NGS: the road to personalising cancer care

Next Generation Sequencing (NGS) is increasingly being applied in clinical practice. Credit: Shutterstock / FOTOGRIN

N​​​​​​​ext Generation Sequencing (NGS) is a rapidly evolving field in cancer.  

Around 190 NGS devices are in various stages of development globally, according to GlobalData’s medical device pipeline database, with 127 in active development, including 59 in early and 68 in late stage development. 

Exact Sciences, which launched its OncoExtra NGS device in 2023, is working to ensure physicians understand and have a minimum awareness of guidelines issued on NGS technology by the American Society of Clinical Oncology (ASCO).  

Focal areas of education for the company include spreading awareness around the drugs in associated targeted therapies, and how many genes physicians need to test with NGS to ensure their patients have been adequately assessed for potentially life-changing targeted therapies. 

“We have a medical affairs team that works in the field, delivering talks regarding these next generation sequencing guidelines and best in class practices,” Exact Sciences CMO, precision oncology Rick Baehner tells Medical Device Network. 

The company also works closely with patient advocacy groups. While it is focused on making sure that doctors understand this complicated technology, it also wants to help patients understand their options when they are faced with a life changing diagnosis like cancer. 

To drive adoption of NGS technology, Exact recently partnered with the Mayo Clinic. It will provide the medical centre with OncoExTra and RiskGuard, a test that screens for hereditary risk of cancer in patients that are currently healthy. 

“The partnership enables us to support their 130,000 unique cancer patients across their three cancer sites, a population which reflects the broad tapestry of the colour of American society,” Baehner says. 

ASCO recently issued guidelines on NGS recommending RNA sequencing be used if a gene mutation cannot be found in DNA testing. 

According to Baehner, the growing literature in the field indicates that RNA sequencing can detect upwards of 30% more therapeutically relevant fusions. 

Bahner says RNA sequencing can be understood as the transcript coming off the DNA, the blueprint by which protein – a key therapy target in cancer treatment – is made.  

“RNA can be powerful to detect fusions, where two pieces of two genes come together and form a new transcript, like an on switch, that can be an oncogenic switch that turns a tumour on,” he explains. “RNA can have a significant impact on patients and what therapy they receive.” 

To highlight the importance of RNA sequencing, he relates a recent case study of a 65-year-old man who had noticed a mass in his neck near a thyroid gland. 

A needle biopsy revealed this was a high-grade BRAF mutation in need of immediate surgical treatment. 

A BRAF mutation is a spontaneous change in the BRAF gene, which causes it to work incorrectly. The mutation causes the gene to turn on the protein and keep it on, which means certain cells receive ongoing signals to keep dividing and no instructions on when to stop. In time, this can lead to the development of a tumour.  

Upon this identification, the question became one of which targeted therapy this patient was eligible for. Immunohistochemistry and standard gene tests found that BRAF was negative for all targeted therapies. 

“But with comprehensive testing, the RNA sequencing part of the test identified a Neurotrophic tyrosine receptor kinase (NTRK) gene fusion,” Baehner says. 

This fusion is very rare. According to Baehner, it represents only around 1% of solid tumours. 

“In this patient's case, finding this NTRK fusion meant that, in addition to surgery, this patient was eligible for an NTRK inhibitor,” he says. 

ASCO recently issued two further guidelines, recommending that all women with breast cancer should be offered genetic testing, irrespective of their age or the stage of advancement of their cancer.  

The association now also recommends for all patients with solid cancer to get genetic testing, and they specify the types of tumours that need to be included in a testing panel, beyond the testing of BReast CAncer gene 1 and 2 (BRCA1/BRCA2), the testing of which aims to identify harmful mutations in these genes that predispose individuals, or their relatives, to cancer. 

With its comprehensive testing capabilities, NGS is effectively a universal platform. It can be used for tumour testing, but also has the capability to target other areas based on new guidance as it releases.  

According to Baehner, studies have shown the importance of Poly (ADP-ribose) polymerase (PARP) inhibitor therapies for patients with cancer, if they have germline mutations in BRCA1/2 in other genes.  

"The platform testing of the tumours is important today, but increasingly, the guidelines are also recommending testing germline, in order to assess for BRCA1/2 in Homologous recombination repair (HRR) genes,” says Baehner. 

“Patients with germline mutations have been shown to benefit from PARP inhibitors.” 

Baehner believes we're looking at a future today, particularly in reflecting on the new ASCO guidelines on BRCA1/2, where protein testing through immunohistochemistry, NGS of the tumour with broad tests, of which its OncoExtra device is capable, and notably germline testing are all important aspects of cancer research. 

"We're starting to see how all these pieces fit together to help cancer patients with their therapy, help their families understand the risk that they may or may not have, as a basis of a germline test, and helping inform the development of new targeted therapies," he says. 

An emergent field Exact would like to enter in the future is Molecular Residual Disease (MRD). MRD is a technology that uses NGS and involves sequencing a patient’s tumour, either via a biopsy or once it has been removed, to determine what mutations are unique to that tumour. Following a surgery, the physician can look through a blood sample to see if the patient still has that tumour’s DNA circulating in their blood. If it remains, a patient may then receive chemotherapy, and undergo monitoring to see if the tumour levels in their blood are going down. 

“This is a powerful new technology,” Baehner says. “Today it's reimbursed in colorectal cancer, but I think this is a technology that will be broadly applicable across solid cancers.” 

President Biden and First Lady Jill Biden’s Cancer Moonshot was outlined in 2022 with the aim to drive down the cancer mortality rate and prevent four million deaths by 2047. The drive advocates for expanding the availability of cancer screening in the US and for earlier cancer detection. 

Baehner believes we can now see the future of cancer in the use of techniques facilitated by NGS. He states the ongoing approach to cancer will centre on several areas, including broad sequencing of patients’ germline DNA, with a priority on understanding patients’ hereditary risk to help prevent cancer in the first place.  

According to Baehner, the modality of Multi-Cancer Detection – using NGS to look in the blood of healthy or at-risk patients to see if they may be harbouring an early cancer – will become a key focus. 

For patients with cancer, the ongoing evolution of approaches to diagnosis will centre on a combination of germline testing and tumour testing to help guide what therapy a patient will need.  

He adds that MRD tests as an outgoing solution, to be able to dynamically show whether patients were cured by therapy alone, are another piece in this puzzle. If chemotherapy or other targeted therapies are needed, the final stages will be in determining whether patients’ circulating tumour DNA levels are staying negative when they return to their oncology team for follow ups. 

Along with NGS technology, Baehner says the pharmaceutical industry has a large hand in helping drive this revolution by its ability to now target personalised therapies to mutations, checkpoint inhibitors, or PARP inhibitors.  

On the future of treatment, he concludes: “There'll definitely be a combination of advanced diagnostics and therapeutics, to help eradicate cancer for those unfortunate enough to have it.”