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Lillemoe HA, Passot G, Kawaguchi Y, DeBellis M, Glehen O, Chun YS, Tzeng CWD, Aloia TA, Lopez J, Vauthey JN. RAS/TP53 Co-mutation is Associated With Worse Survival After Concurrent Resection of Colorectal Liver Metastases and Extrahepatic Disease. Ann Surg 2022; 276:357-362. [PMID: 33351476 DOI: 10.1097/sla.0000000000004672] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To determine if tumor genetics are associated with overall survival (OS) after concurrent resection of colorectal liver metastases (CLM) and extrahepatic disease (EHD). SUMMARY BACKGROUND DATA The prognosis for patients who undergo concurrent resection of CLM/EHD is unclear and the impact of somatic mutations has not been reported. METHODS Patients undergoing concurrent resection of CLM and EHD from 2007 to 2017 were identified from 2 academic centers. From 1 center, patients were selected from a pre-existing database of patients undergoing cytore-ductive surgery with hyperthermic intraperitoneal chemotherapy. The Kaplan-Meier method was used to construct survival curves, compared using the log-rank test. Multivariable Cox analysis for OS was performed. RESULTS One hundred nine patients were included. Most common EHD sites included lung (33 patients), peritoneum (32), and portal lymph nodes (14). TP53 mutation was the most common mutation, identified in 75 patients (69%), and RAS/TP53 co-mutation was identified in 31 patients (28%). The median OS was 49 months (interquartile range, 24-125), and 3- and 5-year OS rates were 66% and 44%, respectively. Compared to patients without RAS/ TP53 co-mutation, patients with RAS/TP53 co-mutation had lower median OS: 39 vs. 51 months ( P = 0.02). On multivariable analysis, lung EHD [hazard ratio (HR), 0.7; 95% confidence intervals (CI), 0.3-1.4], peritoneal EHD (HR, 2.2; 95% CI, 1.1-4.2) and RAS/TP53 co-mutation (HR, 2.8; 95% CI, 1.1-7.2) were independently associated with OS. CONCLUSIONS RAS/TP53 co-mutation is associated with worse OS after concurrent CLM/EHD resection. Mutational status and site of EHD should be included in the evaluation of patients considered for concurrent resection.
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Affiliation(s)
- Heather A Lillemoe
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Guillaume Passot
- Department of Surgical Oncology, CHU Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
- EMR 3738, CICLY, Université Claude Bernard Lyon 1, Lyon, France
| | - Yoshikuni Kawaguchi
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mario DeBellis
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Olivier Glehen
- Department of Surgical Oncology, CHU Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
- EMR 3738, CICLY, Université Claude Bernard Lyon 1, Lyon, France
| | - Yun Shin Chun
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ching-Wei D Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Thomas A Aloia
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jonathan Lopez
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France; Department of Biochemistry and Molecular Biology, Lyon University Hospital, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Lyon, France
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Newhook TE, Vauthey JN. Colorectal liver metastases: state-of-the-art management and surgical approaches. Langenbecks Arch Surg 2022; 407:1765-1778. [DOI: 10.1007/s00423-022-02496-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023]
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Lang H, Baumgart J, Roth W, Moehler M, Kloth M. Cancer gene related characterization of patterns and point of recurrence after resection of colorectal liver metastases. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1372. [PMID: 34733924 PMCID: PMC8506541 DOI: 10.21037/atm-21-292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 05/21/2021] [Indexed: 12/16/2022]
Abstract
Background Outcome after resection of CRLM is hampered by a high rate of recurrence. There are little data about the role of cancer related genes and their mutations in this scenario. The aim of our analysis was to assess the predictive power of cancer-related genes and their mutations on risk for and distribution of recurrence and the time of occurrence after resection of colorectal liver metastases (CRLM). Methods We included 130 patients with 167 liver resections. The work-up consisted of the analysis of a total of 720 cancer-related genes by next-generation sequencing (NGS). Results were correlated with the patterns and time of recurrence and survival. Results At the time of analysis, 89/130 patients (68%) had developed recurrence. This included liver only recurrence in 52%, lung only recurrence in 11% and disseminated disease in 37% of cases. In univariate analysis, alterations in the RAS/RAF pathway and in the SMAD family had significant predictive power for the time of recurrence (P<0.0001) whereas single mutations did not reach statistical significance in multivariate analysis. Mutations of PIK3CA were associated with a better prognosis and a later occurrence of relapse. A recurrence risk score (r-RS) based on mutations in these cancer related genes is predictive of the time of recurrence. Conclusions In conclusion, mutations in the RAS/RAF pathway and the SMAD family are risk factors for early recurrence. Mutations of PIK3CA are associated with a lower risk for recurrence after resection of CRLM. Cancer related genes and their mutations do not correlate with patterns of recurrence but are predictive for the timely onset of recurrence.
