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

L A Huppert; D Wolf; C Yau; L Brown-Swigart; G L Hirst; C Isaacs; L Pusztai; P R Pohlmann; A DeMichele; R Shatsky; D Yee; A Thomas; R Nanda; J Perlmutter; D Heditsian; N Hylton; F Symmans; L J Van't Veer; L Esserman; H S Rugo

doi:10.1016/j.annonc.2024.10.018

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

Ann Oncol. 2024 Oct 28:S0923-7534(24)04070-5. doi: 10.1016/j.annonc.2024.10.018. Online ahead of print.

Authors

L A Huppert¹, D Wolf², C Yau³, L Brown-Swigart², G L Hirst³, C Isaacs⁴, L Pusztai⁵, P R Pohlmann⁶, A DeMichele⁷, R Shatsky⁸, D Yee⁹, A Thomas¹⁰, R Nanda¹¹, J Perlmutter¹², D Heditsian¹², N Hylton¹³, F Symmans¹⁴, L J Van't Veer², L Esserman¹⁵, H S Rugo¹⁶

Affiliations

¹ Department of Medicine, University of California San Francisco, San Francisco, USA. Electronic address: Laura.huppert@ucsf.edu.
² Department of Laboratory Medicine, University of California San Francisco, San Francisco, USA.
³ Department of Surgery, University of California San Francisco, San Francisco, USA.
⁴ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, USA.
⁵ Yale School of Medicine, Yale University, New Haven, USA.
⁶ Department of Breast Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, USA.
⁷ Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
⁸ Division of Hematology/Oncology, University of California San Diego, San Diego, USA.
⁹ Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, USA.
¹⁰ Division of Hematology/Oncology, Duke Cancer Center, Durham, USA.
¹¹ Section of Hematology/Oncology, University of Chicago, Chicago, USA.
¹² I-SPY2 Research Advocate, Ann Arbor, USA.
¹³ Department of Radiology, University of California San Francisco, San Francisco, USA.
¹⁴ Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, USA.
¹⁵ Department of Laboratory Medicine, University of California San Francisco, San Francisco, USA. Electronic address: https://twitter.com/DrLauraEsserman.
¹⁶ Department of Medicine, University of California San Francisco, San Francisco, USA. Electronic address: https://twitter.com/hoperugo.

PMID: 39477071
DOI: 10.1016/j.annonc.2024.10.018

Abstract

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.

Keywords: MammaPrint; basal; intrinsic subtype; luminal; molecular subtype; neoadjuvant therapy.