Molecular residual disease (MRD) has grown in importance as an oncological biomarker1. The use of tumor-informed liquid biopsy has proven effective in early detection of circulating tumor-derived DNA (ctDNA) indicative of cancer recurrence. Standard-of-care radiological-based technologies, including CT, PET, and MRI scans, are limited in their ability to detect MRD due to the minimum tumor volume required2. First generation ctDNA technologies offered earlier detection than imaging, but lacked the sensitivity needed for robust post-diagnosis monitoring. Therefore, reliable, ultra-sensitive detection and quantification of MRD capable of guiding clinical decisions from the earliest stages has remained the goal.
To fill the gap, an industry-leading ctDNA technology has evolved to achieve a sensitivity in the range of 1-3 parts per million, representing a 10-100X increase over other available methods, while requiring only a single tube of blood and 1mm3 of tumor tissue3. At this level of sensitivity, ctDNA holds great potential both in drug development4 and as a clinical tool. When paired with next generation genomic sequencing, this breakthrough technology - NeXT Personal - enables early identification of cancer mutations to rapidly assess therapeutic effect and inform post-resection therapy. NeXT Personal enables detection and quantification of both MRD and clinically-relevant variants in a single platform.
And as described in this article, ctDNA biomarker efficacy in clinical trial design and translational research is growing, building a strong case for ctDNA analysis, where NeXT Personal is poised to make an impact in oncology.
Detecting ESR1 mutation resistance to aromatase inhibitors
Aromatase inhibitors are a class of drugs used in the treatment of breast cancer. Tumors can become resistant to aromatase inhibitors through mutations of Estrogen Receptor alpha (ESR1), which are frequent during disease progression on aromatase-based first-line therapy. French researchers investigated a new intervention among hormone receptor-positive metastatic breast cancer patients5. PADA-1 was the first trial to demonstrate that ESR1 mutations can be detected and targeted before disease progression. After detecting the mutations in cell-free DNA, the team initiated a therapeutic switch from an aromatase inhibitor plus palbociclib to Fulvestrant and palbociclib. This switch resulted in doubled progression-free survival in the phase III PADA-1 trial.
Interestingly, switching the therapy after disease progression resulted in a minor benefit. While Fulvestrant is unaffected by the ESR1 mutations, it did provide limited progression-free survival when used as a second-line therapy, highlighting the importance of detecting ESR1 mutations during first-line aromatase therapy and before disease progression. Moreover, the researchers concluded that monitoring the rise in resistance-associated mutations may create opportunities related to new therapeutic agents. To this point, ctDNA assessment using tumor-informed whole genome sequencing-based and fixed guideline-driven panels in a single assay provides unprecedented insights and facilitates longitudinal therapy response analysis, including variant tracking and proactive monitoring of resistance mechanisms3.
Predicting clinical outcomes sooner with MRD
Neoantigens derived from tumor-specific mutations are promising immunotherapy targets that can be incorporated in personalized therapeutic cancer vaccines (PTCV) to boost T-cell activation. Findings were presented at the Society for Immunotherapy of Cancer 37th Annual Meeting6 illustrating the correlation of disease status (using RECIST 1.1) with ctDNA levels relative to baseline.
Researchers treated patients with unresectable or metastatic hepatocellular carcinoma that were non-responsive to first-line tyrosine kinase inhibitor therapy, with PTCV. They observed a strong correlation between ctDNA quantification and tumor size over 2 years. Importantly, changes in ctDNA measured prior to MRI scans and RECIST 1.1. analysis were directly associated with objective clinical response such as overall survival, with no false-negatives reported. These results show that longitudinal high-sensitivity ctDNA monitoring3 could help predict clinical outcome and guide real time clinical treatment decisions for personalized cancer therapy.
Ease of ctDNA sample handling and analysis, along with rapidly accessible MRD data offer significant advantages for fast and effective drug development. Excitingly, the value of longitudinal ctDNA measurement as a dynamic biomarker for treatment response prediction, understanding of emergent tumor variants and real time clinical treatment decision-making is supported by a growing body of evidence. Learn more about how partnerships between drug and diagnostic developers can enable a highly-personalized approach to cancer management in this upcoming Fierce Webinar.
References:
- Peng, Y. et al. Front Oncol. 11, 763790 (2021)
- Adler, S. et al. EJNMMI Phys. 4, 13 (2017)
- Personalis, Inc. Delivering Industry-Leading Sensitivity to Detect Residual Disease and Recurrence at the Earliest Timepoints
- clinicaltrials.gov.
- Bidard, F.-C. et al. in Cancer Research 82, GS3-05 (2022)
- Perales, R. et al. in (2022) (poster 692 at 37th SITC annual meeting)