MP-High2 and BP-Basal-type disease than those with MP-High1 and BP-Luminal-type disease.
Among patients with high molecular-risk HR+/HER2-negative EBC, the MP-High2, BP-Basal-type, and ImPrint-positive signatures identified a partially overlapping subset of patients who were more likely to achieve pCR in response to neoadjuvant chemotherapy ± targeted agents or immunotherapy compared to patients with MP-High1, BP-Luminal-type, and ImPrint-negative disease. I-SPY2.2 is incorporating the use of these biomarkers to molecularly define specific patient populations and optimize treatment selection.
激素受体阳性（HR+）、人表皮生长因子受体2（HER2）阴性的早期乳腺癌（EBC）是一种异质性疾病。识别更好的临床和分子生物标志物对于指导每位患者的最佳治疗至关重要。
我们在I-SPY2试验的8个新辅助治疗组中，根据临床/分子特征分析了HR+/HER2阴性EBC患者的病理完全缓解（pCR）率和远处无复发生存率（DRFS），这些特征包括：年龄、分期、组织学类型、雌激素受体（ER）阳性百分比、ER/孕激素受体状态、MammaPrint（MP）-High1（0至-0.57）与MP-High2（<-0.57）、BluePrint（BP）-管腔型与BP-基底型以及ImPrint免疫特征。我们对临床/分子异质性进行了量化，评估了这些生物标志物之间的重叠情况，并评估了与pCR和DRFS的关联。
本分析纳入了379例HR+/HER2阴性EBC患者，各治疗组的观察到的pCR率为17%。II期疾病患者的pCR率高于III期疾病患者（21%对9%，P = 0.0013），导管组织学类型患者高于小叶组织学类型患者（19%对11%，P = 0.049），ER阳性百分比较低者（≤66%对>66%）（35%对9%，P = 3.4E-09），MP-High2疾病患者高于MP-High1疾病患者（31%对11%，P = 1.1E-05），BP-基底型疾病患者高于BP-管腔型疾病患者（34%对10%，P = 1.62E-07），ImPrint阳性疾病患者高于ImPrint阴性疾病患者（38%对10%，P = 1.64E-09）。ER百分比较低的患者更有可能患有MP-High2和BP-基底型疾病。在中位随访4.8年时，无论临床/分子特征如何，实现pCR的患者都有良好的预后。在未实现pCR的患者中，MP-High2和BP-基底型疾病患者的DRFS事件比MP-High1和BP-管腔型疾病患者更频繁。
在高危分子的HR+/HER2阴性EBC患者中，MP-High2、BP-基底型和ImPrint阳性特征识别出了一部分重叠的患者子集，与MP-High1、BP-管腔型和ImPrint阴性疾病患者相比，这些患者在接受新辅助化疗±靶向药物或免疫治疗时更有可能实现pCR。I-SPY2.2正在纳入使用这些生物标志物来从分子层面定义特定患者群体并优化治疗选择。
