Abstract P6-03-06: Circulating tumor DNA (ctDNA) for detection of molecular residual disease (MoRD) in breast cancer

Abstract

Abstract Background Metastatic breast cancer (BC) is an incurable condition and treated with palliative intent. Standard diagnostic imaging and serum markers have limited sensitivity and are not recommended in clinical practice. Micrometastatic disease in the bone marrow (DTC) and peripheral blood (CTCs) is a recognized prognostic marker but with limited clinical utility. The detection of asymptomatic disease using a sensitive, reproducible and robust blood-based molecular test, or molecular residual disease (MoRD) could potentially represents a tool with the capability to design early therapeutic interventions and improve outcome. Circulating tumor DNA (ctDNA) has the potential to reflect residual tumor burden with higher diagnostic accuracy. We performed a pilot study in patients with high-risk primary BC. Methods This is a prospective study of 30 patients with either locally advanced BC who had completed primary therapy (21 patients) and had no evidence of disease (NED), or were metastatic but treated with curative intent and currently NED or stable (9 patients). Plasma was analyzed for ctDNA either after completing neo-adjuvant therapy (NAT), for recurrence monitoring after surgery, or when there was a clinical suspicion of recurrence. Guardant360™(Guardant Health) is a ctDNA next generation sequencing panel which produces a quantitative measurement of the mutant allele fraction for single nucleotide variants in 54 genes and copy number variants in 3 genes (panel was expanded to 68 genes in Feb '15) using digital sequencing technology. Results Baseline ctDNA analysis was done for 30 patients and 25 (83%) had serial draws for a total of 76 samples. All patients were stage 3-4 except for two stage 2 patients. ctDNA or MoRD was detected in 17 (57%) of patients and in 39 (51%) of the samples. Of the 18 patients treated with NAT, 11 achieved pCR or had minimal residual disease. Of these 11, six had no ctDNA detected after surgery, 3 had mixed results of no ctDNA and low volume ctDNA alterations on different draws, and 2 had persistent mutations on 2 draws. Ten of these 11 patients remain NED with median follow up of 24 months, while the one patient who recurred had persistent low volume missense ctDNA alterations on serial draws, first detected 6 months before clinically evident recurrence. Of the 7 patients with significant residual disease (less than PR) after NAT, 6 had post-surgical ctDNA detected and 5 have recurred at a median of 13 months after surgery. Four of those patients had ctDNA tested prior to recurrence and all had alterations detected in the blood prior to clinical recurrence. Lastly, one HER2+ metastatic patient treated with curative intent with a subsequent negative PET scan and no ctDNA detected after HER2-targeted therapy progressed on CT 2 months later and repeat ctDNA revealed EGFR mutant allele fraction of 51% and ERBB2 amplification. Conclusions The evaluation of ctDNA in high-risk BC patients can identify MoRD and predict for clinical recurrence. Patients with no or low volume ctDNA after primary treatment remained NED longer than those with multiple or high volume alterations. Future studies will validate these early observations and aid in selecting patients for additional systemic therapy with the hope of improving outcome. Citation Format: Austin L, Jaslow R, Fortina P, Nagy R, Zill O, Talasaz A, Cristofanilli M. Circulating tumor DNA (ctDNA) for detection of molecular residual disease (MoRD) in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-06.