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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Tumor-Informed ddPCR for Personalized Longitudinal ctDNA Monitoring in Advanced Solid Tumors: Molecular–Radiological Concordance and Molecular Lead Time

  • Dadasaheb Akolkar1
  • Sneha Puranik1
  • Sachin Apurwa1
  • Shivani Chaudhari1
  • Pratiksha Nandre1
  • Swapnil Puranik1
  • Vinayak Rao1
  • Raja Dhasarathan2
  • Navin Srivastava1
  • Darshana Patil1
  • Vineet Datta1
  • Prashant Kumar1
4 more authors
  • Raymond Page3
  • Stefan Schuster4
  • Ajay Srinivasan1
  • Rajan Datar1
4 affiliations
  1. 1Research and Innovations, Datar Cancer Genetics (Pvt) Ltd., Nasik 422010, MH, India
  2. 2Quality Assurance, Datar Cancer Genetics UK (Pvt) Ltd., Guildford GU2 7YD, UK
  3. 3Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA 01609, USA
  4. 4Research and Innovations, Datar Cancer Genetics Europe GmbH, 95447 Bayreuth, Germany
Open at sourceDOICite

Abstract

Serial circulating tumor DNA (ctDNA) monitoring may complement episodic radiological response assessment during systemic therapy. We evaluated personalized tumor-informed droplet digital PCR (ddPCR) for longitudinal ctDNA monitoring in advanced solid tumors, focusing on RECIST-associated ctDNA levels, anatomical tumor burden, molecular–radiological concordance, molecular lead time (MLT), and routine implementation. The clinical cohort comprised 61 patients with breast, colorectal, gynecological, head and neck, lung, pancreaticobiliary, or other advanced solid tumors and 385 longitudinal patient-specific ddPCR assessments; 357 assessments were imaging-concurrent. Repeated RECIST-stratified measurements were evaluated descriptively and using patient-clustered generalized estimating equations (GEEs). Longitudinal trajectories were classified using study-specific Longitudinal Concordance Level (LCL) and Molecular Evidence Level (MEL) frameworks. A separate real-world implementation cohort comprised 270 patients and 650 personalized ddPCR assays; 88 patients underwent two or more serial assessments. Among the 357 imaging-concurrent assessments, 90 were partial response (PR), 117 stable disease (SD), and 150 progressive disease (PD). Median VAF was 0.055% in PR, 0.190% in SD, and 0.205% in PD. Patient-clustered GEEs confirmed an overall association between VAF and RECIST category (Wald χ2 = 12.60, p = 0.00183), with lower VAF in PR than SD (Holm-adjusted p = 0.00119) or PD (p = 0.00247), but no separation between SD and PD (p = 0.539). In 210 imaging–ctDNA pairs from 53 patients, correlations with estimated tumor volume (ρ = 0.169) and RECIST SLD (ρ = 0.177) were weak. Of 50 evaluable longitudinal trajectories, 21 (42.0%) were LCL-1. Among 14 patients who developed radiological PD after an initial PR or SD, molecular progression preceded radiological progression in 9 (64.3%), was concurrent in 3 (21.4%), and no qualifying pre-radiological molecular-progression event was identified in 2 (14.3%); positive MLTs had a median of 55 days (IQR 46–83; range 28–209). The real-world cohort included five genomic alteration classes and a median assay-specific LoD of 0.020% VAF (IQR 0.020–0.030%). Personalized tumor-informed ddPCR showed population-level association with RECIST response and structured longitudinal molecular–radiological relationships, while substantial VAF overlap and weak anatomical-burden correlations limit interpretation of isolated measurements. Molecular progression preceded imaging-defined progression in a subset of patients, supporting prospective evaluation of ctDNA-triggered reassessment rather than establishing benefit from ctDNA-guided intervention. The separate real-world cohort supports operational feasibility across diverse assay designs.

