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Prognostic Value of Longitudinal ctDNA Assessment in Oesophageal Cancer

Liquid biopsy findings from a prospective Oesophageal Cancer Classification and Molecular Stratification Consortium study
11 Jan 2021
Gastrointestinal cancers;  Translational research

In a multicentre, prospectively collected study in UK among operable patients with oesophageal cancer, the Oesophageal Cancer Classification and Molecular Stratification (OCCAMS) Consortium investigators demonstrated that the presence of ctDNA in post-operative plasma is strongly associated with cancer recurrence. Dr. Elizabeth Smyth of the Cambridge University Hospitals NHS Foundation Trust, Prof. Rebecca C. Fitzgerald of the University of Cambridge in Cambridge, UK and OCCAMS colleagues wrote on 22 December 2020 in the Annals of Oncology that future research should focus on improving the sensitivity and specificity of ctDNA detection and moving quickly to risk stratifying patients and refining post-operative adjuvant therapies.

The authors wrote in the study background that beyond TNM staging, no reliable risk stratification tools exist in oesophageal cancer and no large-scale studies have profiled ctDNA at relapse. They analyzed the prognostic potential of ctDNA dynamics in oesophageal cancer, taking into account clonal haematopoiesis with indeterminate potential (CHIP).

The aims of the study were to determine whether patients with resectable locally advanced oesophageal adenocarcinoma with ctDNA detected post-operatively would have an increased rate of recurrent metastatic cancer compared to those who were ctDNA negative and to use cfDNA collected at recurrence to sample the genetic landscape of metastatic oesophageal cancer, not yet examined in large cohorts. Finally, the OCCAMS Consortium investigators postulated that removal of CHIP-associated variants would refine the prognostic value of ctDNA detection.

In their paper, the study team elaborated the results from a commercially available pan-cancer mutation panel evaluated with respect to both tumour and white cell cfDNA in a large, prospectively collected and annotated sample cohort from resected oesophageal cancer. The investigators identified 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery. A pan-cancer ctDNA panel comprising of 77 genes was used which revealed that 49% of studied patients had at least one ctDNA mutation or amplification detected pre-operatively. The most frequently detected mutation was TP53 followed by APC and KRAS. Plasma and peripheral blood cell samples were sequenced and ctDNA results correlated with survival.

Patients were predominately (86%) male with median age of 68 years, all with cT3/T4 and 75% cN+. Oesophageal cancer specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria, 16 of 79 (20%) were ctDNA positive post-resection; recurrence was observed in 12 of 16 (75%) of these.

Furthermore, 78 of 97 (80%) had CHIP analyses which enabled filtering for CHIP variants, which were found in 18 of 78 (23%) cases. When CHIP was excluded, 10 of 63 (17%) patients were ctDNA positive and 9 of 10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival in ctDNA positive patients was 10.0 months versus 29.9 months in ctDNA negative (hazard ratio 5.55, 95% confidence interval 2.42- 12.71, p = 0.0003). Similar outcomes were observed for disease-free survival.

The authors concluded that they demonstrated in this large, prospectively collected dataset that ctDNA in plasma following surgery for oesophageal cancer is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, postoperative ctDNA could be used to risk stratify patients into high- and low-risk groups for intensification or de-escalation of adjuvant chemotherapy.

The study was funded by the Cancer Research UK, Research Councils UK, Medical Research Council Programme Grant.

Reference

Ococks E, Frankell AM, Masque Soler N, et al. Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling. Annals of Oncology; Published online 22 December 2020. DOI: https://doi.org/10.1016/j.annonc.2020.12.010.

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