Histopathological and molecular classification of colorectal cancer and corresponding peritoneal metastases

Ubink, Inge; Eden, W. J. van; Snæbjörnsson, Pétur; Kok, Niels F. M.; Kuik, J. van; Grevenstein, Wilhelmina M U van; Laclé, Miangela M.; Sanders, Joyce; Fijneman, Remond J.A.; Elias, Sjoerd G.; Rinkes, Inne H.M. Borel; Aalbers, Arend G. J.; Kranenburg, Onno

doi:10.1002/bjs.10788

Cited by 66 publications

(56 citation statements)

References 29 publications

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“…RAS/RAF mutations alone have been inconsistently assessed in a few series of CRS/HIPEC, with contrasting results. [23][24][25][26][27][28][29][30] Analogously, primary tumor sidedness correlated with prognosis in two American series but not in one French series. [31][32][33][34] Our findings strongly suggest that both BRAF mutations and right-sided primary have to be taken into consideration, not only as prognostic factors in patients undergoing curative-intent treatment but also as stratification factors in future clinical trials.…”

Section: Discussionmentioning

confidence: 86%

“…In previous literature series of CRC-PMs, analysis of mutations outside the KRAS exon 2 was not undertaken, 23 was limited to the BRAF V600E mutation, 24,25,31 was undertaken in a limited number of patients, 26,30 or was not specified. [27][28][29] Furthermore, three studies were multiinstitutional series, 25,27,29 with possible differences in sequencing and/or surgical procedures, and one study 31 also included appendiceal cancers, in which KRAS mutations are more frequent. 36 The proportions of KRASmutated (33-58%) and BRAF-mutated patients (8-13%) were comparable in the literature and our study, with the only exception being the series of Ubink et al, with a 25% BRAF mutation rate.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

et al. 2020

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Background. Selecting patients with colorectal cancer peritoneal metastases (CRC-PMs) for surgery is still a concern. Biological features have the potential to improve prognostic stratification, but their significance in this clinical setting is still unclear. We assessed the prognostic impact of primary side and KRAS/NRAS/BRAF/PIK3CA mutations in patients treated with either cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) or CRS alone. Methods. We reviewed a prospective database of 152 CRC-PM patients selected to undergo perioperative systemic chemotherapy and CRS with or without HIPEC. Extensive mutational analysis of KRAS, NRAS, BRAF, and PIK3CA was performed by polymerase chain reaction (PCR). In 68 patients, Ion Torrent next-generation sequencing technology was used to characterize the hotspot regions of 50 genes. Results. The primary tumor was right-sided in 61 patients (40.1%) and left-sided in 91 patients (59.9%). Right-sided primaries were associated with mutated KRAS (p = 0.01) and normal carcinoembryonic antigen (CEA; p = 0.03). KRAS was mutated in 71/152 patients (46.7%), NRAS in 7/152 patients (4.6%), BRAF in 10/152 patients (6.6%), PIK3CA in 17/78 patients (25.0%), TP53 in 37/68 patients (54.4%), APC in 25/68 patients (36.7%), SMAD4 in 13/68 patients (19.1%), and FBXW7 in 5/68 patients (7.4%). Median follow-up was 54.9 months and median survival from PM diagnosis was 45.1 months. The right-sided primary (hazard ratio [HR] 1.62, 95% confidence interval [CI] 0.43-0.89; p = 0.011), BRAF mutations (HR 2.21, 95% CI 1.05-4.63; p = 0.038), and Peritoneal Cancer Index (HR 1.47, 95% CI 1.03-2.10; p = 0.036) independently correlated with poorer survival, while APC mutations univariately correlated with better survival (p = 0.03). Conclusions. BRAF mutations and right-sided primary are adverse prognostic factors that may be used to optimize therapeutic strategies. APC may be involved in CRC-PM development and progression. Peritoneal metastases (PMs) from colorectal cancer (CRC) are still a significant healthcare problem and an important cause of disease-related death following liver and lung metastases. 1,2 Because of the current limitation of imaging in detecting small-volume peritoneal disease, CRC-PMs are frequently diagnosed at an advanced stage. 3

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

et al. 2020

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“…Second, HIPEC is nearly always preceded by CRS which induces cytokine production that could also influence drug response. Third, intrapatient interlesion heterogeneity may provide an additional level of complexity that is not modelled in the present organoid collection. Despite these limitations, this model of PM from colorectal cancer is a robust in vitro system that allows rapid evaluation of existing and novel HIPEC strategies in a biologically relevant setting.…”

Section: Discussionmentioning

confidence: 99%

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

Ubink

Bolhaqueiro

Elias

et al. 2019

British Journal of Surgery

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Background Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies. Methods Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR. Results MMC was more effective in eliminating peritoneal metastasis‐derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis‐derived organoids to MMC, as the IC50 decreased 2·6–12·4‐fold to well below concentrations commonly attained in clinical practice. Live‐cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC‐induced cell cycle arrest, but caused increased replication stress and accelerated cell death. Conclusion Peritoneal metastasis‐derived organoids can be used to evaluate existing HIPEC regimens on an individual‐patient level and for development of more effective treatment strategies. Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient‐derived organoids can accurately predict clinical therapeutic response in vitro.A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient‐derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery–HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC.Peritoneal metastasis‐derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent‐tailored HIPEC regimens.

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“…A recent study of a Dutch cohort has shown colorectal cancer peritoneal metastases to be enriched for the consensus molecular subtype (CMS) four or the mesenchymal subtype. Eight of twenty-four of these patients had mucinous adenocarcinoma [26]. In a review of clinical, morphological and molecular classification of colorectal cancer, Jass notes that mucinous differentiation is not specific to clinicopathological subtypes [27].…”

Section: Discussionmentioning

confidence: 99%

Survival difference between mucinous vs. non-mucinous colorectal cancer following cytoreductive surgery and intraperitoneal chemotherapy

Huang

Alzahrani

Arrowaili

et al. 2018

International Journal of Hyperthermia

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Histopathological and molecular classification of colorectal cancer and corresponding peritoneal metastases

Cited by 66 publications

References 29 publications

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

Survival difference between mucinous vs. non-mucinous colorectal cancer following cytoreductive surgery and intraperitoneal chemotherapy

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