We know MRD detection is feasible and widely employed for hematological cancers… but what does the future hold for solid tumor MRD technologies? Written by Alex Kernagis, Rayna Saldanha, Claire Liddy and Bryan Kaplan.
A New Frontier
The niche space of minimal residual disease testing is quickly growing within the world of biotech due to great strides in sequencing and biopsy technology development over the last decade. Minimal residual disease (MRD) is a term used to describe detectable residual fragments of cancer in patients who have had cancer treatment with a curative intent such as surgery or chemotherapy. The presence of these cancer fragments post-treatment have been shown to put patients at a higher risk of cancer relapse.
These MRDs can come in various forms depending on the type of disease and can often be detected using specialized assays, commonly used in laboratories to detect the presence, amount or activity of target material or specific biomarkers. There are many different ways of creating suitable assays, but the determining factor for which underlying method of technology is adopted lies primarily in the type of cancer from which the MRD emerges. The difference in assay development between hematological (blood-based) cancers and solid tumor cancers is quite stark.
For hematological cancers, it has become standard procedure to use liquid biopsy assays to monitor MRD post-treatment due to the relatively straightforward nature of monitoring residual cancer in blood when dealing with blood-based cancers. There is little need for personalization and the nature of the cancer allows for a far lower minimum DNA requirement, allowing for standardization and less effort when mass producing because there exist little requirements for patient specific reagents.
However, monitoring MRD in solid tumor cancers is a much newer and largely unexplored field, mostly due to the greater tech specifications required for proper performance.
Caveats for Solid Tumors
When compared to hematological cancers, solid tumors yield far lower amounts of detectable biomarkers post-resection — resulting in the need for far greater performance requirements to detect residual disease. In addition, most solid tumors are genetically unique to individual patients, making it harder to use standardized and non-personalized assays. These assays are more difficult to design and have more intensive sequencing requirements.
As hematological cancers yield much higher rates of ctDNA, hematological assays have higher DNA requirements, allowing them to avoid the growth of false negatives. This is in direct contrast to the solid tumor MRD industry, marked by a race between companies seeking to bolster their specificity and sensitivity performances to reach far lower levels of ctDNA than their hematological cancer counterparts.
The Importance of Sequencing
The development of most MRD assays for solid tumors, especially for the creation of personalized assays for individual patients, utilize resected tumor tissue to identify patient-specific tumor mutation targets that are subsequently built into the assay. Most assays within the industry are in fact tumor-informed, allowing the technology to achieve the sensitivities and specificities required to ensure extremely low false positive rates and proper biomarker detection rates. The need for rigorous sequencing is arguably the largest differentiating factor between current hematological and upcoming solid-tumor assays.
Whole exome sequencing, a technique that maps out a patient’s entire genome, is the most common resected tissue sequencing technique employed by the most promising assays in development. This allows clinicians to identify mutations in the genetic sequence that have given rise to cancer tumors and are present in their fragments (MRDs). By mapping out these mutations, the assay can be customized to target those personalized mutations, and therefore the presence of MRD.
However, one of the limitations of these developing solid tumors assays is the simple difficulty of being tumor-informed.
In late stage or post-resection cases where the cancer has undergone metastasis, causing the origin point of the cancer to become ambiguous, it becomes far more difficult for the assay to gain sufficient genomic information.
There are currently a handful of firms in the industry that are in the process of developing the assays required to detect MRD for solid tumors, each of which has a different style of biomarker detection and sequencing method.
For the most part, the assays in development are either foundationally dependent on polymerase chain reaction (PCR) or multiplex flow cytometry (MPFC).
PCR is especially unique in that it has the characteristic of being tracked in real time. By using quantitative PCR (qPCR) techniques, accurate measures can be taken in real time as the MRD is being shed by solid tumors, even in minimal amounts, allowing for highly sensitive and specific measurements. Similarly, MPFC utilizes a similar technique — using fluorescent tags that are analyzed simultaneously as the MRD is being released.
The most promising biomarkers targeted by assays include circulating tumor DNA (ctDNA), circulating tumor cells (CTC) and ctDNA/methylation.
Circulating tumor DNA (ctDNA) is a clear frontrunner for MRD detection due to its accessible detectability and comparatively higher presence within the body. However, ctDNA/methylation detection has recently been gaining traction by firms and shows potential for further research and development. Accelerating improvements in ctDNA detection should allow further accessibility for personalized treatments or even treatment before recurrence of the cancer.
Future Developments and Insights
There also exist outlier technologies that are beginning to challenge traditional whole exome sequencing with ultra-high coverage values. We are beginning to see companies experiment with the use of extremely low coverage values, allowing for greater breadth, input material and optimal detection sites. In addition, methylation techniques have arisen as one of the largest challengers to traditional sequencing, especially for early cancer detection, and also show promise for monitoring purposes. Another growingly successful technology has been the development of CTC (circulating tumor cell) capture technologies that can be used in combination with ctDNA biopsy platforms — effectively creating a safety net for detection and significantly boosting overall sensitivity.
The commercialization of MRD assays for solid tumor cancers has lagged behind those of hematological assays for a couple reasons. Some of the key culminating advances in the field have only recently arisen, and it has historically proven to be extremely difficult to gain approval because of the strict performance standards set by the FDA, although most leading firms have been publishing clinical results for their assays — quoting relatively high figures for assay sensitivities and specificities.
As of December 2020, companies have yet to receive FDA approval and commercialize their technologies, indicating that far more research and development may be required than originally imagined, OR that we may be on track to witness a wave of approvals within the next couple years.
However, one thing is for certain, an approved and commercializable assay would require consistently high levels of sensitivity and specificities, as their results will dictate further post-resection clinical treatment for patients (such as chemotherapy) making their accuracy and validity highly imperative.
The industry is increasingly growing in size, and in a best-case scenario, the most successful commercially available assays for monitoring solid tumor MRD will hopefully begin to hit the market throughout the next couple years. Many large bets on the efficacy of the industry have been wagered in the form of multi-billion dollar acquisitions by biotechnology companies, the largest of which have been the acquisitions of ArcherDx and GRAIL by Invitae and Illumina, respectively.
ArcherDx is currently in the process of developing and approving their technology, while GRAIL is still focused on their detection platform, but appears to have plans to use their methylation technology for MRD in the near-term future.
It remains to be seen whether these ten-figure wagers will yield a significant return on investment within the MRD industry due to the sheer lack of commercialization, although GRAIL’s methylation is already proving to be a disruptor in the early detection market.
Some of the largest remaining questions are the frequency of MRD testing post-treatment and the cost of testing. The two are ultimately inextricably linked, which is why it appears as though most companies are just beginning to self-determine these figures as they dive further into commercialization phases. In-house tests appear to be less expensive on a cost-basis than their at-home counterpart, however both methods yield unique advantages and downsides regarding turnaround speed, reliability. Many insurers are only beginning to cover MRD testing for post-operative patients, and as more assays become FDA approved, these rates will gradually begin to rise.
Over the next couple years, it will be incredibly exciting to watch these technologies emerge in the unexplored marketplace of MRD monitoring for solid tumors. Hopefully these rising and emerging treatments can become as commonplace as the MRD tests for hematological cancers , helping to reduce the overall rate of solid tumor relapse.