Publication: 19th SGBCC 2025-P201

Authors: Laila Samiian, Adam Brufsky, Sahra Uygun, Isha Kapoor, Victoria Poillucci, Joyce Oโ€™Shaughnessy, William Audeh

Title: Neoadjuvant HER2-Targeted Therapy Response by BluePrintยฎ Gene Expression-Based Molecular Subtyping in patients with HER2+ Early-Stage Breast Cancer from FLEX

Introduction:

โ€ข Clinical HER2+ (cHER2+) early-stage breast cancer (EBC) accounts for 15-20% of invasive EBC cases1.
โ€ข Neoadjuvant HER2-targeted therapy (NHT) combined with chemotherapy is the standard treatment for HER2+ EBC, regardless of ER status2.
โ€ข NBRST3 and I-SPY24 trials showed varying NHT responses in cHER2+ tumors based on genomic molecular subtypes, emphasizing the need to understand tumor biology.
โ€ข The heterogeneity within cHER2+ tumors can be distinguished based on molecular subtyping, which provides insights into the molecular biology of the tumor.
โ€ข Genomic assays MammaPrintยฎ (MP) and BluePrintยฎ (BP) predict therapy response and inform treatment decisions.

Objective: We evaluated the role of BP in identifying cHER2+ tumors more likely to respond to NHT based on MP and BP classification.

Methods:

โ€ข Patients with IHC/FISH-defined cHER2+ disease (n=940) from FLEX (NCT03053193) were included in this analysis (HR+HER2+ n=720; HR- HER2+ n= 220).

โ€ข 353 patients received NHT and among these patients, 183 (51.8%) had Pertuzumab + Trastuzumab treatment.
โ€ข Patients were stratified into MP UltraLow, Low, High 1, or High 2 Risk groups, while BP categorized them as Luminal, HER2, or Basal.
โ€ข Differences in clinical characteristics across BP subtypes and pathological complete response (pCR) rates for Pertuzumab + Trastuzumab treated BP Luminal and HER2 tumors were assessed using Chi-Square or Fisherโ€™s exact tests and proportional Z-test, respectively.

Results:

โ€ข MP classification of cHER2+ tumors (HR+HER2+ and HR-HER2+): 2% UltraLow, 11.6% Low, 45.8% High 1 and 40.5% High 2 (Figure 1).
โ€ข BP further classified 46% as Luminal A/B, 48% as HER2, and 6% as Basal (Figure 1).
โ€ข HR-HER2+ patients with BP HER2 tumors were younger, premenopausal, and had larger tumors compared to patients with Luminal-subtype (T3: 10.6% vs. 3.4%) (Table 1).
โ€ข Nodal involvement was more common in BP HER2 (37.8%) and Basal tumors (Table 1).
โ€ข Regardless of ER status, BP HER2 tumors (69.6%) achieved significantly higher pCR rate than BP Luminal (26.5%) in the cHER2+ tumors subset (Figure 2).
โ€ข pCR rates were significantly higher in BP HER2 tumors (61.2%) in HR+HER2+ subset compared to BP Luminal (26.5%) (Figure 3).

Conclusions:

โ€ข MP and BP further classified cHER2+ tumors into distinct subtypes and BP identified the HER2 subtype as the most responsive to NHT.
โ€ข Consistent with ISPY2, BP HER2 tumors showed significantly higher pCR rates than BP Luminal, suggesting that additional therapeutic strategies are needed to increase the pCR rates in Luminal cancers.
โ€ข Prognostic value of pCR vs no pCR may be different by subtype, and follow-up for outcomes such as DMFS and DMFI is a future goal within the FLEX trial.