Conditional Recurrence-Free Survival after Resection of Colorectal Liver Metastases: Persistent Deleterious Association with RAS and TP53 Co-Mutation

Kawaguchi, Yoshikuni; Lillemoe, Heather A.; Panettieri, Elena; Chun, Yun Shin; Tzeng, Ching‐Wei D.; Aloia, Thomas A.; Kopetz, Scott; Vauthey, Jean‐Nicolas

doi:10.1016/j.jamcollsurg.2019.04.027

Cited by 59 publications

(42 citation statements)

References 34 publications

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“…The graph of estimated hazard function of recurrence of CLM suggests that most of the recurrence occurs within 2 years after initial hepatectomy, and disease‐free interval elapsed from the initial hepatectomy predicts increased probability of survival (Figure 3B). Similar outcomes were also reported in several studies 17,18 . These observations support the rationale for handling CLM as a localized disease in selected cases.…”

Section: Basic Oncological Behavior Of Colorectal Liver Metastasessupporting

confidence: 88%

Risk stratification and goal of systemic therapy for successful surgical management of colorectal liver metastases: Oncological optimization

Shindoh

2021

J Hepato Biliary Pancreat

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For patients with stage IV colorectal cancer (CRC), curative‐intent surgery has actively been performed for expecting prolonged survival outcomes. However, because the population with stage IV CRC is considerably heterogeneous, optimal selection of surgical candidate is inevitable to maximize survival outcomes. In the era of effective chemotherapy, there is an increasing need for a strategic use of chemotherapy as a part of multidisciplinary treatment to expand surgical indications and enhance the clinical outcomes. However, since the fate of each patient is difficult to predict at initial presentation, our clinical practice is rather “tailored”, considering the anatomy, oncological behavior of tumor, response to chemotherapy, and patient's physical status. Given that surgery is the only treatment option for expecting cure of colorectal liver metastases (CLM), the main purpose of chemotherapy for potentially/marginally resectable disease is to clarify the likelihood of surgical benefit through testing the behavior of the tumor and to select an appropriate candidate for surgery. This process of clinical decision is actually optimization of the initial population for surgery through the optimization of treatment for each patient. In this article, theoretical bases of multidisciplinary management for CLM were revisited and the concept of “oncological optimization” underling our clinical decision was discussed.

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Section: Basic Oncological Behavior Of Colorectal Liver Metastasessupporting

confidence: 88%

Risk stratification and goal of systemic therapy for successful surgical management of colorectal liver metastases: Oncological optimization

Shindoh

2021

J Hepato Biliary Pancreat

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“…Although likely influenced by the inclusion of several agents targeting EGFR in the drug testing panel, this separation was also reflected on the genomic and transcriptomic levels, specifically by the well-known markers RAS mutation and TP53 activity. Notably, the "double-resistant" subgroup with RAS and TP53 comutations has known poor prognostic associations after hepatic resection (45,46), reinforcing the challenge of adequate management of these patients. Based on pre-defined, although not yet clinically validated drug nomination criteria, we could suggest potentially effective therapies for eighteen of the totally twenty-two patients, including seven of the nine patients with RAS and TP53 co-mutations.…”

Section: Discussionmentioning

confidence: 99%

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

Bruun

Kryeziu

Eide

et al. 2020

Clinical Cancer Research

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Translational relevance The majority of PDOs from colorectal liver metastases were sensitive to anticancer drugs in clinical use and/or under development in late-phase clinical trials. Together with only a modest level of intrapatient inter-metastatic pharmacological heterogeneity, this reinforces a potential benefit from off-label use of drugs guided by both pharmacological profiling and established molecular markers. Correlation in the overall variation at the drug sensitivity and gene expression levels supports the relevance of transcriptomic profiling in pharmacogenomic assessments. Research.

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“…Recently, our group reported that the probability of recurrence peaked at approximately 1 year and diminished thereafter . 30 Additionally, the risk of recurrence changes over time by the interval free from recurrence after surgery (Fig. 7).…”

Section: Surveillance After Resection Of Clmmentioning

confidence: 99%

“…38 Comutation of RAS and TP53 was associated with worse OS than RAS alteration alone, and median RFS was lower for patients with RAS/TP53 co-mutation than for those with RAS/TP53 wild-type, even among patients who were free of recurrence at 1 year (1.5 years vs. 2.8 years; p = 0.006) or who were free of recurrence at 2 years (3.0 years vs. 5.9 years; p = 0.024) . 30 Somatic gene alterations in RAS (HR, 1.47; 95% CI, 1.20-1.82; p < 0.001), TP53 (HR, 1.40; 95% CI, 1.11-1.78; p = 0.005), and SMAD4 (HR, 1.62; 95% CI, 1.20-2.20; p = 0.002) were associated with worse OS after CLM resection, and alterations in more than one of these three genes were associated with worse OS and RFS than alteration in only one or none of Fig. 6 Four cancer-related signaling pathways associated with prognosis after CLM resection them.…”

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confidence: 99%

Prognostic and Therapeutic Implications of Tumor Biology, Including Gene Alterations, in Colorectal Liver Metastases

Kawaguchi

Kothari

Odisio

et al. 2021

Journal of Gastrointestinal Surgery

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Background For patients with colorectal liver metastases (CLM), the combination of surgical resection with other therapeutic options is essential. This article shows how recent advances in knowledge of tumor biology, including genetic alterations, affect the choice of therapeutic approach for patients with CLM. Methods We reviewed the literature on recent advances in knowledge about CLM tumor biology including genetic profiles, clinical risk score models for CLM, preoperative therapy for CLM, and liver-directed therapy for CLM. Results Studies showed that RAS alteration is a negative prognostic factor in addition to traditional clinical risk factors (e.g., larger diameter and higher number of CLM, spread of the primary tumor to regional lymph nodes). Although the response to preoperative chemotherapy is an important predictor of survival, poor response is not a contraindication to surgical resection. The combination of surgical therapy and percutaneous ablation can be considered in marginally resectable cases; however, a wider ablation margin is required for RAS-mutant CLM. More recently, genetic analysis using next-generation sequencing showed the negative prognostic impact of alterations in TP53, SMAD4, FBXW7, and RAS/BRAF in patients with CLM. In RAS-mutant CLM, intensive follow-up is required in patients who remain recurrence free 2 years after surgery. Discussion In patients with CLM, RAS mutation status is important in predicting postoperative survival, selecting the treatment approach, and tailoring postoperative follow-up. In addition, more recent genetic analyses of CLM have identified additional predictors of survival.

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Conditional Recurrence-Free Survival after Resection of Colorectal Liver Metastases: Persistent Deleterious Association with RAS and TP53 Co-Mutation

Cited by 59 publications

References 34 publications

Risk stratification and goal of systemic therapy for successful surgical management of colorectal liver metastases: Oncological optimization

Risk stratification and goal of systemic therapy for successful surgical management of colorectal liver metastases: Oncological optimization

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

Prognostic and Therapeutic Implications of Tumor Biology, Including Gene Alterations, in Colorectal Liver Metastases

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