28P Rational Thresholding of Circulating Tumor DNA Copy Number for Early Detection of Disease Progression in Advanced Metastatic Breast Cancer

Circulating tumor DNA (ctDNA) is promising as tumor-specific marker for progression surveillance in metastatic cancer. Our aim was to investigate the diagnostic power of ctDNA level for disease progression in metastatic breast cancer and to propose rationally selected ctDNA level thresholds with clinical validity. This prospective single-center observational study conducted from July 1, 2019 to December 1, 2021, recruited 136 subjects with metastatic breast cancer for sequencing of their primary tumor in search of PIKC3A variants amenable for monitoring by droplet digital PCR. This interim analysis reports on 265 on-treatment samples from 19 subjects with PIK3CA variants H1047R or E545K. Subjects were sampled every 3-5 weeks with median follow-up of 85 (13-125) weeks and median of 14 (2-29) ctDNA time points per subject. The primary outcome was progression free survival. ROC analysis and logistic regression was performed to investigate the diagnostic power of quantitative ctDNA analysis and CA15-3 to predict progression within 12 weeks from each sampling time point. Likelihood ratios were used for rational selection of ctDNA result intervals. ctDNA level (AUC: 0.856; 95% CI 0.807-0.897)) outperformed CA15-3 (AUC: 0.737; 95% CI 0.663-0.801, P<0.001) to predict progression within 12 weeks. ctDNA level below 10 mutant copies/mL were reassuring while levels above 100 copies/mL predicted 64% of progressions earlier with median (IQR) lead time of 10 (8-20) weeks versus standard of care. Logistic regression analysis indicated complementary value of ctDNA level and the presence of two consecutive rises of CA15-3, resulting in a derived risk score with AUC of 0.908 (95% CI 0.854-0.947). A risk score < 0.15 and > 0.25 achieved 93% (95%CI 87%-96%) and 82% (95% CI 71%-90%) negative and positive predictive values respectively, resulting in a clinically informative result in 89% of blood draws. Intensive quantitative ctDNA monitoring shows clinical validity for improved surveillance of disease progression in metastatic breast cancer and has potential for risk-informed scheduling of standard clinical care.