Outcome In mCRC Patients Research Articles

Prognostic role of sodium levels in colorectal cancer patients receiving aflibercept plus FOLFIRI.

Aim: To investigate the impact of natremia in metastatic colorectal cancer (mCRC) patients treated with aflibercept plus folinic acid, 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRI). Patients & methods: A total of84 mCRC patients receiving aflibercept plus FOLFIRI as second-line treatmentwere enrolled and divided into two groups based on their median sodium value. Progression-free survival and overall survival were analyzed. Results: Patients with sodium levels ≥140mEq/l had significantly longer median progression-free survival (4.1 vs 2months; p<0.01) and median overall survival (12 vs 7.3months; p<0.01) compared with those with lower levels. Conclusion: This study suggests that higher pretreatment serum sodium levels are associated with improved outcomes in mCRC patients receiving aflibercept and FOLFIRI, potentially serving as a prognostic marker to aid treatment management.

Correlations between Demographic, Clinical, and Paraclinical Variables and Outcomes in Patients with KRAS-Mutant or KRAS Wild-Type Metastatic Colorectal Cancer-A Retrospective Study from a Tertiary-Level Center in Romania.

Colorectal cancer (CRC) is a significant global public health concern and its characteristics in Eastern Europe are underexplored. In this retrospective study, data of 225 patients with metastatic colorectal cancer (mCRC) from the Colțea Clinical Hospital's Oncology Department in Bucharest were analyzed between 2015 and 2023. They were divided into two groups based on the presence of KRAS mutation. The primary objective of the study was to investigate whether the presence of KRAS mutations influenced the prognosis of mCRC and to identify any demographic, clinical, or paraclinical factors associated with KRAS mutations in stage IV CRC. The overall survival for the entire study population was 29 months. There was a trend towards increased survival in the KRAS wild-type group (31 months) compared to the KRAS-mutant group (26 months), but this difference did not reach statistical significance. We found that lower levels of education, advanced T stage, advanced N stage, and M1 stage at diagnosis negatively impacted prognosis. Real-world data are crucial in shaping public policy strategies to better support patients with metastatic CRC. Understanding the correlations between the demographic, clinical, and paraclinical variables and the outcomes in mCRC patients with KRAS-mutant and KRAS wild-type colorectal cancer is essential for improving patient care and treatment strategies in Romania and beyond.

Nomogram for predicting the prognosis of metastatic colorectal cancer patients treated with anti-PD1 therapy based on serum lipids analysis.

Serum lipids have been identified to be used as prognostic biomarkers in several types of cancer. The primary objective of this study was to evaluate the prognostic value of serum lipids in metastatic colorectal cancer (mCRC) patients received anti-PD-1 therapy. Pretreatment and the alteration of serum lipids, including apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), cholesterol (CHO), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) after 2 courses of anti-PD1 therapy, were collected. Kaplan-Meier survival and cox regression analysis were performed to identify the prognostic values on overall survival (OS). Finally, those significant predictors from multivariate analysis were used to construct a nomogram for the prediction of prognosis. Baseline ApoB, CHO, HDL-C, LDL-C and early changes of ApoB, ApoA-I, HDL-C were statistically significant in the ROC analysis, showing good discriminatory ability in terms of OS. In multivariate analysis, treatment lines, lung metastasis, baseline HDL-C (low vs. high, HR, 6.30; 95% CI 1.82-21.80; P = 0.004) and early changes in HDL-C (reduction vs. elevation, HR, 4.59, 95% CI 1.20-17.63; P = 0.026) independently predicted OS. The area under the time-dependent ROC curve at 1 year, 2 years and 3 years consistently demonstrated the satisfactory accuracy and predictive value of the nomogram (AUC: 0.88, 0.85, 0.84). Overall, high level at baseline and an early elevation of HDL-C are correlated with better outcomes in mCRC patients treated with anti-PD1 therapy. The constructed nomogram indicated that the factors are strong predictive markers for response and prognosis to anti-PD-1 therapy in metastatic colorectal cancer.

