Primary Tumor Sidedness, RAS and BRAF Mutations and MSI Status as Prognostic Factors in Patients with Colorectal Liver Metastases Treated with Surgery and Thermal Ablation: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE)

Dijkstra, Madelon; Nieuwenhuizen, Sanne; Puijk, Robbert S.; Timmer, Florentine E. F.; Geboers, Bart; Schouten, Evelien A.C.; Opperman, Jip; Scheffer, Hester J.; Vries, Jan J. J. de; Versteeg, Kathelijn S.; Lissenberg‐Witte, Birgit I.; Tol, M.P. van den; Meijerink, Martijn R.

doi:10.3390/biomedicines9080962

Cited by 26 publications

(20 citation statements)

References 46 publications

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“…Even if all these studies included patients with tumors larger than 3 cm, which is questionable, in multivariate analysis, the 2 main risk factors of local tumor progression were mutational status and ablation margins (Tables 2 and 3). These data were also confirmed by a more recent study from the Amsterdam group [60]. The authors analyzed the impact of primary tumor sidedness, genetic mutations (RAS and BRAF) and the microsatellite instability status to determine the prognosis of patients treated for CRLM enrolled in the Amsterdam Colorectal Liver Met Registry.…”

Section: Implication Of Ras Mutations In Ablative Treatment Of Crlmmentioning

confidence: 71%

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Implications of RAS Mutations on Oncological Outcomes of Surgical Resection and Thermal Ablation Techniques in the Treatment of Colorectal Liver Metastases

Rhaiem

Rached

Tashkandi

et al. 2022

Cancers

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Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. More than 50% of patients with CRC will develop liver metastases (CRLM) during their disease. In the era of precision surgery for CRLM, several advances have been made in the multimodal management of this disease. Surgical treatment, combined with a modern chemotherapy regimen and targeted therapies, is the only potential curative treatment. Unfortunately, 70% of patients treated for CRLM experience recurrence. RAS mutations are associated with worse overall and recurrence-free survival. Other mutations such as BRAF, associated RAS /TP53 and APC/PIK3CA mutations are important genetic markers to evaluate tumor biology. Somatic mutations are of paramount interest for tailoring preoperative treatment, defining a surgical resection strategy and the indication for ablation techniques. Herein, the most relevant studies dealing with RAS mutations and the management of CRLM were reviewed. Controversies about the implication of this mutation in surgical and ablative treatments were also discussed.

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Section: Implication Of Ras Mutations In Ablative Treatment Of Crlmmentioning

confidence: 71%

“…In these studies, the optimal minimal ablation margin was >5 mm [56,58] and raised to 10 mm [57,59]. Wider margins seem to be necessary to reduce rates of local tumor progression in RAS/KRAS mutation patients [60].…”

Section: Implication Of Ras Mutations In Ablative Treatment Of Crlmmentioning

confidence: 94%

Implications of RAS Mutations on Oncological Outcomes of Surgical Resection and Thermal Ablation Techniques in the Treatment of Colorectal Liver Metastases

Rhaiem

Rached

Tashkandi

et al. 2022

Cancers

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“…Regarding microsatellite instability (MSI), a screening study of deficient mismatch repair profiles on colorectal cancer distribution in Romania by Lungulescu showed that MSI status does not carry a significant prognostic role [ 70 ]. Apart from clinical and pathological factors, new insights regarding the role of genetic [ 71 ], transcriptomic [ 72 ] and mass spectrometry imaging proteomics analysis [ 73 ] as prognostic instruments are still under investigation concerning the influence upon clinical decision in loco-regional recurrence prediction. Additionally, immunohistochemical expression of the REG4 proteins, frequently detected in right colon cancer, was significantly correlated with low recurrence-free survival [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

Postoperative Quality Assessment Score Can Select Patients with High Risk for Locoregional Recurrence in Colon Cancer

Livadaru

Moscalu

Ghitun³

et al. 2022

Diagnostics

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Background: Monitoring surgical quality has been shown to reduce locoregional recurrence (LRR). We previously showed that the arterial stump length (ASL) after complete mesocolic excision (CME) is a reproducible quality instrument and correlates with the lymph-node (LN) yield. We hypothesized that generating an LRR prediction score by integrating the ASL would predict the risk of LRR after suboptimal surgery. Methods: 502 patients with curative resections for stage I–III colon cancer were divided in two groups (CME vs. non-CME) and compared in terms of surgical data, ASL-derived parameters, pathological parameters, LRR and LRR-free survival. A prediction score was generated to stratify patients at high risk for LRR. Results: The ASL showed significantly higher values (50.77 mm ± 28.5 mm) with LRR vs. (45.59 mm ± 28.1 mm) without LRR (p < 0.001). Kaplan–Meier survival analysis showed a significant increase in LRR-free survival at 5.58 years when CME was performed (Group A: 81%), in contrast to non-CME surgery (Group B: 67.2%). Conclusions: The prediction score placed 76.6% of patients with LRR in the high-risk category, with a strong predictive value. Patients with long vascular stumps and positive nodes could benefit from second surgery to complete the mesocolic excision.

