Role of plasma circulating HER2/EFTUD2 ratio in predicting pathological complete response (pCR) after neoadjuvant dual anti-HER2 therapy in HER2-positive breast cancer (HER2+ BC).

person Jeffrey CH Chan Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, Hong Kong info_outline Jeffrey CH Chan, William CS Cho, James CH Chow, Kelvin K H Bao, Alex KC Leung, Michelle OY Szeto, Connie HM Ho, Harry HY Yiu

Authors person Jeffrey CH Chan Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, Hong Kong info_outline Jeffrey CH Chan, William CS Cho, James CH Chow, Kelvin K H Bao, Alex KC Leung, Michelle OY Szeto, Connie HM Ho, Harry HY Yiu Organizations Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, Hong Kong, Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, Hong Kong, Hong Kong, Departments of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, Hong Kong, Queen Elizabeth Hospital, Kowloon, Hong Kong, Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, Hong Kong Abstract Disclosures Research Funding No funding received None. Background: Achieving pCR following neoadjuvant chemo and anti-HER2 therapy is associated with a significantly better survival in HER2+ BC. There is currently a lack of a robust biomarker to predict pCR in HER2+ BC. Using EFTUD2 as chromosome 17 reference probe, circulating HER2/EFTUD2 plasma DNA copy number ratio (H-ratio) detected by droplet digital PCR (ddPCR) was shown to have high concordance with the tumor HER2 status. We aim to evaluate whether the change in H-ratio is associated with response to neoadjuvant dual anti-HER2 therapy. Methods: We prospectively recruited patients with HER2+ BC who received neoadjuvant taxane, trastuzumab and pertuzumab followed by radical surgery from May 2019 to April 2022. Serial plasma samples (n = 49) were collected at pre-treatment (Tpre), at 4th cycle (Tmid) and at completion of neoadjuvant treatment (Tpost). H-ratio was determined in each plasma sample using droplet ddPCR (QX200 ddPCR system, Bio-rad). H-ratio responders were defined as patients having a declining Tpost H-ratio, whereas patients having a rising or persistent Tpost H-ratio were defined as H-ratio non-responders. The relationship between pCR, H-ratio and various clinicopathological characteristics were evaluated by Spearman’s correlation, Fisher’s exact test and Wilcoxon signed-rank test. Results: Eighteen clinical stage II or III HER2+ BC patients with a median age of 56 years old (range 33 - 71) were included. The median H-ratio at Tpre, Tmid and Tpost were 1.27, 1.12 and 1.10, respectively. Higher Tpre H-ratio was significantly associated with larger tumor size (p = 0.004) and higher tumor grade (G1-2 vs G3; median H-ratio 1.15 vs 1.78; p = 0.024). Six patients (33.3%) were H-ratio responders. Ten (55.6%) of 18 patients achieved pCR after completion of neoadjuvant treatment. The pCR rate in H-ratio responders was significantly higher than the H-ratio non-responders (100% vs. 36.4%; p = 0.017). In predicting pCR, H-ratio response outperformed hormonal receptor (HR) negativity (HR- vs HR+; 72.7% vs 28.6%; p = 0.088) or high tumor grade (G1-2 vs G3; 66.7% vs 33.3%; p = 0.201). There was no association between pCR and Tpre/Tmid/Tpost H-ratio. With a median follow up of 22.8 months (range 8.2 - 41.8), there were no relapse or death. Conclusions: A high pre-treatment plasma circulating HER2/EFTUD2 ratio is associated with large tumor size and high tumor grade in HER2+ BC. The decline of HER2/EFTUD2 ratio after neoadjuvant dual anti-HER2 therapy predicts pCR, and may serve as a potential biomarker for treatment de-escalation.