Publication: 19th SGBCC 2025-P201
Authors: Laila Samiian, Adam Brufsky, Sahra Uygun, Isha Kapoor, Victoria Poillucci, Joyce OโShaughnessy, 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:
โข Clinical HER2+ (cHER2+) early-stage breast cancer (EBC) accounts for 15-20% of invasive EBC cases1.
โข Neoadjuvant HER2-targeted therapy (NHT) combined with chemotherapy is the standard treatment for HER2+ EBC, regardless of ER status2.
โข NBRST3 and I-SPY24 trials showed varying NHT responses in cHER2+ tumors based on genomic molecular subtypes, emphasizing the need to understand tumor biology.
โข The heterogeneity within cHER2+ tumors can be distinguished based on molecular subtyping, which provides insights into the molecular biology of the tumor.
โข 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:
โข 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).
โข 353 patients received NHT and among these patients, 183 (51.8%) had Pertuzumab + Trastuzumab treatment.
โข Patients were stratified into MP UltraLow, Low, High 1, or High 2 Risk groups, while BP categorized them as Luminal, HER2, or Basal.
โข 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 Fisherโs exact tests and proportional Z-test, respectively.
Results:
โข 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).
โข BP further classified 46% as Luminal A/B, 48% as HER2, and 6% as Basal (Figure 1).
โข 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).
โข Nodal involvement was more common in BP HER2 (37.8%) and Basal tumors (Table 1).
โข 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).
โข pCR rates were significantly higher in BP HER2 tumors (61.2%) in HR+HER2+ subset compared to BP Luminal (26.5%) (Figure 3).
Conclusions:
โข MP and BP further classified cHER2+ tumors into distinct subtypes and BP identified the HER2 subtype as the most responsive to NHT.
โข 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.
โข 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.