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“…After accounting for potential confounders in multivariable analysis using Cox proportional hazards model and performing subgroup analyses to identify heterogeneous treatment effects, the risk of confounding should be minimized and the risk of residual confounding is limited. However, the MSI and RAS and BRAF mutation status were not routinely established and could be potential confounders leading to residual bias, as RAS mutations status might influence LTPFS [ 12 , 43 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. The selection of patients for NAC was based on local expertise, determined by multidisciplinary tumor board evaluations, and not preceded by protocol, which may have driven treatment decisions and could preserve selection bias and might impair the generalizability of the outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Systemic therapy increased 5-year overall survival (OS) of unresectable CRLM from 0–3% for untreated CRLM to 11% for patients treated with palliative chemotherapy [ 5 , 6 , 7 , 8 , 9 ]. Local treatment with curative intent improves 5-year OS up to 58% for resectable and/or ablatable CRLM [ 10 , 11 , 12 , 13 , 14 , 15 ]. Unfortunately, roughly 20% of patients with CRLM are eligible for local treatment options, such as partial hepatectomy or thermal ablation (i.e., radiofrequency ablation (RFA), microwave ablation (MWA)) [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Repeat Local Treatment of Recurrent Colorectal Liver Metastases, the Role of Neoadjuvant Chemotherapy: An Amsterdam Colorectal Liver Met Registry (AmCORE) Based Study

Dijkstra

Nieuwenhuizen

Puijk

et al. 2021

Cancers

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This cohort study aimed to evaluate efficacy, safety, and survival outcomes of neoadjuvant chemotherapy (NAC) followed by repeat local treatment compared to upfront repeat local treatment of recurrent colorectal liver metastases (CRLM). A total of 152 patients with 267 tumors from the prospective Amsterdam Colorectal Liver Met Registry (AmCORE) met the inclusion criteria. Two cohorts of patients with recurrent CRLM were compared: patients who received chemotherapy prior to repeat local treatment (32 patients) versus upfront repeat local treatment (120 patients). Data from May 2002 to December 2020 were collected. Results on the primary endpoint overall survival (OS) and secondary endpoints local tumor progression-free survival (LTPFS) and distant progression-free survival (DPFS) were reviewed using the Kaplan–Meier method. Subsequently, uni- and multivariable Cox proportional hazard regression models, accounting for potential confounders, were estimated. Additionally, subgroup analyses, according to patient, initial and repeat local treatment characteristics, were conducted. Procedure-related complications and length of hospital stay were compared using chi-square test and Fisher’s exact test. The 1-, 3-, and 5-year OS from date of diagnosis of recurrent disease was 98.6%, 72.5%, and 47.7% for both cohorts combined. The crude survival analysis did not reveal a significant difference in OS between the two cohorts (p = 0.834), with 1-, 3-, and 5-year OS of 100.0%, 73.2%, and 57.5% for the NAC group and 98.2%, 72.3%, and 45.3% for the upfront repeat local treatment group, respectively. After adjusting for two confounders, comorbidities (p = 0.010) and primary tumor location (p = 0.023), the corrected HR in multivariable analysis was 0.839 (95% CI, 0.416–1.691; p = 0.624). No differences between the two cohorts were found with regards to LTPFS (HR = 0.662; 95% CI, 0.249–1.756; p = 0.407) and DPFS (HR = 0.798; 95% CI, 0.483–1.318; p = 0.378). No heterogeneous treatment effects were detected in subgroup analyses according to patient, disease, and treatment characteristics. No significant difference was found in periprocedural complications (p = 0.843) and median length of hospital stay (p = 0.600) between the two cohorts. Chemotherapy-related toxicity was reported in 46.7% of patients. Adding NAC prior to repeat local treatment did not improve OS, LTPFS, or DPFS, nor did it affect periprocedural morbidity or length of hospital stay. The results of this comparative assessment do not substantiate the routine use of NAC prior to repeat local treatment of CRLM. Because the exact role of NAC (in different subgroups) remains inconclusive, we are currently designing a phase III randomized controlled trial (RCT), COLLISION RELAPSE trial, directly comparing upfront repeat local treatment (control) to neoadjuvant systemic therapy followed by repeat local treatment (intervention).

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Primary Tumor Sidedness, RAS and BRAF Mutations and MSI Status as Prognostic Factors in Patients with Colorectal Liver Metastases Treated with Surgery and Thermal Ablation: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE)

Cited by 26 publications

References 46 publications

Implications of RAS Mutations on Oncological Outcomes of Surgical Resection and Thermal Ablation Techniques in the Treatment of Colorectal Liver Metastases

Implications of RAS Mutations on Oncological Outcomes of Surgical Resection and Thermal Ablation Techniques in the Treatment of Colorectal Liver Metastases

Postoperative Quality Assessment Score Can Select Patients with High Risk for Locoregional Recurrence in Colon Cancer

Repeat Local Treatment of Recurrent Colorectal Liver Metastases, the Role of Neoadjuvant Chemotherapy: An Amsterdam Colorectal Liver Met Registry (AmCORE) Based Study

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