Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development

Pal, Abhijit; Shinde, Rajiv; Miralles, Manuel Selvi; Workman, Paul; Bono, Johann S. de

doi:10.1038/s41571-021-00489-x

“…An important aspect of TISF ctDNA is that it embeds the evolutionary history of the tumor, a fundamental biological element that cannot be directly measured in humans until now [17][18][19], the main reason is the di culty of obtaining samples [20]. Nevertheless, understanding that history may be critical in developing targeted drugs [21].Therefore, the main message of this study is that tumor gene mutation must be investigated in depth from the point of view of tumor evolution if we are to reveal postoperative brain glioma true behavior.…”

Section: Discussionmentioning

confidence: 99%

Reveal Postoperative Brain Glioma True Behavior by Real-Time Tracking of Tumor Gene Evolution Information

Bu

¹

,

Sheng

²

,

Deng

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Background At present, the in vivo gene evolution of human glioma after surgery is unknown. We need to understand the real-time in vivo gene evolution information of the tumor to dynamically reflect the real behavior of the tumor, so as to drive therapeutic decisions. TISF-ctDNA can provide real-time in vivo gene information after surgery, and then reveal postoperative glioma behavior more realistically. Methods This retrospective, Single center, sample collection, validation study conducted at Zheng Zhou University People's hospital from July 1st, 2016, to November 1st, 2021, assessed patients with glioma who were receiving surgical treatment and adjuvant radiotherapy and chemotherapy. The study including 69 patients, with radiological relapse identified in 44 patients forming the main cohort. RESULTS In the primary tumor, a total of 199 mutations were detected in 58 tumor tissue samples,12 patients (21%) with 1 mutation and 45 patients (79%) with multiple mutations,TP53 (44%) followed by IDH1(39%) and PTEN(25%), mean VAF from 2.1%-79.5%,with a median 40.5%.At or after a diagnosis of recurrence, A total of 613 gene mutations were found through TISF ctDNA sequencing, including TP53 (48%), NF1 (38%), PTEN (31%), mean VAF from 0.2%-34.14%, with a median 1.54%, and we also found Pseudo-progression and hypermutation associated with TMZ resistance. In the main cohort of 44 patients (mean age, 52 years) with a median follow-up of 190 days (20-1530 days), mean VAF of TISF ctDNA during follow-up was associated with relapse (hazard ratio, 4.058; 95% CI, 1.089 to 15.12; P = 0.0012). Similar outcomes were observed for tumor tissue (hazard ratio, 2.214; 95% CI, 1.003 to 4.887; P = 0.0165). Hypermutation was found in 3 patients in the cohort, and the in vivo evolution of hypermutation was tracked in 2 of these patients. CONCLUSIONS TISF ctDNA describes human glioma behavior, demonstrates the real tumor gene mutation landscape in vivo during treatment, providing prognostic and response data of clinical relevance.

show abstract

“…Targeted NGS, whole-exome sequencing and whole-genome sequencing of cfDNA or ctDNA, as well as analysis of circulating tumor cells, are receiving tremendous attention towards implementation into the clinical setting for early diagnosis, individualized prediction of drug response, patient monitoring to readily detect relapse and drug development ( 30 , 41 ). Indeed, beyond large innovative projects ( 42 ), several comprehensive pan-cancer multi-gene panels, including for CRC, have already been developed and approved by federal regulatory institutions as companion diagnostics for tumor profiling within modern guidelines, highlighting the introduction of Precision Oncology into clinical practice ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Proof-of-Concept Pilot Study on Comprehensive Spatiotemporal Intra-Patient Heterogeneity for Colorectal Cancer With Liver Metastasis

Kyrochristos

¹

,

Glantzounis

²

,

Goussia

³

et al. 2022

Front. Oncol.

4

0

View full text Add to dashboard Cite

IntroductionThe mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood.ObjectiveWe evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability.MethodsA total of 122 multi-regional tumor and perioperative liquid biopsies from 18 patients were analyzed via targeted next-generation sequencing (NGS).ResultsThe proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored mutations targetable by molecularly targeted drugs, either approved or currently under evaluation.ConclusionOur proof-of-concept prospective study provides initial evidence on potential clinical superiority of IPH and warrants the conduction of precision oncology trials to evaluate the clinical utility of I PH-driven matched therapy.

show abstract

“…An important aspect of TISF ctDNA is that it embeds the evolutionary history of the tumor, a fundamental biological element that cannot be directly measured in humans until now [17][18][19], the main reason is the di culty of obtaining samples [20]. Nevertheless, understanding that history may be critical in developing targeted drugs [21].Therefore, the main message of this study is that tumor gene mutation must be investigated in depth from the point of view of tumor evolution if we are to reveal postoperative brain glioma true behavior.…”

Section: Discussionmentioning

confidence: 99%

Reveal Postoperative Brain Glioma True Behavior by Real-time Tracking of tumor gene evolution information

Bu

¹

,

Sheng

²

,

Deng

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Background At present, the in vivo gene evolution of human glioma after surgery is unknown. We need to understand the real-time in vivo gene evolution information of the tumor to dynamically reflect the real behavior of the tumor, so as to drive therapeutic decisions. TISF-ctDNA can provide real-time in vivo gene information after surgery, and then reveal postoperative glioma behavior more realistically. Methods This retrospective, Single center, sample collection, validation study conducted at Zheng Zhou University People's hospital from July 1st, 2016, to November 1st, 2021, assessed patients with glioma who were receiving surgical treatment and adjuvant radiotherapy and chemotherapy. The study including 69 patients, with radiological relapse identified in 44 patients forming the main cohort. RESULTS In the primary tumor, a total of 199 mutations were detected in 58 tumor tissue samples,12 patients (21%) with 1 mutation and 45 patients (79%) with multiple mutations,TP53 (44%) followed by IDH1(39%) and PTEN(25%), mean VAF from 2.1%-79.5%,with a median 40.5%.At or after a diagnosis of recurrence, A total of 613 gene mutations were found through TISF ctDNA sequencing, including TP53 (48%), NF1 (38%), PTEN (31%), mean VAF from 0.2%-34.14%, with a median 1.54%, and we also found Pseudo-progression and hypermutation associated with TMZ resistance. In the main cohort of 44 patients (mean age, 52 years) with a median follow-up of 190 days (20-1530 days), mean VAF of TISF ctDNA during follow-up was associated with relapse (hazard ratio, 4.058; 95% CI, 1.089 to 15.12; P = 0.0012). Similar outcomes were observed for tumor tissue (hazard ratio, 2.214; 95% CI, 1.003 to 4.887; P = 0.0165). Hypermutation was found in 3 patients in the cohort, and the in vivo evolution of hypermutation was tracked in 2 of these patients. CONCLUSIONS TISF ctDNA describes human glioma behavior, demonstrates the real tumor gene mutation landscape in vivo during treatment, providing prognostic and response data of clinical relevance.

show abstract

Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development

Cited by 19 publications

References 154 publications

Reveal Postoperative Brain Glioma True Behavior by Real-Time Tracking of Tumor Gene Evolution Information

Reveal Postoperative Brain Glioma True Behavior by Real-Time Tracking of Tumor Gene Evolution Information

Proof-of-Concept Pilot Study on Comprehensive Spatiotemporal Intra-Patient Heterogeneity for Colorectal Cancer With Liver Metastasis

Reveal Postoperative Brain Glioma True Behavior by Real-time Tracking of tumor gene evolution information

Contact Info

Product

Resources

About