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COLUMNS
Collective wisdom in action
Experts at ACT Genomics and Bumrungrad International Hospital shed insight on the current practice of molecular tumour boards in the Asia Pacific

The past decade witnessed a major breakthrough in cancer management. This was made possible and applied in standard care due to: 1) Matching genetic biomarkers with targeted and immuno-therapies, 2) increasing number of targeted anti-cancer agents recommended in clinical guidelines, and 3) genetic analysis tools such as next-generation sequencing (NGS) becoming more accessible and affordable.

This also means that cancer specialists have to deal with multiple test-platforms, and patients’ complex genetic alterations in test reports, such as cancer-related gene mutations, copy number variations (CNVs), gene re-arrangement (i.e., fusion genes), and RNA expression. Additionally, they must interpret such genomic information to guide treatment for their cancer patients.

Deciphering genetic alterations at the molecular level is no easy task for clinicians, especially for those who are not molecuarly trained. In most cases, they turn to their clinical peers to learn and exchange treatment insight, either privately or via attending clinical conferences.

To allow such experience sharing to be more effective and timely, advanced tertiary hospitals have turned to setting up multi-disciplinary tumour board (TB) meetings. For a TB meeting to provide cross-disciplinary recommendations, it traditionally comprises specialists in oncology, surgery, pathology, and radiology.1,2 However, regular TB attendees tend to not include experts in genetics, bioinformatics, and biostatistics, who can facilitate interpretation and implementation of adequate genetics-guided cancer care in current clinical settings.

Therefore, to bridge a rapidly growing gap between clinical knowledge and genetic potential in cancer care, molecular tumour boards (MTBs) arose to add a molecular component to traditional TB meetings.

MTBs are meant to integrate clinical and molecular parameters, and have been proposed as a new platform to address the disparity of applying increasingly multifaceted genetic information to clinical decision making.3

What is the current status of MTBs in the Asia Pacific?

Having access to MTBs is likely to improve and inform the application of genetics-guided cancer care with optimal clinical benefits.4 Hence, the setup and organisation of the MTB is now one of the central focuses across various advanced healthcare systems, mainly in the United States, the United Kingdom, and the European Union.

Still, the setup of MTBs is rather new with minimal shared experiences in the literature. In particular, how have MTBs fared in Asia Pacific’s clinical organisations? Here we take Bumrungrad International Hospital, the first Asian hospital accredited by the Joint Commission International, to exemplify MTB practice in the region.

A single centre experience

Bumrungrad International Hospital (BIH), located in Bangkok, Thailand, initiated the first MTB within their cancer centre in August 2017 (Figure 1).

Initially, the MTBs placed emphasis on educating clinical members on the fundamental knowledge of cancer genomics, immuno-oncology, and molecular diagnostics, etc. The function of the MTBs subsequently evolved, and they now currently focus more on deliberating clinical implications of tumour profiling results.

In BIH, the 90-minute-long MTB meeting is held monthly. Run by an interdisciplinary team of medical and scientific experts with a focus on clinical and translational oncology, the discussion for each clinical case starts with reviewing the patient’s clinical, pathological, and radiographic data.

Subsequently, the NGS-based diagnostic results are presented to the MTB meeting by scientific experts in cancer genomics and bioinformatics, contributed by the respective tumour profiling service provider.

The thrust of inviting service providers’ expertise to be part of the MTB setup is multi-fold as they can provide the following clinical insight, which is critical in strategising each patient’s treatment plan: 1) Tumour-specific genomic landscape, known molecular predictive or prognostic markers, 2) strengths and limitations of different molecular diagnostic methodologies (e.g. reverse transcription polymerase chain reaction, mass-spectrometry, immunohistochemistry, next-generation sequencing, etc.), 3) strengths and limitations of an assay (hotspot based versus comprehensive panel testing), 4) discrepancies between different panel tests, and 5) the potential on- and off-label molecular targeted treatments.

After discussion, treatment advice is given to each patient and supported by levels of clinical evidence based on published molecular biomarker recommendations.5

Concurrently, there is ongoing assessment to determine the optimal molecular diagnostic test to be used for each clinical case. In particular, if NGS-based genomic findings are insufficient in pointing to a treatment strategy, nor do they adequately answer MTB members’ queries, the investigative process of information gathering, information integration and interpretation, and diagnosis confirmation will resume.

