Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

Abstract

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful.

A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy

“…Our study was performed as part of the ICGC, which is designed to examine the landscape by virtue of examining a large number of tumor:normal pairs, and hence, we were generally unable to perform multiregional sampling. Findlay et al (2016) recently reported results from their exome anlaysis of 30 preand post-chemotherapy EAC samples, and in this study, they purposefully selected cases showing a range of responses to chemotherapy. They associated good clinical response, as determined by the histopathological Mandard score generated from the post-chemotherapy surgical resection specimen, with evidence for genomic bottlenecking as a result of chemotherapy.…”

“…However, we also note they are two of the cases with the best pathological TNM staging. Any approach to prognosticate based on genomic factors (e.g., perhaps following the results of Findlay et al 2016) should at most temper established prognostic factors such as these fundamental phenotypic characteristics. Moreover, as discussed, some mutations were found to be more recurrent following chemotherapy, and this is an area ripe for further research as the appropriate cohorts become available.…”

“…We took the opportunity to critically evaluate the impact of chemotherapy on the genomic landscape. It has recently been reported from exome data that chemotherapy imposes a bottleneck on tumor evolution (Findlay et al 2016). We therefore first sought to establish the genetic relationship between 10 matched pre-and postchemotherapy samples and the point at which the samples diverged.…”

Adjuvant chemotherapy following trimodality therapy for esophageal carcinoma—Is the evidence sufficient?

“…Shifting towards a focus on the underlying molecular and/or genetic mechanisms contributing to both response to therapy and longterm outcomes may add granularity to guide therapeutic decision making. Recent work has suggested genetic bottlenecking or intratumoral heterogeneity as potential markers for response to platinum-based therapy (20,21). In a study of 149 esophageal ACs potentially actionable gene alterations were identified in nearly half, while only one [ERBB2 (HER2)], is being routinely targeted (21).…”

Challenges in assessing response of oesophageal cancer to neoadjuvant therapy, and the potential of composite PET-CT and multimodal metrics

“…These include highly complex molecular interactions in individual cancer cells (genetic, epigenetic, transcriptomic, proteomic), compounded by cellular interactions, tumour microenvironment, clonal heterogeneity, and tumour evolution during therapy (5). As a consequence, the effect sizes of these markers tend to be limited, and certainly an insufficient basis on which to decide whether to give or omit specific therapies (6).…”