Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: Research points to the potential for routine use of comprehensive next-generation sequencing (NGS) for identifying the primary tumour site in patients with carcinoma of unknown primary origin (CUP), as well as germline analysis of DNA repair genes in those with metastatic solid cancer.
The cohort study investigators say that the NGS approaches used in their study are able to identify “a subset of patients who derive substantial clinical benefit from sequencing information”.
As reported in JAMA Oncology, NGS was successfully performed on metastatic tumour samples taken from 1015 of the 1138 study participants, of whom 53.0% were male and the average age was 57.7 years.
Overall, 80.5% of the participants had a genomic alteration with the potential of being clinically actionable, say Arul Chinnaiyan, from the University of Michigan in Ann Arbor, USA, and co-authors.
They write that 94.8% of the alterations associated with increased risk of cancer, a specific cancer diagnosis, or an indication of likely benefit or resistance to a specific therapy were detected using DNA sequencing and 63.5% by RNA sequencing, with 5.0% identified only by the latter technique.
Moreover, sequencing-directed therapy (SDT) was available for 16.2% of the patients with alterations, of whom 74 were treated in a clinical trial, 43 received off-label therapy and 15 on-label treatment. The majority (70.5%) of these SDTs were small molecular inhibitors, such as CDK4/6 or PARP inhibitors, but other SDTs included immune checkpoint inhibitors (22.0%), EGFR2 inhibitors (6.1%) and anti-oestrogen agents (1.5%).
Over a third (37.1%) of patients given a SDT derived a clinical benefit, including “exceptional” responses in 19.7%, lasting for at least 12 months. These included 10 patients with alterations in the DNA repair genes BRCA1, BRCA2 or MSH2 and five patients with driver gene fusions.
“None of these therapies would have been recommended per standard of care guidelines, indicating that sequencing information was of significant value”, the researchers emphasize, adding that “some patients achieved exceptional response to targeted therapy administered on the basis of a driver gene fusion, which would not have been identified without RNA sequencing.”
The researchers also found 169 pathogenic germline variants (PGVs) in 15.8% of the cohort; 30.0% of individuals with PGVs – 4.8% of the cohort – had potentially targetable mutations in genes such as BRCA1, BRCA2 or MSH2. This included first detection of a PGV in 37 of the 49 affected individuals.
Among the 55 patients with CUP, the primary tumour site was identified by NGS in 50.9% of cases. Six of the 13 CUP patients who received an SDT achieved a clinical benefit from this, including one patient who received two SDTs serially. This gave a clinical benefit rate of 53.8%.
And PGVs were found in eight (14.5%) CUP patients, including four patients with BRCA1, BRCA2 or MSH2 mutations that were potentially amenable to SDT.
“Our data support a recommendation for germline testing of DNA repair genes as standard practice in patients with metastatic solid tumors and comprehensive NGS profiling at diagnosis for patients with CUP”, Arul Chinnaiyan and co-workers conclude.
“With continued discovery of genomic biomarkers predictive of clinical benefit from anticancer therapies, we anticipate even broader clinical applicability of this technology.”
Discussing the study in an accompanying editorial, Timothy Yap and co-authors from the University of Texas MD Anderson Cancer Center in Houston, USA, note that “the vast majority (88.6%) of patients received SDTs within a trial or off label, indicating the lack of approved genomically matched treatments for patients and supporting the need for continued efforts in novel drug development”.
They also note that there was a median delay of 3.8 months from study enrolment to the initiation of an SDT in the study “which is not ideal for patients with progressing advanced cancers and which also stresses the importance of the timely availability of genomically matched therapies for such patients.”
The authors conclude: “Integrated analysis is likely to have a long enough turnaround time that it is more likely to influence the next-line therapy choice; thus, testing early in the metastatic course may be more meaningful.”
Cobain EF, Wu Y-M, Vats P, et al. Assessment of clinical benefit of integrative genomic profiling in advanced solid tumors. JAMA Oncol; Advance online publication 25 February 2021. doi:10.1001/jamaoncol.2020.7987
Yap TA, Johnson A, Meric-Bernstam F. Precision medicine in oncology–Toward the integrated targeting of somatic and germline genomic aberrations. JAMA Oncol; Advance online publication 25 February 2021. doi:10.1001/jamaoncol.2020.7988
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