Given that MTBs are critical in closing the growing gap between clinical practice and genetic potential in cancer care, the implementation of MTBs in Asia Pacific is still at its infancy. What is holding us back, and indeed, what is considered an optimal MTB? We list four (but not limited to) major hurdles that cripple the development and the adoption of MTBs in the region:

1. When to test and on which platform?

Tumours exhibit tremendous genetic heterogeneity. Such heterogeneity is not only found within a single tumour, but also among different kinds of tumours. Adding to this complexity is that tumours undergo genomic evolution over time, exhibiting intratumour and intratumour heterogeneity between primary and metastatic sites.6,7

As such, exploring genomic alterations by time series analysis becomes critical, and necessary, to identify 1) factors that drive a tumour’s evolution along the treatment, and 2) the molecular targets of drug resistance, responsible for tumour progression.

This is particularly evident, for example, for acquired mutations in epidermal growth factor receptor (EGFR) and estrogen receptor 1 (ESR1) targeted therapies,8,9 or beta-2-microglobulin (B2M) biallelic loss that indicates resistance to immune checkpoint inhibitor.10 Therefore, when possible, the most current sample (e.g., biopsy at a cancer metastatic site, or biopsied tissue showing resistance to the current treatment) should be used for genomic profiling. Notably, the decision to perform sequential analyses should take into consideration 1) the lines and types of treatment that the patient has gone through, and 2) the sample logistical issues (including feasibility and safety) in taking a new biopsy.

If the patient’s tissue sample is unavailable, liquid biopsy assays for circulating tumour DNA (ctDNA) have the potential to demonstrate tumour heterogeneity.11 But liquid biopsies have their limitations.

It might miss subclonal alterations that are typically low in allele frequency. Patients with limited tumour burden and tumour lineages would have limited amount of ctDNA in their blood stream. As such, it would be harder to assess resistance mechanisms in patients with mixed response.

Lastly, insurance coverage and procedural availability to justify sequential testing can vary greatly, making it challenging to provide broad recommendations. All the challenges and limitations aforementioned should be fully discussed during the MTB meeting.

2. Discrepancy in bioinformatics pipelines and genomic findings among sequencing vendors

The lack of consensus for genomic marker-guided therapeutic implication, as well as poor definition of actionability for a genomic mutation, are commonly regarded as major hurdles for a functional MTB to take shape.

In particular, the difference in the computational algorithms and database used for mutation calling/variant annotation by different service providers can result in a substantial discrepancy in their respective genomic findings of the same specimen.

Therefore, to arrive at a fair comparison among testing results, it is mandatory for cancer scientists who participate in the MTB to be well-versed with their own NGS bioinformatics pipelines and assay designs, and cognizant of the four-tiered variants interpretation guidelines (Table 1) by the American Society of Clinical Oncology and the College of American Pathologists.4

3. Unsolicited findings in germline mutations

Most NGS-based cancer diagnostics are performed on tumour specimens. However, potential germline mutations inclined to hereditary diseases may be incidentally found in panel testing. Such findings, known as unsolicited findings, may impact not only individual patients, but also their immediate relatives. Therefore, pre-defined guidelines for unsolicited findings should be established for the MTB to determine which unsolicited finding needs to be reported (and which do not), who should disclose the information to the patient and relatives, and how to initiate genetic counseling in such incidents.

Notably, in Asia-Pacific, the shortage of qualified genetic counselors, together with the cultural and context-specific factors such as religion, and language, should be taken into account. At BIH, a certified genetic counselor is invited to attend the MTB. In particular, genetic counseling will be arranged for patients who harbour breast cancer 1/2 (BRCA1/2) mutations or MSI-associated genes mutation with allele frequency showing hetero- or homo-zygosity in the respective panel testing.

4. Limited drug access and/or molecular-guided clinical trials

In the United States, patients can be assigned to on-going large, multicenter precision oncology trials based on alterations found in their tumours via genomic sequencing (i.e., NCI-MATCH*, NCI-MPACT** and TAPUR***). MTB serves the function of identifying and matching the best candidate with the appropriate molecular-guided clinical trial. Unfortunately, clinical trials are not abundantly available in the Asia-Pacific. Thus, it heavily reduces the accessibility for patients to be enrolled in these basket trials.