Serial ctDNA monitoring to predict response in mCRC patients treated with anlotinib in combination with oxaliplatin and capecitabine (CAPEOX) as the first-line therapy.

e15581 Background: Circulating tumour DNA (ctDNA) sequencing offers a non-invasive approach to monitor therapeutic efficacy in colorectal cancer. However, the mutational landscape of ctDNA during treatment and its impact on clinical outcomes remain unknown. This study aimed to investigate the value of ctDNA in predicting treatment response and PFS in mCRC patients treated with anlotinib plus CAPEOX as first-line therapy. Methods: We conducted a multicenter, single-arm, phase II, exploratory study of patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer (mCRC) who underwent Anlotinib in combination with CAPEOX as the first-line therapy (NCT04080843). Plasma samples from 26 patients were collected at three timepoints: 1 week before treatment (baseline), close to the time of optimal remission (C1) and the time of the last blood collection or the time of disease progression (C2). The maximum somatic allele frequency (MSAF) was calculated for each case and used to provide an estimate of the ctDNA fraction in the blood. Results: 77 plasma samples from the 26 enrolled mCRC patients were sequenced by NGS based on a panel comprising 202 genes. 90 variations were detected in baseline plasma, with a positive rate of 96.2% (25/26). Adenomatous polyposis coli ( APC), was the most mutated gene (84.6%, 22/26). Other mutated genes were TP53 (80.8%, 21/26), FBXW7 (19.2%, 5/26), KRAS (11.5%, 3/26), PIK3CA (11.5%, 3/26) and ROS1 (11.5%, 3/26). The median MSAF of baseline ctDNA was significantly higher in patients who had only liver metastases. Compared with baseline, the ctDNA MSAF level at C1 timepoint was decreased among the whole 26 patients (p &lt; 0.001). By comparing ctDNA positive group (ctDNA MSAF &gt; 0) and ctDNA negative group (ctDNA MSAF = 0) at C1 timepoint, CR cases were mainly in ctDNA negative group, while PD cases accounted for a high proportion in the ctDNA positive group. The median progression-free survival (mPFS) of the whole patients was 11.27 months (95%CI 7.33m to 14.52m). The mPFS was 14.52 months (95% CI 14.4 to NR) of patients with ctDNA negative at C1, which was longer than 9.17 months (95% CI 7.16 to 14.06) of patients with ctDNA positive at C1 (p = 0.012). For 25 patients who had plasma samples of three timepoints, we divided the patients into Non-PD group and PD group according to the clinical outcome at C2 timepoint. Compared with C1 timepoint, the ctDNA MSAF level at C2 timepoint was increased in both Non-PD group and PD group. However, the increment of ctDNA MSAF level in PD group was higher than that in non-PD group (p = 0.000069 vs p = 0.024). Conclusions: This ctDNA profiling study revealed the utility of ctDNA in predicting clinical outcomes in mCRC patients under first-line treatment. Serial ctDNA monitoring might become useful in an active surveillance strategy for the management of mCRC. Clinical trial information: NCT04080843 .

Patient-derived organoids as a platform for drug screening in metastatic colorectal cancer.

Introduction: Most advanced colorectal cancers are aggressive, and there is a lack of effective methods for selecting appropriate anticancer regimens. Patient-derived organoids (PDOs) have emerged as preclinical platforms for modeling clinical responses to cancer therapy. Methods: In this study, we successfully constructed a living biobank with 42 organoids derived from primary and metastatic lesions of metastatic colorectal cancer patients. Tumor tissue was obtained from patients undergoing surgical resection of the primary or metastatic lesion and then used to establish PDOs. Immunohistochemistry (IHC) and drug sensitivity assays were performed to analyze the properties of these organoids. Results: The mCRC organoids were successfully established with an 80% success rate. The PDOs maintained the genetic and phenotypic heterogeneity of their parental tumors. The IC50 values of5-fluorouracil (5-FU), oxaliplatin, and irinotecan (CPT11) were determined for mCRC organoids using drug sensitivity assays. The in vitro chemosensitivity data revealed the potential value of PDOs for clinical applications in predicting chemotherapy response and clinical outcomes in mCRC patients. Discussion: In summary, the PDO model is an effective platform for in vitro assessment of patient-specific drug sensitivity, which can guide personalized treatment decisions for patients with end-stage CRC.

Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

Plasma metabolomics, lipidomics and cytokinomics profiling predict disease recurrence in metastatic colorectal cancer patients undergoing liver resection.

In metastatic colorectal cancer (mCRC) patients (pts), treatment strategies integrating liver resection with induction chemotherapy offer better 5-year survival rates than chemotherapy alone. However, liver resection is a complex and costly procedure, and recurrence occurs in almost 2/3rds of pts, suggesting the need to identify those at higher risk. The aim of this work was to evaluate whether the integration of plasma metabolomics and lipidomics combined with the multiplex analysis of a large panel of plasma cytokines can be used to predict the risk of relapse and other patient outcomes after liver surgery, beyond or in combination with clinical morphovolumetric criteria. Peripheral blood metabolomics and lipidomics were performed by 600 MHz NMR spectroscopy on plasma from 30 unresectable mCRC pts treated with bevacizumab plus oxaliplatin-based regimens within the Obelics trial (NCT01718873) and subdivided into responder (R) and non-R (NR) according to 1-year disease-free survival (DFS): ≥ 1-year (R, n = 12) and < 1-year (NR, n = 18). A large panel of cytokines, chemokines, and growth factors was evaluated on the same plasma using Luminex xMAP-based multiplex bead-based immunoassay technology. A multiple biomarkers model was built using a support vector machine (SVM) classifier. Sparse partial least squares discriminant analysis (sPLS-DA) and loading plots obtained by analyzing metabolomics profiles of samples collected at the time of response evaluation when resectability was established showed significantly different levels of metabolites between the two groups. Two metabolites, 3-hydroxybutyrate and histidine, significantly predicted DFS and overall survival. Lipidomics analysis confirmed clear differences between the R and NR pts, indicating a statistically significant increase in lipids (cholesterol, triglycerides and phospholipids) in NR pts, reflecting a nonspecific inflammatory response. Indeed, a significant increase in proinflammatory cytokines was demonstrated in NR pts plasma. Finally, a multiple biomarkers model based on the combination of presurgery plasma levels of 3-hydroxybutyrate, cholesterol, phospholipids, triglycerides and IL-6 was able to correctly classify patients by their DFS with good accuracy. Overall, this exploratory study suggests the potential of these combined biomarker approaches to predict outcomes in mCRC patients who are candidates for liver metastasis resection after induction treatment for defining personalized management and treatment strategies.

Real-world outcomes among patients with metastatic colorectal cancer treated first line with a bevacizumab biosimilar (bevacizumab-awwb).

Bevacizumab-awwb (MVASI®) was the first U.S. Food and Drug Administration-approved biosimilar to Avastin® (reference product [RP]) for the treatment of several different types of cancers, including metastatic colorectal cancer (mCRC), an indication approved based on extrapolation. Evaluate treatment outcomes in mCRC patients who received first-line (1L) bevacizumab-awwb at treatment initiation or as continuing bevacizumab therapy (switched from RP). A retrospective chart review study. Adult patients who had a confirmed diagnosis of mCRC (initial presentation of CRC on or after 01 January 2018) and initiated 1L bevacizumab-awwb between 19 July 2019 and 30 April 2020 were identified from the ConcertAI Oncology Dataset. A chart review was conducted to evaluate patient baseline clinical characteristics and effectiveness and tolerability outcomes during the follow-up. Study measures were reported stratified by prior use of RP: (1) naïve patients and (2) switchers (patients who switched to bevacizumab-awwb from RP without advancing the line of therapy). At the end of study period, naïve patients (n = 129) had a median 1L progression-free survival (PFS) of 8.6 months [95% confidence interval (CI), 7.6-9.9] and a 12-month overall survival (OS) probability of 71.4% (95% CI, 61.0-79.5%). Switchers (n = 105) had a median 1L PFS of 14.1 months (95% CI, 12.1-15.8) and a 12-month OS probability of 87.6% (95% CI, 79.1-92.8%). During treatment with bevacizumab-awwb, 20 events of interest (EOIs) were reported in 18 naïve patients (14.0%) and 4 EOIs reported in 4 switchers (3.8%), of which the most commonly reported events were thromboembolic and hemorrhagic events. Most EOIs resulted in emergency department visit and/or treatment hold/discontinuation/switch. None of the EOIs resulted in death. In this real-world cohort of mCRC patients who were treated 1L with a bevacizumab biosimilar (bevacizumab-awwb), the clinical effectiveness and tolerability data were as expected and consistent with previously published findings from real-world studies of bevacizumab RP in mCRC patients.