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Cite

BibTeXRIS
BibTeX
@article{akolkar2026tumorinformed,
  title = {{Tumor-Informed ddPCR for Personalized Longitudinal ctDNA Monitoring in Advanced Solid Tumors: Molecular–Radiological Concordance and Molecular Lead Time}},
  author = {Dadasaheb Akolkar and Sneha Puranik and Sachin Apurwa and Shivani Chaudhari and Pratiksha Nandre and Swapnil Puranik and Vinayak Rao and Raja Dhasarathan and Navin Srivastava and Darshana Patil and Vineet Datta and Prashant Kumar and Raymond Page and Stefan Schuster and Ajay Srinivasan and Rajan Datar},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = sep,
  doi = {10.3390/ijms27188340},
  url = {https://www.mdpi.com/1422-0067/27/18/8340},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Tumor-Informed ddPCR for Personalized Longitudinal ctDNA Monitoring in Advanced Solid Tumors: Molecular–Radiological Concordance and Molecular Lead Time
AU  - Dadasaheb Akolkar
AU  - Sneha Puranik
AU  - Sachin Apurwa
AU  - Shivani Chaudhari
AU  - Pratiksha Nandre
AU  - Swapnil Puranik
AU  - Vinayak Rao
AU  - Raja Dhasarathan
AU  - Navin Srivastava
AU  - Darshana Patil
AU  - Vineet Datta
AU  - Prashant Kumar
AU  - Raymond Page
AU  - Stefan Schuster
AU  - Ajay Srinivasan
AU  - Rajan Datar
PY  - 2026
DA  - 2026/09/19
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27188340
UR  - https://www.mdpi.com/1422-0067/27/18/8340
AB  - Serial circulating tumor DNA (ctDNA) monitoring may complement episodic radiological response assessment during systemic therapy. We evaluated personalized tumor-informed droplet digital PCR (ddPCR) for longitudinal ctDNA monitoring in advanced solid tumors, focusing on RECIST-associated ctDNA levels, anatomical tumor burden, molecular–radiological concordance, molecular lead time (MLT), and routine implementation. The clinical cohort comprised 61 patients with breast, colorectal, gynecological, head and neck, lung, pancreaticobiliary, or other advanced solid tumors and 385 longitudinal patient-specific ddPCR assessments; 357 assessments were imaging-concurrent. Repeated RECIST-stratified measurements were evaluated descriptively and using patient-clustered generalized estimating equations (GEEs). Longitudinal trajectories were classified using study-specific Longitudinal Concordance Level (LCL) and Molecular Evidence Level (MEL) frameworks. A separate real-world implementation cohort comprised 270 patients and 650 personalized ddPCR assays; 88 patients underwent two or more serial assessments. Among the 357 imaging-concurrent assessments, 90 were partial response (PR), 117 stable disease (SD), and 150 progressive disease (PD). Median VAF was 0.055% in PR, 0.190% in SD, and 0.205% in PD. Patient-clustered GEEs confirmed an overall association between VAF and RECIST category (Wald χ2 = 12.60, p = 0.00183), with lower VAF in PR than SD (Holm-adjusted p = 0.00119) or PD (p = 0.00247), but no separation between SD and PD (p = 0.539). In 210 imaging–ctDNA pairs from 53 patients, correlations with estimated tumor volume (ρ = 0.169) and RECIST SLD (ρ = 0.177) were weak. Of 50 evaluable longitudinal trajectories, 21 (42.0%) were LCL-1. Among 14 patients who developed radiological PD after an initial PR or SD, molecular progression preceded radiological progression in 9 (64.3%), was concurrent in 3 (21.4%), and no qualifying pre-radiological molecular-progression event was identified in 2 (14.3%); positive MLTs had a median of 55 days (IQR 46–83; range 28–209). The real-world cohort included five genomic alteration classes and a median assay-specific LoD of 0.020% VAF (IQR 0.020–0.030%). Personalized tumor-informed ddPCR showed population-level association with RECIST response and structured longitudinal molecular–radiological relationships, while substantial VAF overlap and weak anatomical-burden correlations limit interpretation of isolated measurements. Molecular progression preceded imaging-defined progression in a subset of patients, supporting prospective evaluation of ctDNA-triggered reassessment rather than establishing benefit from ctDNA-guided intervention. The separate real-world cohort supports operational feasibility across diverse assay designs.
SN  - 1422-0067
ER  -