Pathologic complete response (pCR) rates for patients with HR+/HER2− high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial

Background: 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. Patients and methods: 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. Results: 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. Conclusions: 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.