ESMO verdict on next generation sequencing


By Mardi Chapman

28 Aug 2020

New guidelines give a thumbs down for routine use of next generation sequencing (NGS) in common cancers such as breast cancer – but a thumbs up in other tumours types such as advanced non-squamous NSCLC, prostate cancer, ovarian cancer and cholangiocarcinoma.

The European Society for Medical Oncology (ESMO) recommendations for the use of next generation sequencing in patients with metastatic cancers are also ambivalent about its use in metastatic colorectal cancer.

“Since most level I alterations are hotspot mutations in KRAS, NRAS and BRAF, and considering that MSI status is determined by IHC or PCR, there is no need to test samples using multigene NGS in the context of daily practice,” ESMO says.

“Nevertheless, multigene NGS can be an alternative to PCR tests only if it does not generate extra cost compared to standard techniques already implemented in routine [practice]. This would allow detection of ERBB2 amplifications, and, in some panels, detect MSI status with high accuracy.”

ESMO concludes there is no need to perform tumour multigene NGS in patients with metastatic gastric cancer, advanced pancreatic ductal adenocarcinoma or advanced hepatocellular carcinoma.

The recommendations, published in Annals of Oncology, include a positive recommendation to determine tumour mutational burden (TMB) only in cervical cancer, NET, salivary cancers, vulvar cancers and thyroid cancers.

ESMO says additional studies are needed before implementing TMB in all cancers where anti-PD(L)1 antibodies were not approved.

And it says alternative and cheaper diagnostic tests are available for detecting NTRK fusions.

“There is a need to regulate the volumes of NGS procedures at the national level,” the ESMO guidance states.

In explaining its opposition to routine use of NGS, ESMO says it would require significant investment and the results of panels could lead to use of expensive drugs outside their approved indications.

But there is an upside to investment in NGS as well.

“ESMO strongly recommends that clinical research centres perform multigene sequencing as part of their missions to accelerate cancer research and drug development through clinical trials, provide access to innovation to patients and to collect data,” it says.

Australian perspective

Dr Richard Tothill

Commenting on the recommendations, Dr Richard Tothill tells the limbic that the ESMO statement is a fair snapshot of where the field stands at the moment.

“It’s a conservative statement based on the current literature plus it seems some incomplete trials.”

“They have covered all bases because from a diagnostic testing perspective they are not recommending going to panels because it is not cost effective over single gene tests. But at the same time they are recommending that these sorts of assays should be used by tertiary hospitals for clinical research purposes to get patients onto trials.”

Dr Tothill, Cancer Genomics Group Leader at the University of Melbourne, says the tests are already being used frequently in Australia despite not being reimbursed.

“Either patients are self funding and sending away their samples overseas or they are getting done locally. So despite the fact that they are not rebatable tests, there is still so much activity going on in this area and it is certainly the future.”

“Speaking to my colleagues in clinical testing labs, they would say within 2-3 years the cost of these large gene panel tests will come down to a point where it is economically viable to do the panel rather than single genes,” he adds.

“Purely on that basis as a test we are going to get there pretty quickly and people will adopt this.”

Dr Tothill says he isn’t convinced by everything in the statement – as some claims, such as the recommendation the TMB should be determined in well differentiated NET, are lacking information.

“In respect to TMB they are referring to this one trial that is not even finished and the only information I could find there was an ASCO abstract,” he says.

“I work on this disease as well and it was sort of a surprise to me because it’s a very broad group of tumours and so they must be referring to a subset of these tumours but the details are not clear in the article.”

He also has doubts about a statement saying  panel testing may be used for carcinoma of unknown primary (CUP).

“They cite one paper which was probably one of the more minor papers that has been published in this area. So I don’t think they have presented strong enough evidence that testing is really useful in this cancer type.”

However Dr Tothill says his team has been applying these type of tests to CUP since 2014, “… and we are seeing these tests are really useful not only for potentially finding what is actionable but also in the diagnostic sense. CUP is essentially a disease where you can’t resolve what that cancer type is despite extensive clinical work up. Pathologists will do all they can to try and identify the tumour and when they get the mutation profiling results it gives them further leads.”

“So it is incredibly important for diagnosis as well as for the therapeutic component.”

He notes there are a number of big studies underway in the US and Europe which would lead to recommendation updates in the near future.

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