Mutational Status of SMAD4 and FBXW7 Affects Clinical Outcome in TP53–Mutated Metastatic Colorectal Cancer

Next-generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first-line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time-dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%), and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (p = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (p = 0.02; HR, 3.31) as well as double-mutated TP53 and SMAD4 (p = 0.03; HR, 2.91). Analysis of the MSK-IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time-dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53-defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53-altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first-line regimens.

PD-1 Inhibitor Combined with Radiotherapy and GM-CSF with or not IL-2 (PRaG regimen) in Patients with Microsatellite Stable Metastatic Colorectal Cancer

<h3>Purpose/Objective(s)</h3> Immunotherapy has improved outcomes for metastatic colorectal cancer(mCRC) patients with MSI-H/dMMR but has not been effective in MSS/pMMR tumors, which comprise 95% of mCRC. Radiotherapy is able to stimulate tumor specific immune response and improve the efficacy of PD-1/PD-L1 inhibitors in metastatic cancers. The synergistic effects of radiotherapy and PD-1/PD-L1 inhibitors can be reinforced by adding cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2(IL-2). Our previous PRaG trial demonstrated that radiotherapy in combination with PD-1 inhibitors and GM-CSF could improve clinical response in patients with advanced refractory solid tumors, which was presented at the ASTRO congress 2021. We found that mCRC patients with MSS/pMMR could also benefit from the PRaG regimen. <h3>Materials/Methods</h3> Patients of mCRC with MSS/pMMR were collected from the PRaG trial and PRaG 2.0 trial. A treatment cycle consisted of radiotherapy (5 or 8 Gy × 2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 14 days(d1-14), or GM-CSF 200μg (d1-7), and then sequentially followed by IL-2 200 million IU SC once daily for 7 days(d8-14). PRaG regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose. Pooled analysis of response rate (ORR), median progression-free survival (PFS), and treatment-related adverse events were calculated. The PRaG trial was registered in chictr.org.cn (No. ChiCTR1900020175) and the PRaG 2.0 trial was registered in clinicaltrials.gov (NCT04892498). <h3>Results</h3> With the cutoff date of 15 February 2022, a total of 12 mCRC patients with MSS/pMMR were enrolled. All of the patients completed at least 2 cycles of PRaG therapy and one evaluation. The median follow-up was 7.0 months (95%CI, 4.7, 9.3). The ORR was 25%, and the disease control rate (DCR) was 58.3%. The median PFS was 4.7 months (95%CI, 0.9 to 8.5). One patient got complete remission, with PFS over 18 months. Treatment-related adverse events (TRAE) occurred in 10 of 12 (83.3%) patients. One patient (8.3%) occurred Grade3 TRAE of renal insufficiency. <h3>Conclusion</h3> Our preliminary results suggest that the PRaG regimen could improve clinical outcomes in mCRC patients with MSS/pMMR with acceptable toxicity. Radiotherapy could have radiosensitization effect on immunotherapy of mCRC with MSS/pMMR.

Zebrafish Patient-Derived Xenograft Model to Predict Treatment Outcomes of Colorectal Cancer Patients.

