Whole-Exome Sequencing Shows Clinical Potential for Metastatic Patients

Metastatic cancer treatment could be directed by mutation findings from whole-exome sequencing

medwireNews: Whole-exome sequencing (WES) of metastases and healthy tissue can help identify the most effective treatment for patients with treatment-resistant cancer, show results of a precision-medicine trial.

Sequencing of tissue sample pairs from 97 patients with 19 different solid tumours and metastases at 12 different sites gave information on actionable or biologically informative Mutations in 94% of cases, the authors report in JAMA Oncology.

For example, a patient with recurrent, platinum-resistant urothelial carcinoma with metastases to the liver and lungs was found to have numerous mutations including Amplification of HER2 and FGFR1. On detection of HER2 overexpression, the patient began trastuzumab and paclitaxel treatment and achieved a “complete response”, including resolution of metastases, that has been maintained for at least 9 months.

However, WES results were used to direct treatment in just 5% of patients because of difficulties in accessing trial drugs and permissions for off-label use of the agents, the researchers admit.

“Our approach of using WES for a population with advanced, treatment-resistant disease rather than a focused Gene assay is supported by the realization that the pace of genomic discoveries and development of novel targeted therapies is rapid”, say Himisha Beltran, from Weill Cornell Medical College–New York Presbyterian Hospital in the USA, and team.

“What may not be considered actionable today, and therefore missed on a highly targeted panel, could become actionable tomorrow. Furthermore, there is potential to identify novel resistance-associated mutations and/or pathways using this approach.”

Indeed, they highlight the case of a patient with aggressive small-cell neuroendocrine prostate cancer and extensive metastases who had an “exceptional” near-complete response to cisplatindocetaxel chemotherapy and a “dramatic and durable remission”.

WES revealed a somatic hemizygous deletion of the DNA repair gene FANCA in both the primary and metastatic malignancies, as well as a germline missense variant in FANCA on his second Allele, thought to be associated with loss of function.

In vitro and patient-derived xenograft laboratory results confirmed that loss of FANCA resulted in platinum hypersensitivity and so WES was able to elucidate a potential “biological rationale and functional evidence for his extreme clinical response”, Himisha Beltran et al write. They recommend further investigation into FANCA as a potential Biomarker.

Helen Chen and Jeffrey Abrams, from the National Cancer Institute in Rockville, Maryland, USA, note in an accompanying comment that as WES becomes more cost-effective, effort will be required to increase the clinical utility of the technique.

“Because no single trial or profiling effort will be sufficient to cover all relevant agents or capture all study participants for rare molecular subtypes, development of a “matchmaking” database could be envisioned that would vastly facilitate patient assignment or referral to appropriate studies”, they propose.

They emphasise: “[T]o capitalize fully on all the information available from WES and other nascent technologies, oncology stakeholders, including patients, researchers, and physicians, will need to be able to share and interrogate genomic information routinely if the potential of these new diagnostic tools is to be realized.”

References

Beltran H, Eng K, Mosquera JM, et al. Whole-exome sequencing of metastatic cancer and biomarkers of treatment response. JAMA Oncol 2015; Advance online publication 28 May. doi:10.1001/jamaoncol.2015.1313

Chen HX, Abrams JS. Genomic profiling. Building a continuum from knowledge to care. JAMA Oncol 2015; Advance online publication 28 May. doi:10.1001/jamaoncol.2015.1333

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