Abstract 3138: Changes in tumor cell-free DNA copy number instability (CNI) predict therapeutic response in metastatic cancers

Abstract

Background: Tumor cell-free DNA (cfDNA) has the potential to provide minimally invasive patient specific biomarkers to monitor tumor burden. Gains and losses of chromosomal regions - as a hallmark of cancer - have been detected in plasma as copy number aberrations (CNAs), and for several cancers a relation to tumor size has been reported. Longitudinal observations during anti-cancer therapy have been mostly anecdotal. We measured CNAs changes during treatment by computing a genomic copy number instability index (CNI) of cfDNA to evaluate its potential to predict cytotoxic chemotherapy (chemo) response. Methods: 24 patients (pts) with advanced esophageal cancer (EC; n = 2), colorectal cancer (CRC; n = 3), non-Hodgkin lymphoma (NHL; n = 3), pancreatic ductal adenocarcinomas (PDAC; n = 4), and non-small cell lung cancer (NSCLC; n = 12) were included and assessable for response. DNA was extracted from pre-treatment plasma samples at baseline and sequentially for up to six cycles of chemotherapy. Copy-numbers were called from shotgun sequencing (Illumina) after mapping and quality filtering reads were counted in 5.5MBp windows (sliding) yielding a read coverage of 24,000-fold per bin. The read counts were transformed into log2 ratios and converted into a score based on Gaussian transformations. Concentration of total cfDNA was determined by digital PCR. Treatment response by imaging was recorded by RECIST 1.1 or EORTC PET/CT criteria. For pts with baseline CNI>40 (representing the 99.99% level for non-cancer healthy controls), CNI change was considered predictive of response or stable disease when there was a reduction of CNI ≥50% relative to baseline. Disease progression was demonstrated when: 1) CNI was ≥50% over nadir and <80% reduction relative to baseline; OR, 2) CNI was ≥5 fold the nadir; OR, 3) CNI demonstrated an absolute increase by 1,000 above baseline CNI. For pts with baseline CNI≤40, CNI change was considered predictive of response or stable disease when CNI remained ≤40, and PD when CNI≥2X above the baseline CNI. CNI was an early predictor of response if these results were observed by ∼3-8 weeks prior to imaging or a major change in pt's clinical status. Results: CNI was measured in 124 samples. Median baseline cfDNA was 7,238 cp/mL (range 2,319-91,978) and CNI was 171 (range 26-10,170). In general, NHL and tumors with high lymph node disease burden had highest baseline cfDNA and CNI, whereas overall the CNI was not correlated to the cfDNA content. 22 of 24 pts (91.7%) had CNI changes that were predictive of treatment response. For at least 15 pts, CNI change predicted response ∼3-8 weeks prior to scan results demonstrating response or PD. Conclusions: CNI change may serve as predictor (potentially early predictor) of therapeutic response to standard chemo for the investigated cancer types. Highest baseline cfDNA and CNI appear to be present in lymph node predominant disease, suggesting more readily shed DNA into the circulation. Citation Format: Glen J. Weiss, Julia Beck, Donald P. Braun, Kirsten Bornemann-Kolatzki, Heather Barilla, Rhiannon Cubello, Ashish Sangal, Robert P. Whitehead, Madappa Kundranda, Vivek Khemka, Howard B. Urnovitz, Ekkehard Schutz. Changes in tumor cell-free DNA copy number instability (CNI) predict therapeutic response in metastatic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3138.

Tumor Cell–Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

“…If the measured CNI score does not decrease substantially, the chance of progression is over 90% in our validation group. We have seen similar effects for cytotoxic chemotherapy (24). These data justify prospective studies in specific cancer cohorts with defined approved treatment to validate the apparent universality of the CNI method for quantifying chromosomal instability.…”

Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients

“…To date, cfDNA derived CNA and CIN have been used to investigate response to treatment in in metastatic disease. For example, Weiss et al 32 showed that changes in cfDNA copy number instability (CNI) score could predict standard of care chemotherapy response in metastatic cancer. Here, we firstly assessed mCRC cfDNA samples for the ability to detect CNAs, and showed that CIN patterns from cfDNA reflected those from matched tumor samples, thus confirming the potential of plasma analysis for mCRC CIN subtyping.…”

Analysis of Cell-Free DNA to Predict Outcome to Bevacizumab Combination Therapy in Metastatic Colorectal Cancer Patients

“…To date, CNA and CIN have been used to investigate response to treatment in cfDNA in metastatic disease. Weiss et al 33 showed that changes in cfDNA copy number instability (CNI) score could predict therapeutic response in 24 metastatic cancer patients including mCRC. Overall, it was suggested that CIN changes might represent an early predictor of therapeutic response to standard chemotherapy.…”