Abstract
PurposeSelection of cytotoxic chemotherapy agents (CCA) based on pre-treatment evaluation of drug sensitivities is a desirable but unmet goal for personalized anticancer treatment strategies. Prior attempts to correlate in vitro Chemo-Response Profiles (CRP) of tumor explants or Circulating Tumor Cells (CTCs) with clinical outcomes have been largely unsuccessful.MethodsWe present results from a large cohort (n = 5090, three Arms) of patients with various solid organ tumors, where CRP of Circulating Tumor-Associated Cells (C-TACs) was determined against cancer-specific CCA panels to generate a database of 56,466 unique CRP.ResultsIn Arm 1 (n = 230), 93.7% concordance was observed between CRP of C-TACs and concurrently obtained Tumor tissue Derived Cells (TDCs). In arm 2 (n = 2201, pretreated), resistance of C-TACs to ≥ 1 CCA was observed in 79% of cases. In a blinded subset analysis of 143 pretreated patients with radiologically ascertained disease progression, CRP of C-TACs was 87% concordant with in vivo treatment failure. In Arm 3 (n = 2734, therapy naïve), innate resistance of C-TACs to ≥ 1 CCA was observed in 61% of cases. In a blinded subset analysis of 77 therapy naïve patients, in vitro chemo-sensitivity of C-TACs was concordant with radiologically ascertained treatment response to first line CCA in 97% of cases.ConclusionTo our knowledge, this is the first expansive and in-depth study demonstrating that real-time CRP of C-TACs is a viable approach for non-invasive assessment of response to CCA in solid organ cancers.
Highlights
Despite the development of targeted anticancer therapies such as Tyrosine Kinase Inhibitors (TKI) and Immune Checkpoint Inhibitors (ICI), Cytotoxic Chemotherapy Agents (CCA) remain essential agents in the neo-adjuvant, adjuvant and metastatic settings in the management of most solid tumors
CCA sensitivities of circulating tumor‐associated cells (C‐TACs) are concordant with tissue Derived Cells (TDCs)
Though it is agreed that timely identification of drug resistance is critical for optimal therapy management, there are presently no technologies or biomarkers for real time surveillance or prospectively determining drug resistance
Summary
Despite the development of targeted anticancer therapies such as Tyrosine Kinase Inhibitors (TKI) and Immune Checkpoint Inhibitors (ICI), Cytotoxic Chemotherapy Agents (CCA) remain essential agents in the neo-adjuvant, adjuvant and metastatic settings in the management of most solid tumors. Choice of monotherapy or combination chemotherapy regimens is largely based on clinical guidelines with minimal or no guidance from molecular or functional indications. This inability to inform optimal therapy in individual patients and subsequently low response rates reflect the limitations of such non-personalized therapy selection. Resistance to CCA is random, and unpredictable, and becomes apparent only at response evaluation imaging or clinical assessment. This inability to detect emerging sub-clinical drug resistance in real time is the undeniable Achilles heel of purposive strategic vigilance against treatment failure
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