590P - Assessment of circulating tumor (ct)DNA in patients (pts) with locally advanced rectal cancer (LARC) pts treated with neoadjuvant therapy (NAT)

Background

Approximately 30% of colorectal cancers arise from the rectum with surgical resection being the mainstay of treatment. For rectal cancers with high-risk pathological features or cases of LARC, preoperative NAT followed by total mesorectal excision +/- adjuvant therapy is recommended. However, this paradigm is associated with questionable survival benefits and high morbidity. Post-NAT and post-surgical risk stratification using ctDNA may help predict outcomes in LARC pts.

Methods

Plasma samples (n=90) from pts with LARC (N=30, median age: 67 years) were analyzed retrospectively. A tumor-informed assay (Signatera™) was used to quantify ctDNA pre-NAT, post-NAT, and post-surgery. Neoadjuvant rectal (NAR) score was calculated and compared to ctDNA status to predict recurrence risk and survival outcomes.

Results

At the pre-NAT time point, ctDNA detection rate was 90% (27/30). Pts who were ctDNA-positive either post-NAT (N=5) or post-surgery (N=3) had worse recurrence-free survival (RFS) (HR 8.4, 95%CI: 2.3-30, p<0.001 and HR 14, 95%CI: 3.1-66, p<0.001, respectively), when compared to ctDNA-negative pts. Similarly, pts with a high NAR score exhibited an inferior RFS when compared to those with a low-risk score (HR: 21, 95%CI: 2.6-2731, p=0.001). When utilized in combination with ctDNA status in the post-NAT setting, ctDNA-positive with an intermediate-high NAR score exhibited an inferior RFS compared to ctDNA-negative pts with a low NAR score (HR 33.5, 95%CI: 3.7-4419, p<0.001) with 100% recurrence rate. Likewise, post-surgery, ctDNA-positive pts with an intermediate-high NAR score exhibited an inferior RFS, with a recurrence rate of 37.5%, when compared to ctDNA-negative pts with a low NAR score, none of whom recurred (HR 75, 95%CI: 2.6-4916, p<0.001). In multivariate analysis, ctDNA status post-surgery (p=0.039) and pathological nodal status (p=0.033) were the most significant risk factors associated with recurrence.

Conclusions

Post-treatment ctDNA status either as a sole surrogate outcome measure or as an adjunct to the NAR score may predict NAT response, improve risk stratification and potentially improve outcomes in LARC pts.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

G. Laliotis, E. Spickard: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks/Shares: Natera, Inc. G.V. George: Financial Interests, Personal, Financially compensated role: Natera, Inc.. S. Sharma, A. Jurdi, H. Sethi: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks or ownership: Natera, Inc. M.C. Liu: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks/Shares: Natera, Inc.; Financial Interests, Institutional, Research Grant: Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Financial Interests, Personal, Other: AstraZeneca, Genomic Health, Ionis; Financial Interests, Institutional, Advisory Board: AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax. G. Martinelli: Financial Interests, Institutional, Research Funding: Novartis, Bristol Myers Squibb, Amgen, AIRC, AIL, Genzyme, Celgene; Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Bristol Myers Squibb, Amgen, AIRC, AIL, Genzyme, Celgene, Ariad Pharma, Roche; Financial Interests, Personal, Speaker’s Bureau: Novartis, Bristol Myers Squibb, Amgen, AIRC, AIL, Pfizer, Genzyme, Celgene Arida GSK; Financial Interests, Personal, Other: Novartis, Bristol Myers Squibb, Amgen, AIRC, AIL, Pfizer, Genzyme, Celgene Arida GSK. All other authors have declared no conflicts of interest.