In parallel, the tardy drug approval process in the Asia-Pacific results in limited access to targeted therapies as compared to the West. The introduction of MTBs would help to keep track of and inform the registration or approval of the targeted therapies in a systematic manner. The availability of investigator-initiated clinical trials associated with biomarker-guided therapies in the region should be updated accordingly.

What we have achieved via MTB meetings in the Asia-Pacific?

In a previous survey on oncologists’ insight on NGS testing in the Asia-Pacific,12 it showed that NGS panel testing is currently underutilised in the clinical setting. The multiple platforms available, interpretation of results, and curation of genomic databases used by different service providers are some of the many hurdles for the adoption of NGS-based diagnostic testing.

Therefore, the educational component in the MTB is an important aspect for this region. With more cases discussed at MTBs, oncologists at BIH believe the objectives of the MTB in its initial years has been met in the following ways:

Firstly, clinicians can distinguish the strengths and limitations of different assays. Often, the smaller panel is more beneficial for newly diagnosed cancer patients, especially in early stages, whereas the comprehensive larger panels can add value to guide clinical trials or off-label use at the advanced stage.

Secondly, it serves as a forum disseminating laboratory updates, analysis software, and limitations in genetic data interpretation and utilisation that ultimately increases the oncologist’s confidence in and efficiency of utilising molecular diagnostics.

Thirdly, for unsolicited findings associated with pathogenic germline mutations, a standard operating procedure has been developed for the case to be referred to a qualified genetic counselor.

Moving forward, it is time to consider how MTBs can be strategically facilitated in both public and private hospitals in this region, as well as maintaining and increasing the trust of patients, clinicians, scientists, and the medical industry towards genetics-guided therapy.

The way forward

Precision medicine is an exciting and rapidly evolving field. There is interest in broadening molecular testing such as transcriptomic analysis or metabolomics for patients to address clonal evolution and molecular heterogeneity. This calls for more data to be analysed.

Together with the ever-growing possibility for genetics-guided therapy, there is a critical need for more sophisticated and organised MTB to harness the full potential of precision medicine in routine cancer care.

Furthermore, we should construct a systematic database to include the genomic and clinic-pathological information of each patient in Asia-Pacific, where the ultimate goal is to ensure that patients are receiving the best possible treatment without unnecessary costs or risks.

References

  • NIH website: www.cancer.gov
  • Keating NL et al. J Natl Cancer Inst. 2013; 105(2): 113-121
  • ASCO website: www.university.asco.org/motb
  • Li MM et al. J Mol Diagn. 2017; 19(1):4-23
  • Rolfo C et al. ESMO open. 2018; 3:e000398
  • Jamal-Hanjani M et al. Clin Cancer Re.s 2015; 21(6): 1258-1266
  • Meric-Bernstam F et al. Mol Cancer Ther. 2014; 13(5): 1382-1389
  • Kuang Y, et al. NPJ Breast Cancer. 2018; 4:22
  • Wu SG and Shih JY. Mol Cancer. 2018; 17(1):38
  • Sade-Feldman M et al. Nat Commun. 2017; 8(1):1136
  • Neumann MHD et al. Comput Struct Biotechnol. J 2018; 16:190-195
  • Lai et al. Asia-Pacific Biotech News


Dr. Poon Song Ling is the senior medical science liaison and project manager at ACT Genomics Singapore.

Dr. Harit Suwanrusme is the medical oncologist at Bumrungrad International Hospital, Thailand.

Dr. Surasit Saleh Issarachai is the medical oncologist and hematologist at Bumrungrad International Hospital, Thailand.

Dr. Allen Lai is the regional managing director at ACT Genomics Singapore.

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EDITORS' CHOICE  
COLUMNS  

APBN Editorial Calendar 2019
January:
Taiwan Medical tourism
February:
Marijuana as medicine — Legal marijuana will open up scientific research
March:
Driven by curiosity
April:
Career developments for researchers
May:
What's cracking — Antibodies in ostrich eggs
June:
Clinical trials — What's in a name?
July:
Traditional Chinese medicine in modern healthcare — Integrating both worlds
Editorial calendar is subjected to changes.
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