Personalized circulating tumor DNA analysis as predictor of efficacy of neoadjuvant therapy in HER2-positive breast cancer: A prospective study (NCT06479460).

e12604 Background: In the neoadjuvant treatment (NAT) setting, dual HER2-targeted therapy is associated with higher rates of pathologic complete response (pCR) compared to each therapy administered individually but with considerable variation between different patients. There is a pressing need for biomarkers that can predict treatment response during NAT. This study aims to evaluate the association between circulating tumor DNA (ctDNA) and response to anti-HER2 targeted therapy. Methods: In this prospective, observational study (ClinicalTrials.gov identifier, NCT06479460), we enrolled patients with HER2-positive early breast cancer who underwent NAT. Serial plasma samples before NAT (T0), at mid-therapy (T1), before surgery (T2), after surgery (T3), and paired pretreatment tumor biopsies were collected. A personalized ctDNA test was designed to detect up to 20 patient-specific mutations (from targeted sequencing of paired pretreatment tumor) by ultra-deep sequencing. Results: A total of 47 patients with HER2-positive early breast cancer were enrolled. At the time of data cutoff (13 January 2025), 31 patients (66%, 31/47) had completed NAT treatment, with 19 patients had achieved pathological complete response (pCR) and 12 did not. The median number of characterized alterations per patient was 7 (range, 1-26 alterations) for tissue samples. At T0, 35 of 47 (75%) patients were ctDNA-positive, which decreased over time (T1: 25%; T2: 4%). Additionally, ctDNA-positive at T0 was associated with greater number of positive lymph nodes ( P = 0.02) but not with any of the other clinical or pathological features analyzed. Interestingly, patients who remained ctDNA-positive at T1 were significantly more likely to have residual disease after NAT (86% non-pCR) compared to those who cleared ctDNA (17% non-pCR; P = 0.003). After NAC, 15 patients who achieved pCR were ctDNA negative (n = 16, 94%). Conclusions: Our study demonstrated that ctDNA can be used to predict tumor response to NAT in HER2-positive early breast cancer, providing information to tailor an individual’s therapeutic regimen. Clinical trial information: NCT06479460 .