By Diagnostics World Staff
March 5, 2025 | In a paper published last month in Nature Scientific Reports (DOI: 10.1038/s41598-025-90013-3), authors validate Northstar Response, BillionToOne's novel tissue-free circulating tumor DNA (ctDNA) liquid biopsy test that enables physicians to monitor cancer treatment response in Stage III-IV cancers with a blood draw.
Northstar Response is a pan-cancer assay that enables physicians to longitudinally monitor a patient's response to therapy by monitoring hundreds of cancer-specific methylation sites using blood samples. This method can enable a more robust approach to monitoring, given the rapid evolution of tumors in late-stage cancers under systemic therapy. The test’s Tumor Methylation Scores correlate with clinical outcomes, which can potentially allow physicians to detect treatment resistance significantly earlier than conventional imaging.
The assay's foundation is BillionToOne's patented Quantitative Counting Template (QCT) technology, which acts as a “molecular ruler” that enables absolute quantification down to a single molecule level, bringing new precision to NGS-based analysis in molecular diagnostics. When applied to Northstar Response, this translates to the ability to accurately discriminate between small differences in ctDNA burden with high precision (i.e. tumor fraction changes as small as 0.25%).
In the study, researchers queried The Cancer Genome Atlas (TCGA) for subjects with methylation data from matched tumor and normal tissue of the following cancer types: bladder urothelial carcinoma, breast invasive carcinoma, colon adenocarcinoma, esophageal carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, and uterine corpus endometrial carcinoma. To choose targets for normalization loci that are highly methylated in buffy coat, tumor, and normal tissue, methylation data were analyzed from six tumor tissue types: breast invasive carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma.
To test whether the assay could detect changes in methylation that were concordant with clinical outcomes, samples were prospectively collected from cancer patients at Ochsner Health (New Orleans, LA) and Christus Health (Irving, TX) on behalf of Accio Biobank Online (UK) and iSpecimen (Lexington, MA). Patients that were diagnosed with cancer and had not started treatment were enrolled.
Methylation in Broad Monitoring
“Northstar Response maintained accuracy and sensitivity across a diversity of tumors and patients, suggesting that methylation-based therapy response monitoring has the potential to benefit a broad patient population,” the authors write in their discussion. “The assay correctly detected increases from 1 to 2% tumor fraction with 98.1% sensitivity for 54 solid tumors from 12 distinct tissue types.”
They continue: “Despite the heterogeneity often observed in cancer biology, this implies that sampling a panel of hypermethylated loci enables tumor-naive tracking of tumor progression in a variety of tissue types. In the future, additional tumor samples from untested tissues of origin should be tested to further validate the assay as an effective therapy response monitoring test for all solid tumors.”
This pan-cancer analytical validation follows the recent publication of a separate clinical validity and utility study in Clinical Lung Cancer (DOI: 10.1016/j.cllc.2024.10.013) that examined the correlation between Tumor Methylation Scores and therapy response in a real-world setting that successfully predicted anti-PD1/immunotherapy response in late-stage NSCLC patients. In that study, Northstar Response's changes in TMS measured 4-10 weeks after starting anti-PD1 based immunotherapy treatment significantly predicted real-world progression free survival (rwPFS, P < 0.0001), compared to standard imaging assessments which did not reach statistical significance (P = 0.55). The study showed that the test reliably detected treatment response and progression earlier than CT scans, with high concordance between TMS and clinical outcomes.
"Traditional methods for monitoring cancer treatment response, such as imaging, are limited by infrequent testing schedules, inability to detect subtle tumor changes, and other problems such as pseudo-progression," said Gary Palmer, Chief Medical Officer, Oncology at BillionToOne in a press release. "Northstar Response can measure tumor burden at the molecular level, adding an unprecedented level of precision to cancer monitoring. Northstar Response's precise quantification of the tumor burden is an important aspect for therapy response monitoring in late-stage cancers. It is differentiated compared to minimal residual disease (MRD) assays that are typically designed for Stage I-II cancers with fundamentally qualitative ctDNA positive/negative assessments."