Investigating the feasibility of tumour molecular profiling in gastrointestinal malignancies in routine clinical practice

Abstract

NCT02112357.

Ultra-sensitive mutation detection and genome-wide DNA copy number reconstruction by error corrected circulating tumour DNA sequencing

“…Together, these data show that our cfDNA analysis technology may address the subset of 20% or more of CRC patients who cannot be molecularly profiled due to unobtainable or inadequate biopsy tissues (17). Due to its minimally invasive nature, ultra-sensitive cfDNA sequencing can also be applied serially at multiple time-points, for example to monitor the evolution of subclonal drug resistance driver mutations in target gene panels without prior knowledge of specific loci where resistance mutations will occur.…”

“…cfDNA was extracted from the plasma of 58 patients with metastatic colorectal cancer (mCRC) enrolled in the FOrMAT trial at the Royal Marsden Hospital (ClinicalTrials.gov NCT02112357) (17). Plasma samples had either been collected from treatment naïve patients (n=19) or at the time tumours started to progress after prior palliative systemic treatment (n=39).…”

“…Archival or fresh tumour specimens from patients enrolled in the FOrMAT trial had been sequenced with solution hybrid capture enrichment of 46 cancer driver genes relevant for gastrointestinal cancers as described (17). Mutation calls, BAM files of tumour and blood sequencing data as well as clinical data were available for our analyses.…”

Precision Treatment and Prevention of Colorectal Cancer—Hope or Hype?

“…Various efforts to systematically molecularly profile metastatic cancers, including CRCs, with sequencing of tumor tissue and/or circulating cell-free DNA have claimed high rates of therapeutic actionability in anywhere from 37%-66% of all cases tested. [25][26][27][28] A consistent critique of such headline-worthy results, however, has been that "therapeutic actionability" has typically been defined as the availability of a clinical trial for which a given molecular alteration is an entry criteria, rather than the existence of a proven effective molecularly targeted therapy. For example, one such study 28 reported "actionable" findings in 66% of all tested CRCs, yet more than half of these were activating KRAS mutations that were considered "actionable," yet their main actionability is that they predict for lack of benefit from anti-EGFR-based therapies (described above).…”

Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine?

“…CCA are often diagnosed with cytology or small biopsies which do not enable a comprehensive and full molecular and genomic characterization. Feasibility studies on targeted captured sequencing in gastrointestinal cancers within routine clinical practice have shown that sequencing may be successful only in a minority of CCA patients (26% in advanced CCA vs >50% advanced colorectal cancers) . In addition, success has often been limited to iCCA narrowing the appreciation of genomic differences between different subtypes in the advanced setting.…”