Circulating tumor DNA, pathologic response after neoadjuvant therapy, and survival: First results from TBCRC 040 (the PREDICT-DNA trial).

1009 Background: Patients with Stage II/III breast cancer that overexpresses the human epidermal growth factor-2 (HER2+) or is triple-negative (TNBC) generally receive upfront neoadjuvant therapy (NAT) before definitive surgery. Pathologic complete response (pCR) after NAT is associated with improved survival but a small proportion of patients remain at risk for recurrence. Circulating tumor DNA (ctDNA) in patients whose primary tumors have detectable mutations could improve the identification of patients who remain at risk after NAT. Methods: The Pathologic Response Evaluation and Detection In Circulating Tumor-DNA (PREDICT-DNA) trial was a prospective, multi-center study aimed at validating ctDNA as a biomarker for treatment response in Stage II/III HER2+ or TNBC. The primary aim was to determine the negative predictive value (NPV) of ctDNA for residual disease following NAT; secondary aims included five-year invasive disease-free survival (IDFS), which were fit to a Cox proportional hazards model. Mutations were identified from tumor tissue; ctDNA was then analyzed in pre- and post-NAT blood and compared with surgical pathology. Proposed sample size was 229 patients based on simulation to control expected half-width of a confidence interval on NPV to be ≤15% when NPV=90%. The Personalis NeXT Personal ctDNA assay was centrally performed. Results: 228 participants were enrolled in 24 sites between 2016 and 2018. 53% had TNBC, and 47% had HER2+ disease. 92.2% (n=166/180) had detectable ctDNA at baseline, and 46% of patients had pCR (42% TNBC, 50% HER2+). 54% of all post-NAT ctDNA detections were in the ultrasensitive range below 100 PPM. Among 112 subjects with undetectable ctDNA prior to surgery, 45 were found to have residual disease resulting in an NPV of 60% (CI 0.51-0.69). Patients with TNBC and detectable ctDNA prior to surgery were approximately 12 times more likely to experience a recurrence regardless of pCR (HR 12.8 [95% CI: 2.3-71.5]). See Table describing landmark IDFS analyses after surgery. Conclusions: While lack of ctDNA detection after NAT and before surgery did not predict pCR, initial analysis of predefined secondary objectives suggest that ctDNA-negative patients before surgery have excellent prognosis regardless of pCR, particularly if TNBC. This suggests that ctDNA may be a better biomarker for long term clinical outcomes than pCR. Further correlations and interactions will be presented. Clinical trial information: NCT02743910 . Invasive disease-free survival (IDFS) by breast cancer subtype, according to ctDNA after NAT and pathologic response. TNBC (total n=64) 3y IDFS(n=40) 4y IDFS(n=32) 5y IDFS(n=18) ctDNA- & pCR (n=20) 94.1% 94.1% 94.1% ctDNA- & RD (n=25) 95.8% 89.8% 89.8% ctDNA+ & RD (n=19) 48.9% 48.9% 48.9% HER2+ (total n=58) 3y IDFS(n=41) 4y IDFS(n=31) 5y IDFS(n=17) ctDNA- & pCR (n=19) 94.1% 94.1% 94.1% ctDNA- & RD (n=31) 92.6% 87.5% 87.5% ctDNA+ & RD (n=8) 60.0% 60.0% 60.0%