Northfelt, D. W. | bioRxiv Science

bioRxiv2022

Integration of multi-omics data shows downregulation of mismatch repair, purin, and tublin pathways in AR-negative triple-negative chemotherapy-resistant breast tumors

Triple negative breast cancer (TNBC) patients who fail to achieve a pathological complete response to neoadjuvant chemotherapy (NAC) will likely experience recurrence of the disease within 3-4 years. Prognostic assessment of early recurrence could facilitate clinical decisions and impact disease survival. This study investigated pre- and post-NAC multi-omics data from both an in-house and a public clinical study to identify biomarkers of NAC response. We observed significant transcriptional differences associated with response in the residual disease (post-NAC biopsies), which did not exist in the pre-NAC biopsies. We further refined the post-NAC transcriptional changes to a 17-gene signature and machine learning models were applied to evaluate the signatures diagnostic potential (area under the curve [≥] 0.8). Interestingly, the signature was enriched with down-regulated immune genes and several of these genes demonstrated prognostic potential in basal TNBC tumors. Our 17-gene signature provides additional insight into TNBC recurrence, which warrants further investigation.

cancer biology↗

bioRxiv2018

Detection of residual disease after neoadjuvant therapy in breast cancer using personalized circulating tumor DNA analysis

Accurate detection of minimal residual disease (MRD) can guide individualized management of early stage cancer patients, but current diagnostic approaches lack adequate sensitivity. Circulating tumor DNA (ctDNA) analysis has shown promise for recurrence monitoring but MRD detection immediately after neoadjuvant therapy or surgical resection has remained challenging. We have developed TARgeted DIgital Sequencing (TARDIS) to simultaneously analyze multiple patient-specific cancer mutations in plasma and improve sensitivity for minute quantities of residual tumor DNA. In 77 reference samples at 0.03%-1% mutant allele fraction (AF), we observed 93.5% sensitivity. Using TARDIS, we analyzed ctDNA in 34 samples from 13 patients with stage II/III breast cancer treated with neoadjuvant therapy. Prior to treatment, we detected ctDNA in 12/12 patients at 0.002%-1.04% AF (0.040% median). After completion of neoadjuvant therapy, we detected ctDNA in 7/8 patients with residual disease observed at surgery and in 1/5 patients with pathological complete response (odds ratio, 18.5, Fishers exact p=0.032). These results demonstrate high accuracy for a personalized blood test to detect residual disease after neoadjuvant therapy. With additional clinical validation, TARDIS could identify patients with molecular complete response after neoadjuvant therapy who may be candidates for nonoperative management.\n\nOne Sentence SummaryA personalized ctDNA test achieves high accuracy for residual disease.

genomics↗