Natalie LaFranzo, PhD
Director, Marketing Communications

Beyond MRD: Developing patient-centered diagnostics through tumor-informed comprehensive insights

A recap of a roundtable discussion with industry thought leaders

In March 2022, Personalis jumped back into in-person meetings with a series of oncology executive events organized by hubXchange on both the east and west coasts of the United States. First, on March 15, Personalis joined a group of approximately 50 leaders from pharma, healthcare, and biotech at hubXchange’s East Coast Hybrid Oncology Companion Diagnostics program in Boston. This intimate meeting brought together executives from across the precision medicine ecosystem to discuss some of the most pressing challenges for implementing genomics-led precision medicine strategies in oncology.

In addition to joining a number of facilitated roundtable discussions focused on topics including clinical biomarkers, clinical development, and next-generation companion diagnostics (CDx), Personalis also hosted its own roundtable discussion centered on liquid biopsy assays. Below is a brief summary of the key points addressed during the discussions, and some of the challenges that were highlighted during the discussions.

Tumor Agnostic vs. Tumor Informed Assays

The roundtable kicked off with a discussion regarding the advantages and challenges of tumor-agnostic vs. tumor-informed assays. The group agreed that sensitivity is greatly improved through tumor-informed approaches. For example, NeXT Personal™ has been shown to have 100-fold analytical sensitivity over tumor-agnostic approaches. However, the group also acknowledged that some tumors are either not resectable, or are difficult to resect, and so there is also a clinical need for tumor-agnostic approaches.

When considering the utility of variant tracking for treatment decisions, the group agreed that there is value in understanding the dynamic evolution of variants, such as tumor-derived driver mutations, tumor-specific mutations, and/or variants of clinical and biological relevance, such as where there is an FDA-approved therapy. With a tumor-informed and customized approach, NeXT Personal customers have the opportunity to add additional content that may be important for analyzing the results of the specific treatment plan or clinical trial, such as PARPi genes, targeted genes, etc.

Impact of Sensitivity

The impact of sensitivity was noted as being particularly important in earlier stages of disease, and for those cancer types where tumors are known to shed less DNA. Therefore, it is clear there is significant value in continuing to increase the sensitivity of ctDNA detection in these clinical areas. Importantly, it was recognized that there will always be variability across patients, cancer stages, and cancer types, and therefore a consistent, high-sensitivity assay that is validated in multiple indications is essential. Personalis achieves its impressive analytical sensitivity from only 15 ng DNA from 4 ml plasma (across multiple cancer types), which includes both wet-lab and bioinformatic approaches to reducing noise and improving variant tracking.

It was noted in the discussion that, in some indications (e.g., prostate cancer), advanced ctDNA assays will need to show utility and positive health economics to justify the use of a higher complexity test, as compared to the inexpensive standard of care test (e.g., prostate-specific antigen (PSA) blood test).

Qualitative vs. Quantitative Molecular Residual Disease (MRD)

While there was clear agreement that quantitative MRD provides more biological information, it was noted that additional clinical studies are essential to understand the additional utility of quantitative assessment. Personalis noted that it has many clinical collaborations that are underway with partners who are disease-experts across multiple indications.

Clinical Path for Laboratory Developed Tests

The discussion next led to the path forward for laboratory developed assays to be utilized in clinical trials and for CDx development. The group emphasized the need for partners to be open and collaborative when addressing reimbursement pathways, as reimbursement is essential for clinical adoption. The Personalis team discussed its CAP/CLIA laboratory and validation study design for NeXT Personal, and how its collaborations (described above) are an essential part of demonstrating the clinical utility of its assay and facilitates the creation of its dossier for reimbursement. The Personalis team also shared how it is able to process retrospective clinical trial samples, including using ImmunoID NeXT in China with our Shanghai laboratory.

What is the ideal ctDNA assay?

The group quipped – cheap and fast, of course!

While suggested somewhat in jest, the group unpacked the needs of the community including cost and turnaround time. A timeframe of 3-5 days from specimen submission to results was considered ideal, but anything shorter than 10 days is acceptable. Importantly, the data must be clinically useful. And, all were in agreement that there may be no compromises on sensitivity and specificity in detecting MRD; the performance of ctDNA assays must continue to improve to avoid false positives and, perhaps just as importantly, false negatives. The conversation shifted to the need to go beyond ctDNA and look at other facets of biology including RNA markers, immune signals, etc. Personalis reflected on how this could be accomplished by combining our two molecular workstreams – NeXT Personal and ImmunoID NeXT – from the same tissue and blood specimens. With this approach, customers would gain access to immunogenetic profiling (DNA, RNA, and immune markers) alongside the MRD and variant data from NeXT Personal. The group agreed this comprehensive approach is an important step forward for interrogating the breadth of biology to better characterize disease.  Further, thinking about how to measure emerging biomarkers in the blood including CHIP variants, blood-based TMB, methylome and 5HMC may prove to be valuable.

Returning to in person events has been both exciting and rewarding! This roundtable discussion reinforced the need to continue advancing the technologies available for ctDNA testing and ensuring the most sensitive and specific assays are available for clinical trials and clinical practice. The Personalis team has been eager to reconnect with friends and colleagues and reflect on the progress that’s being made in advancing the field of oncology genomics. We look forward to seeing you at AACR and sharing more about our NeXT Personal tumor-informed ctDNA assay.

Please note: the NeXT Personal assay is currently intended for Research Use Only and not for use in diagnostic procedures.