Research ArticleCancer

Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients

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Science Translational Medicine  09 Oct 2019:
Vol. 11, Issue 513, eaay2574
DOI: 10.1126/scitranslmed.aay2574
  • Fig. 1 Generation of PDOs from patients with metastatic CRC enrolled in the TUMOROID study.

    (A) Flow chart indicating the number of patients with metastatic CRC included, the number of evaluable patients, reasons for non-evaluability, and the success rate of establishing cultures from patients. (B) Overview of all patients, corresponding mutations in genes commonly mutated in CRC, and clinical parameters [sex, primary location, biopsied metastasis, microsatellite instability (MSI) status, and previous systemic treatment]. Gray boxes indicate that data were not available. On the right side are bar graphs representing the fraction of samples with a genetic aberration identified per gene, plotted and compared to those of Yaeger and colleagues (24). “Altered” was defined as a given variant being predicted pathogenic by COSMIC. (C) Clinical responses of patients, indicated in either blue (PR/SD) or red (PD), on the relevant treatment indicated on the left. The clinical and genetic data are described in more detail in tables S1 to S3.

  • Fig. 2 PDO drug sensitivity predicts response to treatment with irinotecan.

    (A) Waterfall plot of each patient’s overall response and best response of the biopsied lesion in the irinotecan-treated PDO cohort. Red indicates progressive disease (PD), and orange indicates stable disease (SD). *, new lesion(s). (B) Fitted dose-response curves (DRCs) of 10 PDOs exposed to SN-38 in vitro. Blue lines represent PDOs derived from SD patients, and red lines represent PDOs from PD patients. GR values represent in vitro sensitivity of PDOs to SN-38. The screen was plated in technical triplicate and performed twice, once each by independent researchers. Red indicates PD, and blue indicates SD. (C) Log2(GR50 SN-38) was interpolated from the fitted DRCs shown in (B). Groups were compared using a two-tailed Mann-Whitney test. Dots/squares represent individual PDOs, horizontal bars represent the mean, and error bars indicate SEM. (D) The area under the DRC (AUCDRC) was calculated by integrating the DRC of each PDO in (B). Groups were compared using a two-tailed Mann-Whitney test. Dots/squares represent individual PDOs, horizontal bars represent the mean, and error bars indicate SEM. (E) The data point with the largest window of effect (captured by the variance) was calculated (3.2 nM SN-38; fig. S3A), and response was compared using a two-tailed Mann-Whitney test. (F) The data of (E) were plotted as an ROC curve. The dotted line represents an AUCROC of 0.5, which indicates no predictive value. CI, confidence interval. (G) Summary graph of the AUCROCs and 95% CIs on the basis of the in vitro parameters GR50 and AUCDRC.

  • Fig. 3 PDO drug sensitivity predicts response to treatment with 5-FU/capecitabine and irinotecan.

    (A) Waterfall plot of each patient’s overall response and best response of the biopsied lesion in the FI-treated PDO cohort. Red indicates PD, orange indicates SD, and blue indicates partial response (PR). *, new lesion(s). (B) GR scores of FI-treated PDOs derived from lesions with PR/SD and PD. Scores of PR/SD (n = 6) versus PD (n = 6) patients were compared using a two-tailed Mann-Whitney test. The screen was plated in technical triplicate and performed two times, once each by independent researchers. GR scores representing in vitro sensitivity of PDOs to FI were calculated by summing the 11 data points in the two complementary rows and columns in the drug matrix (fig. S5A). Dots/squares represent individual PDOs, horizontal bars represent the mean, and error bars indicate SEM. (C) ROC curve of the FI cohort illustrating the potential to predict response. AUCROC = area under the receiver operating characteristic curve. (D) Kaplan-Meier curve depicting the PFS of the 50% most sensitive versus 50% most resistant PDOs. Groups were compared using the Mantel-Cox log-rank test. (E) Summary of the AUCROC and 95% CI for lesion response, calculated based on the in vitro parameters GR50 and AUCDRC. (F) GR scores of irinotecan-treated PDOs derived from lesions with PR/SD and PD. The test developed using the FI set [described in (B)] was applied to the 10 PDOs from the patients in the irinotecan monotherapy cohort: All PDOs were exposed to the 11 concentrations identified in (B), and GR scores representing in vitro sensitivity of PDOs to irinotecan were calculated analogous to the method described there. GR scores for PDO were compared to our threshold [GR > 0.46, represented by the dotted line in the figure, as identified previously in (B)] to determine whether PR/SD (n = 5) and PD (n = 5) patients were correctly classified by this method. Groups were compared using a two-tailed Fisher’s exact test. (G) The data of (F) are plotted as an ROC curve.

  • Fig. 4 PDO drug sensitivity does not predict response to treatment with 5-FU/capecitabine and oxaliplatin.

    (A) Waterfall plot of the best lesion and overall responses in the FO-treated PDO cohort. Red indicates PD, orange indicates SD, and blue indicates PR. *, new lesion(s); #, lesion could not be measured. (B) GR scores of FO-treated PDOs derived from lesions with PR/SD and PD. Scores of PR/SD (n = 9) versus PD (n = 4) patients were compared using a two-tailed Mann-Whitney test. The screen was plated in technical triplicate and performed two times, once each by independent researchers. GR scores representing in vitro sensitivity of PDOs to FO were calculated by summing the six data points of equimolar concentrations of 5-FU and oxaliplatin to generate a GR score. Dots/squares represent scores for individual PDOs (except for P1a-d, which are represented as the average of these four samples), horizontal bars represent the mean, and error bars represent the SEM. n.s., not significant. (C) ROC curve of the FO cohort illustrating the potential to predict response. (D) Summary graph of the AUCROCs and 95% CIs calculated on the basis of in vitro parameters GR50 and AUCDRC.

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/11/513/eaay2574/DC1

    Fig. S1. Overview of clinical and genetic parameters in PDO cohorts.

    Fig. S2. Overview of the irinotecan PDO-patient cohort.

    Fig. S3. Development and cross-validation of an irinotecan classifier.

    Fig. S4. Overview of the 5-FU–irinotecan PDO-patient cohort.

    Fig. S5. Development and cross-validation of a 5-FU–irinotecan classifier.

    Fig. S6. Overview of the 5-FU–oxaliplatin PDO-patient cohort.

    Fig. S7. 5-FU–oxaliplatin drug responses of synchronous and paired metastases.

    Fig. S8. The effects of clinical and genetic parameters on patients and PDO responses.

    Table S1. Characteristics and clinical history of all patients included in the TUMOROID study.

    Table S2. Genetic and pathological characteristics of patients in the TUMOROID study.

    Table S3. Overview of the three cohorts and previous treatments and procedures.

  • This PDF file includes:

    • Fig. S1. Overview of clinical and genetic parameters in PDO cohorts.
    • Fig. S2. Overview of the irinotecan PDO-patient cohort.
    • Fig. S3. Development and cross-validation of an irinotecan classifier.
    • Fig. S4. Overview of the 5-FU–irinotecan PDO-patient cohort.
    • Fig. S5. Development and cross-validation of a 5-FU–irinotecan classifier.
    • Fig. S6. Overview of the 5-FU–oxaliplatin PDO-patient cohort.
    • Fig. S7. 5-FU–oxaliplatin drug responses of synchronous and paired metastases.
    • Fig. S8. The effects of clinical and genetic parameters on patients and PDO responses.
    • Table S1. Characteristics and clinical history of all patients included in the TUMOROID study.
    • Table S2. Genetic and pathological characteristics of patients in the TUMOROID study.
    • Table S3. Overview of the three cohorts and previous treatments and procedures.

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