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Affiliation(s)
- Hauke Lang
- Department of General, Visceral and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany
| | - Janine Baumgart
- Department of General, Visceral and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany
| | - Wilfried Roth
- Department of Pathology, Universitätsmedizin Mainz, Mainz, Germany
| | - Markus Moehler
- Department of Gastroenterology and Hepatology, Universitätsmedizin Mainz, Mainz, Germany
| | - Michael Kloth
- Department of Pathology, Universitätsmedizin Mainz, Mainz, Germany
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Fang T, Liang T, Wang Y, Wu H, Liu S, Xie L, Liang J, Wang C, Tan Y. Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal cancer: a systematic review and meta-analysis. BMC Gastroenterol 2021; 21:297. [PMID: 34301194 PMCID: PMC8299661 DOI: 10.1186/s12876-021-01864-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Approximately 5.0-24.2% of colorectal cancers (CRCs) have inactivating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of SMAD4 gene mutation in CRC patients. METHODS A detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between SMAD4 mutations and the demographic and clinicopathological characteristics in CRC patients. The hazard ratios (HRs) with 95% confidence intervals (CI) were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS). RESULTS Ten studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from 5 studies and data on PFS/RFS were available from 3 studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% CI 1.28-1.67, P = 0.001), the summary HR for PFS/RFS was 1.59 (95% CI 1.14-2.22, P = 0.006). In terms of clinicopathology parameters, 9 studies have data that can be extracted, SMAD4 mutations were associated with tumor location (odds ratio [OR] = 1.15, colon/rectum, 95% CI 1.01-1.31, P = 0.042), TNM stage (OR = 1.28, stage IV/I-III, 95% CI 1.03-1.58, P = 0.025), lymph node metastasis (OR = 1.42, N1 + N2/N0, 95% CI 1.20-1.67, P < 0.001), mucinous differentiation (OR = 2.23, 95% CI 1.85-2.70, P < 0.001) and rat sarcoma viral oncogene homolog (RAS) mutation status (OR = 2.13, 95% CI 1.37-3.34, P = 0.001). No connection was found with age, gender, tumor grade, microsatellite instability status and b-viral oncogene homolog B1 mutation status. Besides, publication bias was not observed in any study. CONCLUSIONS This meta-analysis suggests that SMAD4 mutation was associated with OS, PFS/RFS, and clinicopathological parameters, including tumor site, disease stage, RAS status, lymph node metastasis and mucinous differentiation. Our meta-analysis indicated that SMAD4 mutations could predict the poor prognosis and aggressive clinicopathological characteristics of CRC. More large-sample cohort studies are needed to confirm this conclusion. Since SMAD4 mutations are closely related to RAS mutations, their relationship warrants further investigation.
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Affiliation(s)
- Tian Fang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Tingting Liang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Yizhuo Wang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Haitao Wu
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Shuhan Liu
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Linying Xie
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Jiaying Liang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Chang Wang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China.
| | - Yehui Tan
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China.
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Krasnodebski M, Kim BJ, Wei SH, Velasco JD, Nishioka Y, Vauthey JN. Chemotherapy in combination with resection for colorectal liver metastases – current evidence. SURGERY IN PRACTICE AND SCIENCE 2020. [DOI: 10.1016/j.sipas.2020.100021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Lang H. Liver resection is beneficial for patients with colorectal liver metastases and extrahepatic disease. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1122. [PMID: 33240971 PMCID: PMC7576061 DOI: 10.21037/atm-20-4416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Hauke Lang
- Department of General, Visceral and Transplantation Surgery, University Medical Center, Mainz, Germany
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De Raffele E, Mirarchi M, Cuicchi D, Lecce F, Casadei R, Ricci C, Selva S, Minni F. Simultaneous colorectal and parenchymal-sparing liver resection for advanced colorectal carcinoma with synchronous liver metastases: Between conventional and mini-invasive approaches. World J Gastroenterol 2020; 26:6529-6555. [PMID: 33268945 PMCID: PMC7673966 DOI: 10.3748/wjg.v26.i42.6529] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/05/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
The optimal timing of surgery in case of synchronous presentation of colorectal cancer and liver metastases is still under debate. Staged approach, with initial colorectal resection followed by liver resection (LR), or even the reverse, liver-first approach in specific situations, is traditionally preferred. Simultaneous resections, however, represent an appealing strategy, because may have perioperative risks comparable to staged resections in appropriately selected patients, while avoiding a second surgical procedure. In patients with larger or multiple synchronous presentation of colorectal cancer and liver metastases, simultaneous major hepatectomies may determine worse perioperative outcomes, so that parenchymal-sparing LR should represent the most appropriate option whenever feasible. Mini-invasive colorectal surgery has experienced rapid spread in the last decades, while laparoscopic LR has progressed much slower, and is usually reserved for limited tumours in favourable locations. Moreover, mini-invasive parenchymal-sparing LR is more complex, especially for larger or multiple tumours in difficult locations. It remains to be established if simultaneous resections are presently feasible with mini-invasive approaches or if we need further technological advances and surgical expertise, at least for more complex procedures. This review aims to critically analyze the current status and future perspectives of simultaneous resections, and the present role of the available mini-invasive techniques.
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Affiliation(s)
- Emilio De Raffele
- Division of Pancreatic Surgery, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Mariateresa Mirarchi
- Dipartimento Strutturale Chirurgico, Ospedale SS Antonio e Margherita, 15057 Tortona (AL), Italy
| | - Dajana Cuicchi
- Surgery of the Alimentary Tract, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Ferdinando Lecce
- Surgery of the Alimentary Tract, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Riccardo Casadei
- Division of Pancreatic Surgery, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Claudio Ricci
- Division of Pancreatic Surgery, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Saverio Selva
- Division of Pancreatic Surgery, Department of Digestive Diseases, Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy
| | - Francesco Minni
- Division of Pancreatic Surgery, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
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Lang H, Lordick F. Precision Medicine for Visceral Cancer: Does the Future Lie in Molecular Stratification? Visc Med 2020; 36:349-350. [PMID: 33178730 DOI: 10.1159/000509887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/03/2020] [Indexed: 11/19/2022] Open
Affiliation(s)
- Hauke Lang
- Department of General, Visceral, and Transplantation Surgery, University Hospital Mainz, Mainz, Germany
| | - Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, Leipzig University Medical Center, Leipzig, Germany
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