Cutoff value of IC50 for drug sensitivity in patient-derived tumor organoids in colorectal cancer

Tang, Yuting; Wang, Ting; Hu, Yaowen; Ji, Hongli; Yan, Botao; Hu, Xiarong; Zeng, Yunli; Hao, Yifan; Xue, Weisong; Chen, Zexin; Lan, Jianqiang; Wang, Yanan; Deng, Haijun; Deng, Chu‐Xia; Wu, Xiufeng; Yan, Jun

doi:10.1016/j.isci.2023.107116

Cited by 7 publications

(8 citation statements)

References 45 publications

(50 reference statements)

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“…In our study, organoid response (GR AUC ) positively correlated with patient response (% size change in metastatic lesions) for 5-FU & oxaliplatin, despite the small sample size. Furthermore, classifying PDOs as sensitive and resistant based on GR AUC , resulted in a clinically relevant difference in median PFS in the sensitive and resistant group, which is in line with previous reports including PDOs treated with 5-FU & oxaliplatin [ 14 , 22 ]. In addition to the correlation with patient response, we show that CRC PDOs adequately reflect key clinical aspects regarding drug sensitivity and capture heterogeneity in treatment response.…”

Section: Discussionsupporting

confidence: 89%

“…For oxaliplatin-based treatments, a ratio screen is preferred to capture the additive effect of both compounds. This is in line with studies that used a comparable ratio [ 14 , 16 , 22 ] or a drug matrix and found a good association with patient response, while no association was found in studies that used different methods for combination screens [ 20 , 23 ].…”

Section: Discussionsupporting

confidence: 87%

“…This makes PDOs a novel promising biomarker to predict treatment response for various cancer and treatment types, and a valuable screening platform to identify new treatment types [ 7 , 12 , 13 ]. Previous studies involving colorectal cancer (CRC) patients have demonstrated a correlation between organoid response and patient response to different forms of chemotherapy and targeted treatment [ 7 , 14 – 22 ]. However, these results are not consistent, especially not for oxaliplatin which is one of the main treatments for mCRC [ 20 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response

Smabers,

Wensink,

Verissimo

et al. 2024

J Exp Clin Cancer Res

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Background The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies. Methods We optimized drug screen methods on 5–11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient’s response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness. Results Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003). Conclusions Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response

Smabers,

Wensink,

Verissimo

et al. 2024

J Exp Clin Cancer Res

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“…Patients with organoids sensitive to irinotecan and radiation had more complete clinical response, and longer disease free- and metastasis free survival. Patients with organoids sensitive to 5-FU had more complete clinical response, but no differences in disease free- and metastasis free survival n.a Tang et al 24 Stage II-IV colorectal cancer, both mucinous- and adenocarcinoma 5-FU or capecitabine in combination with oxaliplatin (FOLFOX/XELOX), in addition to other drugs not used in response prediction Tumor samples were harvested by surgery or biopsy, and cultured according to organoid protocols, and exposed to drugs for 96 h before assessing viability. Patients were treated according to MDT decisions CellTiter-Glo 3D cell viability assay, and IC50 of the tested drugs Size-change of lesions upon image diagnostics (assumed to refer to the RECIST criteria), AJCC/CAP tumor regression grade, and CEA-levels.…”

Section: Resultsmentioning

confidence: 95%

“…Seven of the included studies provided measures of accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), or the values needed to calculate these, and were thus eligible for our meta-analysis 12 , 16 , 20 , 24 – 26 , 29 . Four additional studies likely had these data but did not disclose them in the main text or the supplementary material 10 , 18 , 22 , 27 .…”

Section: Methodsmentioning

confidence: 99%

Systematic review: predictive value of organoids in colorectal cancer

Sakshaug,

Folkesson,

Haukaas

et al. 2023

Sci Rep

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While chemotherapy alone or in combination with radiotherapy and surgery are important modalities in the treatment of colorectal cancer, their widespread use is not paired with an abundance of diagnostic tools to match individual patients with the most effective standard-of-care chemo- or radiotherapy regimens. Patient-derived organoids are tumour-derived structures that have been shown to retain certain aspects of the tissue of origin. We present here a systematic review of studies that have tested the performance of patient derived organoids to predict the effect of anti-cancer therapies in colorectal cancer, for chemotherapies, targeted drugs, and radiation therapy, and we found overall a positive predictive value of 68% and a negative predictive value of 78% for organoid informed treatment, which outperforms response rates observed with empirically guided treatment selection.

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Nanopipette: A high-precision portable programmable instrument for nanoliters to milliliters liquid handling

Mao,

Tan,

Dou

et al. 2024

Sensors and Actuators A: Physical

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Cutoff value of IC50 for drug sensitivity in patient-derived tumor organoids in colorectal cancer

Cited by 7 publications

References 45 publications

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response

Systematic review: predictive value of organoids in colorectal cancer

Nanopipette: A high-precision portable programmable instrument for nanoliters to milliliters liquid handling

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