Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases

Chun, Yun Shin; Passot, Guillaume; Yamashita, Satoshi; Nusrat, Maliha; Katsonis, Panagiotis; Loree, Jonathan M.; Conrad, Claudius; Tzeng, Ching Wei D.; Xiao, Lianchun; Aloia, Thomas A.; Eng, Cathy; Kopetz, Scott; Lichtarge, Olivier; Vauthey, Jean Nicolas

doi:10.1097/sla.0000000000002450

Cited by 139 publications

(107 citation statements)

References 32 publications

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“…This meta‐analysis did not report on the pooled median OS to allow comparisons with unresectable CRLM patients. However, individual studies have reported median OS for KRAS vs wild‐type tumors as 42 vs 63.3 months, 44.9 vs 59.8 months, and 48 vs 71 months, respectively …”

Section: Resultsmentioning

confidence: 99%

“…In addition to different KRAS variants, the effects of genetic cooperation of other mutations concomitant to the RAS mutations was only recently investigated. Chun et al found that the survival of patients with concurrent RAS and high EAp53 mutations was as low as 12.2%, raising the question of whether those patients would benefit from surgery. The broader message of this study is that the interplay of concurrent mutations should be considered.…”

Section: Resultsmentioning

confidence: 99%

“…However, individual studies have reported median OS for KRAS vs wild-type tumors as 42 vs 63.3 months, 44.9 vs 59.8 months, and 48 vs 71 months, respectively. 5,12,27 There is no meta-analysis or systematic review of the patterns of recurrence, and we will mention only the most important studies. 28 Vauthey et al 29 from MD Anderson were the first to report on the patterns of recurrence following resection of KRAS-mutated CRLM.…”

Section: Recurrence Rate and Time To Recurrence Patterns Of Recurrmentioning

confidence: 99%

“…In addition to different KRAS variants, the effects of genetic cooperation of other mutations concomitant to the RAS mutations was only recently investigated. Chun et al 27…”

Section: Kras Alone Vs Genetic Risk Score Systems For Surgical Selementioning

confidence: 99%

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Mutation status and surgical selection

Margonis

Kreis

Wolfgang

et al. 2019

Journal of Surgical Oncology

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Current evidence cannot support denying metastasectomy in otherwise resectable patients solely based on their overall KRAS or BRAF mutational status. The combination of KRAS or BRAF mutational status with certain clinicopathologic characteristics has defined groups of patients who may not derive benefit from metastasectomy, but external validation is needed. The effect of certain KRAS or BRAF variants on survival may be more pronounced and therefore future studies should consider them for surgical selection.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Recurrence Rate and Time To Recurrence Patterns Of Recurrmentioning

confidence: 99%

“…In addition to different KRAS variants, the effects of genetic cooperation of other mutations concomitant to the RAS mutations was only recently investigated. Chun et al 27…”

Section: Kras Alone Vs Genetic Risk Score Systems For Surgical Selementioning

confidence: 99%

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Mutation status and surgical selection

Margonis

Kreis

Wolfgang

et al. 2019

Journal of Surgical Oncology

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“…4 In addition, co-occurrence of RAS and TP53 mutations is associated with shorter overall survival (OS). 5 The presence of BRAF mutation is also a poor prognostic marker associated with higher risk of recurrence. [6][7][8] While some patients with limited CLM can be cured, many CRC patients have liver metastases too extensive for resection or recur after surgery.…”

Section: Introductionmentioning

confidence: 99%

Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion

Smith¹,

Chatila²,

Sánchez-Vega³

et al. 2019

Cancer Medicine

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BackgroundResection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit.MethodsWe performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels.ResultsThree hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort.ConclusionsConcurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI.

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Genomic and prognostic heterogeneity among RAS/BRAF^V600E/TP53 co‐mutated resectable colorectal liver metastases

et al. 2021

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Colorectal cancer commonly metastasizes into multiple liver foci, but intermetastatic heterogeneity remains poorly described. Here, we demonstrate that mutations of RAS/BRAF/TP53 are homogeneous within patients, while DNA copy number aberrations can vary greatly. RAS/BRAF/TP53 co‐mutations conferred a dismal prognosis, and co‐mutations combined with a high burden and heterogeneity of copy number aberrations identified patients with the poorest outcome.

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Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases

Cited by 139 publications

References 32 publications

Mutation status and surgical selection

Mutation status and surgical selection

Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion

Genomic and prognostic heterogeneity among RAS/BRAF^V600E/TP53 co‐mutated resectable colorectal liver metastases

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Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases

Cited by 139 publications

References 32 publications

Mutation status and surgical selection

Mutation status and surgical selection

Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion

Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases

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Genomic and prognostic heterogeneity among RAS/BRAF^V600E/TP53 co‐mutated resectable colorectal liver metastases