The use of zebrafish embryos for personalized medicine has become increasingly popular. We present a co-clinical trial aiming to evaluate the use of zPDX (zebrafish Patient-Derived Xenografts) in predicting the response to chemotherapy regimens used for colorectal cancer patients. zPDXs are generated by xenografting tumor tissues in two days post-fertilization zebrafish embryos. zPDXs were exposed to chemotherapy regimens (5-FU, FOLFIRI, FOLFOX, FOLFOXIRI) for 48 h. We used a linear mixed effect model to evaluate the zPDX-specific response to treatments showing for 4/36 zPDXs (11%), a statistically significant reduction of tumor size compared to controls. We used the RECIST criteria to compare the outcome of each patient after chemotherapy with the objective response of its own zPDX model. Of the 36 patients enrolled, 8 metastatic colorectal cancer (mCRC), response rate after first-line therapy, and the zPDX chemosensitivity profile were available. Of eight mCRC patients, five achieved a partial response and three had a stable disease. In 6/8 (75%) we registered a concordance between the response of the patient and the outcomes reported in the corresponding zPDX. Our results provide evidence that the zPDX model can reflect the outcome in mCRC patients, opening a new frontier to personalized medicine.

GNRI And Conut Scores: Simple Predictors of Sarcopenia in Metastatic Colorectal Cancer Patients.

To evaluate the correlation between sarcopenia and inflammation- and nutrition-based markers in metastatic colorectal cancer (mCRC) patients. Age, body mass index (BMI), neutrophil/lymphocyte ratio (NLR), modified Glasgow prognostic score (mGPS), prognostic nutrition index (PNI), cachexia index (CIn), skeletal muscle index (SMI), controlling nutritional status (CONUT) score, and geriatric nutritional risk index (GNRI) were evaluated in 185 patients. Ideal cut-off values for the GNRI score were determined with the ROC curve analysis, and the patients were divided into two groups as low and high GNRI. Sarcopenia was diagnosed using CT scanning, the gold standard method. Univariate and multivariate Cox proportional hazard analyses were done based on the above-listed parameters to assess the correlation between sarcopenia and changes in immuno-nutrition and inflammatory response. Kaplan-Meier analysis was also done to evaluate survival. Univariate analysis of the 185 patients based on the EGWSOP 2018 threshold values showed correlation between the presence of sarcopenia and male gender, diagnosed colon cancer, history of metastasectomy, BMI < 24, high mGPS score, PNI score ≥ 45, high CONUT score, and low GNRI score (p < 0.05). In multivariate analysis, low GNRI (HR: 2.40; 95% CI: 1.03-5.544; p = 0.040), and high-CONUT scores (HR: 2.01; 95% CI: 1.06-3.73; p = 0.029) were identified as independent prognostic factors for the presence of sarcopenia. GNRI and CONUT scores are elementary and practical predictors for sarcopenia, a condition which is associated with poor outcomes in mCRC patients.

Abstract 4112: Patient derived organoids predict clinical response: A patient in the lab

Abstract Colorectal cancer (CRC) is the third leading cause of cancer and cancer-related death. A large fraction of the CRC patients diagnosed with de novo metastatic disease do not benefit from the standard of care but still experience substantial side effects. Therefore, there is the urgency for a new model to predict clinical response. Adult epithelial stem cell (ASC) -derived organoids are proving to be a major breakthrough in pre-clinical models. ASC-derived organoids can be developed from healthy as well as diseased tissue, including cancer lesions and therefore are often referred to as patient-derived organoids (PDOs or HUB Organoids࣪). These model is established directly from patient tissue, represent the tissue of origin and faithfully recapitulate patient disease in vitro and can be propagated for drug testing in a matter of weeks. PDOs bridges the gap between the lab and the clinic and effectively bring a “patient in the lab.” In this study we aimed to validate the predictive value of PDOs in the stratification of metastatic CRC (mCRC) patients for treatment with chemotherapeutic agents. PDOs from mCRC tissues were established following our optimized procedures and drug screening was performed. Clinical response was compared with PDO drug response and the best predicting drug response parameters (growth rate (GR), GRmax, GR50 and area under the curve) were identified. The patient response was evaluated by the percentage of change in size of the target lesions on response scans (% size change), best Response Evaluation Criteria in Solid Tumors (RECIST) response and progression-free survival (PFS). Importantly, we validated the predictive value of organoids towards fluorouracil (5-FU). We are validating these results in a large trial. Current efforts to further expand our PDO and drug sensitivity biobank will enable the implementation of the personalized HUB Organoid Technology to accurate and fast predict of the treatment response to improve clinical outcome of mCRC patients. Citation Format: Carla S. Verissimo, Lidwien Smabers, Emerens Wensink, Esmee Koedoot, Maarten Huismans, Celia Higuera Barón, Ricardo Korporaal, Emma Teal, Katerina-Chara Pitsa, Edwin van Oosten, Roshni Nair, Liselot Valkenburg, Geert Cirkel, Anneta Brousali, Jorieke Salij, René Overmeer, Manon Braat, Sjoerd Elias, Robert Vries, Onno Kranenburg, Miriam Koopman, Sylvia F. Boj, Jeanine Roodhart. Patient derived organoids predict clinical response: A patient in the lab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4112.

