Mapping tumor heterogeneity: ex-vivo drug responses in matched primary and metastatic tumors using a 3D functional precision platform
- 1University of California San Francisco
Abstract
IntroductionTumors are known to develop genomic heterogeneity over time, particularly in metastatic disease, raising concerns that a single-site biopsy may be insufficient to accurately predict response to medications.
MethodsWe used our 3D microtumor functional profiling platform that preserves key features of the native tumor microenvironment. We tested (i) six split samples from primary tumors and (ii) seven samples from primary tumors (ovarian, colon, and breast cancer) matched with their locoregional or distant metastases. Fresh tissue specimens were processed within 24 hours after surgery and treated with NCCN guideline-recommended chemo or targeted therapies at concentrations over four orders of magnitude. Cytotoxicity was evaluated after three days to generate dose-response curves. The response correlations between the split sample or between the two matched sites were quantified using the concordance correlation coefficient ({rho}c) for the drug efficacy metrics.
ResultsWe compared a total of 275 drug responses. The six split samples resulted in a strong correlation between the two tumor areas ({rho}c=0.95, p<0.001), supporting high assay reproducibility across distinct regions of the same tumor. Locoregional metastases were highly correlated with their primaries (ovarian-omentum {rho}c=0.97, p<0.001; ovarian-liver capsule {rho}c=0.93, p<0.001; colon-peritoneum {rho}c=0.91, p<0.001). A lesser correlation was observed with lymphogenic metastases (breast-axilla {rho}c=0.87, p<0.001), and the correlations of hematogenic metastases were even lower (colon-lung {rho}c=0.69 p<0.001; ovarian-soft tissue/colon {rho}c=0.58, p<0.001). No correlation was observed among specimens that were resistant to all tested medications.
ConclusionTumor drug responses were highly preserved in locoregional metastases, whereas somewhat greater divergence was observed in lymphogenic or hematogenic metastases. Single-site functional profiling may remain informative for identifying treatment resistance and might reduce the risk of ineffective therapy selection in metastatic disease.
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BibTeX
@misc{nitiyanandan2026mapping,
title = {{Mapping tumor heterogeneity: ex-vivo drug responses in matched primary and metastatic tumors using a 3D functional precision platform}},
author = {R. Nitiyanandan and I. Trus and C. Maestri and R. J. Parker and W. Cance and B. Apfel and C. C. Apfel},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.26357781},
url = {https://www.medrxiv.org/content/10.64898/2026.09.22.26357781v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Mapping tumor heterogeneity: ex-vivo drug responses in matched primary and metastatic tumors using a 3D functional precision platform
AU - R. Nitiyanandan
AU - I. Trus
AU - C. Maestri
AU - R. J. Parker
AU - W. Cance
AU - B. Apfel
AU - C. C. Apfel
PY - 2026
DA - 2026/09/22
PB - medRxiv
DO - 10.64898/2026.09.22.26357781
UR - https://www.medrxiv.org/content/10.64898/2026.09.22.26357781v1
AB - IntroductionTumors are known to develop genomic heterogeneity over time, particularly in metastatic disease, raising concerns that a single-site biopsy may be insufficient to accurately predict response to medications. MethodsWe used our 3D microtumor functional profiling platform that preserves key features of the native tumor microenvironment. We tested (i) six split samples from primary tumors and (ii) seven samples from primary tumors (ovarian, colon, and breast cancer) matched with their locoregional or distant metastases. Fresh tissue specimens were processed within 24 hours after surgery and treated with NCCN guideline-recommended chemo or targeted therapies at concentrations over four orders of magnitude. Cytotoxicity was evaluated after three days to generate dose-response curves. The response correlations between the split sample or between the two matched sites were quantified using the concordance correlation coefficient ({rho}c) for the drug efficacy metrics. ResultsWe compared a total of 275 drug responses. The six split samples resulted in a strong correlation between the two tumor areas ({rho}c=0.95, p<0.001), supporting high assay reproducibility across distinct regions of the same tumor. Locoregional metastases were highly correlated with their primaries (ovarian-omentum {rho}c=0.97, p<0.001; ovarian-liver capsule {rho}c=0.93, p<0.001; colon-peritoneum {rho}c=0.91, p<0.001). A lesser correlation was observed with lymphogenic metastases (breast-axilla {rho}c=0.87, p<0.001), and the correlations of hematogenic metastases were even lower (colon-lung {rho}c=0.69 p<0.001; ovarian-soft tissue/colon {rho}c=0.58, p<0.001). No correlation was observed among specimens that were resistant to all tested medications. ConclusionTumor drug responses were highly preserved in locoregional metastases, whereas somewhat greater divergence was observed in lymphogenic or hematogenic metastases. Single-site functional profiling may remain informative for identifying treatment resistance and might reduce the risk of ineffective therapy selection in metastatic disease.
ER -