Next-Generation Sequencing (NGS) drives precision oncology in Singapore

27 August 2020

By labinsights.com

Traditionally, cancer is treated according to tumour types or histology. But with high treatment failure and low survival rates, many oncologists are now realising that it is often critical to understand their patients’ molecular profile.

Over the last half-century, the study of gene and molecular alterations has been transformed by the replacement of Sanger sequencing of single gene fragments with next-generation sequencing (NGS) of entire genomes. What makes NGS so appealing is that it can generate information on hundreds of thousands of genetic mutations and variants in just a single test. This unprecedented level of genetic information has helped drive precision oncology and personalised healthcare forward.

But what exactly is NGS and how is it being used for precision oncology in Asia today? The Lab Insights team recently spoke with Dr David Tan, an oncology consultant from the National University of Singapore’s Department of Medicine and the National University Cancer Institute, Singapore (NCIS), to better understand its potential in a region where NGS adoption is only just beginning to take root.

An intro to NGS and precision oncology

NGS refers to the range of high-throughput sequencing technologies that can read millions of DNA and RNA sequences simultaneously. In oncology, NGS provides key genetic evidence and information on each patient’s tumour genome and transcriptome profile. It can be applied to both tissue and blood samples, and should be considered a core component of any cancer medicine toolkit.

DNA-based NGS starts with fragmentation of the DNA, followed by amplification of the fragments to create libraries which go through multiple, simultaneous cycles of sequencing. A large amount of raw data is produced, analysed and compared to a reference human genome to identify variants or mutations. Unlike conventional Sanger sequencing, the older NGS technologies were able to read larger DNA sequences rapidly but generated data that was difficult to interpret. The newer and more sensitive NGS systems have improved on these problems and can now also detect rare genetic variants and single nucleotide polymorphisms (SNPs) while covering the whole genome or transcriptome.

NGS has proven valuable in a variety of situations, such as when all single mutation or hotspot tests fail to show targetable mutations or when insufficient tumour material is available for sequential single biomarker tests. With many genes assessed in a single test, clinicians can gain broader diagnostic insights on the potential therapeutic interventions possible, some of which are patient specific.

Matching NGS data from cancer genomes to available therapies has already led to positive patient outcomes for some cancers. In lung cancer, for example, it facilitates the use and effectiveness of various targeted therapies, such as EGFR TKIs[1] and ALK inhibitors[2]. When advanced cancer patients were given mutation-matched treatments, they survived longer with a better overall response rate and a longer time to treatment failure than those who were unmatched[3]. Matching for specific molecular aberrations, such as copy number amplification (e.g. HER2) or protein expression (ER/PR/HER2 expression), have also led to improved patient outcomes.

Despite the rapid advances we have seen in the field of precision oncology, many NGS-sequenced tumours will still harbour pathogenic mutations that cannot currently be matched to available treatments or clinical trials. However, NGS can capture a more comprehensive array of cancer mutations and abnormalities in tumours which may be amenable to treatment with targeted agents that have been associated with deep and durable responses, and identify patients who may benefit from novel therapeutic approaches and clinical trials.

Dr Tan’s experience in Singapore

Dr Tan cites the example of a patient with metastatic clear cell endometrial cancer who is currently under his care. As these cancers are typically very resistant to chemotherapy, relapse occurred 3 months after an initial treatment response. NGS revealed the ataxia telangiectasia mutation in this patient’s tumour and allowed her to enrol in a clinical trial of an inhibitor that resulted in a positive response with resulting disease control for over a year and a half. Similar patients on conventional treatment approaches would usually have experienced a far shorter progression free survival of less than 6 months.  

Profiling at the point of diagnosis has also become necessary as patients are presenting with unique phenotypes and genotypes. Dr Tan understands that unless physicians capture this heterogeneity in their therapeutic strategies, they would not be able to offer precision therapies. For example, the presence of homologous recombination deficiencies (HRD) in ovarian cancers may make treatment with PARP inhibitors very effective for patients, and it is only through comprehensive genomic profiling that specific features of HRD can be identified in the tumour genome.

“We’ve recognised that apart from the recurrent/refractory cancers, there is now an increasing importance for NGS in the front-line setting for certain diseases, like lung and ovarian cancers, where the results of comprehensive genomic profiling will become crucial for therapeutic stratification,” says Dr Tan.

As early adopters of NGS in Asia, the drug development team at NCIS established an early phase clinical trials unit, the NCIS Developmental Therapeutics Unit (DTU),  to provide sequencing at no cost to eligible patients. NCIS also launched the Integrated Molecular Profiling of Cancers (IMAC) programme in 2014, which has grown from a panel of just 50 gene targets to 324 genes today.

Molecular tumour boards at NCIS

With many NGS studies successfully showing clinical efficacy, doctors without significant genomics expertise should participate in molecular tumour boards (MTBs). In MTBs, real-world patient NGS reports, which can be difficult to interpret, are actively reviewed by domain experts from multiple clinical and scientific disciplines.

MTBs typically include at least one medical oncologist familiar with the available targeted treatment and clinical trial options and the patient’s specific factors; a molecular pathologist with information on the molecular analysis; and a cancer geneticist who can provide input on germline implications of any identified somatic mutations. MTBs are also an ideal forum for physician education as they increase understanding of genomic data, sequencing technologies and sequencing-matched therapies.

At NCIS, weekly MTBs are held by the NCIS Developmental Therapeutics Unit (DTU) to review molecular profiling data. The NCIS DTU team is comprised of tumour-site specific and early phase drug development experts. MTBs are instrumental in identifying mutations and patients who should be enrolled into clinical trials, but even if no trial is found to be suitable, NGS data may be used to determine if an alternative targeted  drug options should be used.

Within MTBs, each patient’s unique mutational profile is used to determine their treatment plan. “Every cancer is a rare disease due to the multiplicity of the mutational profiles that exist in each patient’s tumour. This mutational data also facilitates biomarker-driven drug development in a way that is ethnically agnostic, which is especially important in Asia,” he observes.

For countries just beginning on this journey of genomic profiling, Dr Tan emphasises the importance and value of partnerships to enhance accuracy and reduce infrastructure and expertise costs while accelerating treatment for patients able to afford precision care. His recent publication[4] is recommended for anyone seeking concrete ideas on overcoming the challenges in using NGS-based diagnostics clinically. 

As precision oncology and drug development continues to lead the way in achieving better outcomes for cancer patients, and medical innovations facilitate multi-omic (such as proteomics and genomics) tumour characterization and liquid biopsies, the clinical demand for NGS-based profiling of tumours is likely to increase. It is therefore incumbent upon all stakeholders in cancer care to foster an ecosystem that can support precision medicine and the appropriate use of targeted therapies. In this regard, MTBs are the perfect environment in which to address critical patient care issues, while leveraging the power of NGS data to realise the promise of precision therapy in cancer.  

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[1] Zhao J, et al. “Next generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib.” Lung Cancer. 2020 Mar; vol. 141:114-118.

[2] Zhy Y, et al. “Durable complete response to alectinib in a lung adenocarcinoma patient with brain metastases and low-abundance EML4-ALK variant in liquid biopsy: a case report.” Frontiers in Oncology. 2020 Jul; 10:1259.

[3] Tismberidou, AS, et al. “Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.” Clin Cancer Res. 2012 Nov; 18(22):6373-83.

[4] Tan DSP, et al. “Recommendations to improve the clinical adoption of NGS-based cancer diagnostics in Singapore.” Asia Pacific Journal of Clinical Oncology. 2020 Apr; Volume 16, Issue 4.