The response of PD-1 inhibitor combined with Radiotherapy and GM-CSF(PRaG) with or without IL-2 in microsatellite stable metastatic colorectal cancer: Analysis of pooled data from two phase II trials.

e15561 Background: Immunotherapy has improved outcomes for metastatic colorectal cancer(mCRC) patients with MSI-H/dMMR but has not been effective in MSS/pMMR tumors, which comprise 95% of mCRC. In metastatic cancers, radiotherapy can be used as a local therapy and a sensitizer to PD-1/PD-L1 inhibitors. The synergistic effects of radiotherapy and PD-1/PD-L1 inhibitors can be reinforced by adding cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2(IL-2). Our previous PRaG trial demonstrated that PD-1 inhibitors in combination with radiotherapy and GM-CSF could improve clinical response in patients with advanced refractory solid tumors. We found that mCRC patients with MSS/pMMR could also benefit from the PRaG regimen. Methods: Patients of mCRC with MSS/pMMR were collected from the PRaG trial and PRaG 2.0 trial. A treatment cycle consisted of radiotherapy (5 or 8Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 14 days(d1-14), or GM-CSF 200μg (d1-7), and then sequentially followed by IL-2 200 million IU SC once daily for 7 days(d8-14). PRaG regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose. Pooled analysis of response rate (ORR), median progression-free survival (PFS), and treatment-related adverse eventswere calculated. Results: With the cutoff date of 31 December 2021, a total of 9 mCRC patients with MSS/pMMR were enrolled. All of the patients completed at least 2 cycles of PRaG therapy and one evaluation. The median follow-up was 7.6 months (95%CI, 3.8, 11.4). The ORR was 22.2%, and the disease control rate(DCR) was 66.7%. The median PFS was 5.6 months (95%CI, 1.5 to 9.7). One patient got complete remission, with PFS over 17months. Treatment-related adverse events (TRAE) occurred in 7 of 9 (77.8%) patients. One patient (11.1%) occurred Grade3 TRAE of renal insufficiency. Conclusions: Our preliminary results suggest that the PRaG regimen could improve clinical outcomes in mCRC patients with MSS/pMMR with acceptable toxicity.

Amlodipine improves the outcomes of regorafenib in metastatic colorectal cancer.

Regorafenib is a multikinase inhibitor. It is used for metastatic colorectal cancer (mCRC) treatment. It has a mild effect. Regorafenib outcomes, and side effects may vary across patients. This study was aimed to evaluate the factors that affect regorafenib outcomes in mCRC patients. We conducted a single-center and retrospective study. Fifty-six patients were included. All patients had received regorafenib for mCRC. Some clinical and pathological factors and the effects of these factors on overall survival (OS), progression-free survival (PFS), and disease control rates (DCR) were analyzed. Concomitant amlodipine intake with regorafenib improved OS [14.26 vs. 6.97 months; 95% confidence interval, 4.04-20.84; P = 0.031] and DCR at 12th week (90% vs. 46%; P = 0.012). Hepatic metastasis was found as the poorest prognostic factor in both univariate and multivariate analyses. Patients who received chemotherapy after regorafenib had better OS. Good performance status was the strongest indicator of better OS. Patients taking amlodipine for arterial hypertension at the same time with regorafenib had numerically better OS and PFS and statistically better DCR. Amlodipine itself already has anticancer effects, and it has additive anticancer effects with regorafenib. The presence of hepatic metastases was found to be the most important prognostic factor for OS. There were not any predictive factors of side effects to regorafenib.

