Oncology
whereas BRCA mutations in breast and ovarian cancer are best treated with PARP inhibitors. For years, traditional gene sequencing has
required surgical biopsies from the tumour itself. However, ctDNA is a much simpler sampling source. These tumour DNA fragments are collected easily via a quick blood draw, then assayed to identify mutations which indicate the presence of disease and determine therapy options. This approach has the potential to make precision oncology much more accessible than was previously possible. It could enable more effective treatment across much larger patient numbers. And it offers ways to unlock individualised patient care where the right treatment is delivered at the right time based on the nature of the tumour.
Regulatory milestones Specific mutations in blood-circulating free DNA fragments (cfDNA) were first detected in 1994. However, it wasn’t until June 2016 that the FDA first approved a liquid biopsy test to detect mutations in specific parts (exons) of a gene. This approval was for the detection of exon 19 deletions or exon 21 (p.L858R) substitution mutations in the EGFR gene to identify patients with metastatic non-small cell lung cancer (NSCLC) eligible for treatment with Tarceva (erlotinib).1 Four years later, three FDA regulatory
milestones were reached for liquid biopsy tests, diagnostics and companion diagnostics. These included approvals for the first liquid biopsy for minimum residual disease detection (Adaptive Biotechnologies’ ColonoSEQ Assay for chronic lymphocytic leukemia2
) and the first NGS liquid
biopsy test (Guardant360 as a companion diagnostic for NSCLC3
CDx for NSCLC and prostate cancer4
). FoundationOne’s Liquid was the
first liquid biopsy test that FDA approved as a companion diagnostic for two cancers. FDA later approved that device as a companion diagnostic for additional therapies and/or additional gene
mutations.5
So, 2020 was a watershed moment
for FDA’s regulation of liquid biopsies; as we enter 2023, where does the technology go next?
Getting from insight to action faster There are two key goals of cancer liquid biopsy genetic tests: to detect the presence of disease as early as possible when the patient has the best chance for survival, and to provide clinically actionable information based on a tumour’s individual genomic profile. The genetics of lung cancer (predominantly NSCLC) illustrate this very well. For a gene panel
There are many opportunities to improve the coverage, sensitivity, and speed of liquid biopsy genetic test devices. This is an area where a lot of activity is expected over the coming months and years. While liquid biopsy testing is currently used for treatment decisions and post surveillance, it is moving into diagnosis where symptoms are present; later it will move into screening.
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to highlight actionable treatment opportunities, only a handful of genes need to be screened, as approved by the American Society of Clinical Oncology (ASCO). Focusing on EGFR mutations, tumours with common exon 19 deletions respond well to first-generation inhibitor drugs such as Gefitinib and Erlotinib. The most common substitution (p.L858R mutation) also responds to these drugs, but to a lesser degree. However, if a KRAS p.G12 mutation is found in the same tumour, this overrides any EGFR therapies, negating their effect. New drugs targeting specific KRAS mutations (e.g. Sotorasib) hope to use this precise information to improve the outcomes for these particular patients. To further complicate the patient journey, tumours continue to evolve during cancer treatment and new mutations arise. During EGFR therapy involving Gefitinib/Erlotinib, the sudden appearance of mutation p.T790M immediately causes resistance to these drugs, negating their effectiveness. New precision drugs, designed exactly to this mutation are required to continue successful patient therapy, and Osimertinib has been very successful in p.T790M tumours. Of course, novel mutations have subsequently been found which cause resistance to this new drug, creating an ‘arms race’ between precision pharmaceuticals and the growing tumour.
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