A real-world comparison of trifluridine/tipiracil and regorafenib in refractory metastatic colorectal cancer in the United States.

39 Background: For patients with refractory metastatic colorectal cancer (mCRC), both trifluridine/tipiracil (TAS-102) and regorafenib have received approval for use in the United States. The approvals of these agents were based on modest improvements in overall survival (OS) when compared to best supportive care plus a placebo in the RECOURSE and CORRECT trials, respectively. However, TAS-102 and regorafenib have never been directly compared in a prospective clinical trial. This study utilized a large real-world database to compare clinical outcomes with use of these agents. Methods: The nationwide de-identified Flatiron Health EHR-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least two lines of guideline recommended therapy for advanced disease followed by treatment with TAS-102 and/or regorafenib in the third line or greater were included for analysis. Patients who did not have a visit or medication order within 90 days of metastatic diagnosis were excluded to ensure patients were engaged with care at the data-providing institution. Kaplan-Meier and propensity score weighted models were used to compare survival outcomes between groups. Results: The records of 22,078 patients with mCRC were reviewed. Of the 4,407 patients that received at least two lines of standard therapy, 2,072 subsequently received regorafenib and/or TAS-102. Of these, 813 (39.2%) received TAS-102 alone, 275 (13.3%) TAS-102 followed by regorafenib, 736 (35.5%) regorafenib alone, and 248 (12.0%) regorafenib followed by TAS-102. Median OS for patients treated with TAS-102 alone or prior to receiving regorafenib was 6.66 months (95% CI 6.16-7.18) compared to 6.30 months (95% CI 5.80-6.79) for those treated with regorafenib alone or prior to receiving TAS-102 (p = 0.36). A propensity score weighted analysis controlling for age, race, stage at initial diagnosis, performance status at start of therapy, MSI/MMR status, RAS/RAF status, and line in which TAS-102 or regorafenib was received did not demonstrate a significant difference in survival between groups (HR 0.99, 95% CI: 0.90 -1.09, p = 0.82). A subgroup analysis did not identify any significant differences in outcomes stratified by age, performance status, MSI status, or RAS/RAF status. Conclusions: This analysis of real-world data did not identify a significant difference in survival outcomes in mCRC patients who were treated with TAS-102 or regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. This data should be considered when discussing the risks and benefits of TAS-102 and regorafenib with mCRC patients who are eligible for third line or greater treatment.

Mutational landscape of circulating tumor DNA identifies distinct molecular features associated with therapeutic response in patients with metastatic colorectal cancer.

Background:We investigated the mutational landscape of circulating tumor DNA (ctDNA) in predicting tumor response to first-line treatment in patients with metastatic colorectal cancer (mCRC).Methods:We included 41 patients with initially unresectable mCRC, treated with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX)/5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with/without bevacizumab (Bev)/cetuximab (Cet). Blood samples were prospectively collected at two timepoints: at baseline and after four cycles of first-line treatment. Mutational status of 1086 genes were studied in ctDNA by targeted next-generation sequencing (NGS). Molecular mutational burden (MMB) was defined as mean mutation frequency among obtained mutations for each gene. To evaluate the association between molecular characteristics of cfDNA and therapeutic response better, we divided these patients into MMB-high and MMB-low group according to the median value of MMB (0.3).Results:Among the 41 enrolled patients, alterations of six genes (TRIM24, SPEN, RNF43, PRKAR1A, KRAS, and KDM5 C) were found at baseline. Baseline MMB of six genes was significantly lower in partial response (PR)/stable disease (SD) patients than progression disease (PD) patients (p = 0.0012). Further analysis demonstrated that genomic profiling of ctDNA from pretreatment blood samples was significantly different between PR/SD (non-PD) group and PD group. By comparing the baseline levels of KRAS MMB in the two subgroups, we found that PD cases were all MMB-high, whereas non-PD cases were mainly in MMB-low subgroup. Furthermore, patients with low-KRAS MMB had superior response rate, significantly longer progression-free survival (PFS) and longer overall survival (OS) than high-KRAS MMB group.Conclusions:This prospective and serial genomic profiling study revealed the utility of ctDNA in predicting clinical outcomes in mCRC patients under first-line treatment. Levels of KRAS MMB might aid in monitoring therapeutic efficacy in mCRC patients at pretreatment/after four cycles of first-line treatment.

Clinical significance of circulating tumour cells and tumour marker detection in the chemotherapeutic evaluation of advanced colorectal cancer.

AimSystemic chemotherapy combining biological targeted therapies is the standard therapy for patients with metastatic colorectal cancer (mCRC), but effective markers are needed to identify clinical responders. Circulating tumour cells (CTCs) have been associated with prognosis in patients with mCRC. This study aimed to explore the relationship between CTC number and the clinical response of patients with advanced CRC.MethodEpithelial cell adhesion molecule‐independent enrichment and CD45− fluorescence in situ hybridization immunofluorescence were used to detect peripheral blood CTCs in 79 patients with advanced CRC. Fisher's exact test and Spearman's rank correlation coefficient were used to analyse the correlation between CTC number and efficacy of chemotherapy. Kaplan–Meier and Cox regression analyses were used to evaluate progression‐free survival (PFS).ResultsAmong the evaluable patients, CTCs were significantly correlated with clinical response (r =4.891, p = 0.031). High CTC numbers were associated with a poor treatment response (r = −0.250, p = 0.027). Dynamic decrease in CTC number was associated with clinical response (p = 0.046). High baseline CTC number and carcinoembryonic antigen levels were prognostic factors for unfavourable PFS in multivariable analysis [hazard ratio (HR) = 3.30, p = 0.011 and HR = 2.04, p = 0.044, respectively]. Compared with the CTC‐positive group, the CTC‐negative group showed superior PFS (median PFS 15.53 vs. 9.43 months, p = 0.041) among CRC patients receiving first‐line treatment.ConclusionCTC number is a feasible biomarker for predicting outcomes in mCRC patients receiving systemic chemotherapy.

Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer.

Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided. Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P < .001) but not for right-sidedness. The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.

Outcomes of isolated distant lymph node metastases in colorectal cancer.

84 Background: The optimal management of isolated distant lymph node metastases (IDLNM) in metastatic colorectal cancer (mCRC) is not clearly established. Small case series and prior data from the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry support the use of radical treatment with curative intent (local resection, chemo-radiation or stereotactic radiotherapy), which may lead to better outcomes in mCRC patients with IDLNM. Aims: This study investigates the clinical characteristics and outcomes of mCRC patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. Methods: Clinical data were collected and reviewed from the TRACC registry, a prospective, comprehensive registry for mCRC from multiple tertiary hospitals across Australia from 01/07/2009 to 30/06/2020. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with other organ metastases. Fisher exact test was used for significance tests and Kaplan Meier curves for survival analyses. Results: Of 3408 mCRC patients with a median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC with other organ metastases, patients with IDLNM were younger (mean age: 62.1 vs 65.6 years, p=0.0200), more likely to have metachronous disease (57.0% vs 38.9%, p=0.0005), be KRAS wild-type (74.6% vs 53.9%, p=0.0012) and BRAF mutant (12.9% vs 6.2%, p=0.0100). There was no overall survival difference between with IDLNM and those with other organ metastases (median OS 27.24 vs 25.92 months, p=0.2300). Twenty-four patients (25.8%) with IDLNM received treatment with curative intent, with a trend towards improved overall survival compared to those with other organ metastases treated with curative intent (73.5 vs 62.7 months, p=0.8200). Amongst mCRC patients with IDLNM, those who received treatment with curative intent had a significantly better overall survival than those treated with palliative intent (73.5months vs 23.2 months, p=0.0070). Conclusions: Our findings suggest that there are differences in the patterns of presentation of IDLNM and other organ metastases. Radical treatment with curative intent options should be considered for mCRC patients with IDLNM where appropriate.