Prognostic and Therapeutic Implications of Tumor Biology in Colorectal Liver Metastases

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 15983

Special Issue Editors

1. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
2. Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, 12203 Berlin, Germany
Interests: surgical oncology; hepatobiliary tumors; colorectal liver metastases; tumor biology
Special Issues, Collections and Topics in MDPI journals
Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, 12203 Berlin, Germany
Interests: surgical oncology; hepatobiliary tumors; gastric cancer; esophageal cancer
Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, 12203 Berlin, Germany
Interests: surgical oncology; hepatobiliary tumors; pancreas cancer

Special Issue Information

Dear Colleagues,

There has been a recent revolution in the availability and analysis of genetic data in resectable colorectal cancer liver metastases (CRLMs).  During the past decade, somatic mutations such as RAS or BRAF have been repeatedly associated with worse overall and recurrence-free survival. More recently, less-common somatic mutations, alone or in combination with RAS mutations (e.g., “triple mutation” in RAS, TP53, and SMAD4) have been demonstrated to predict prognosis. However, the association of somatic mutations with cure (defined as 10-year survival) is unknown, as previous studies restricted analyses to 5-year outcomes. Similarly, little is known about the prognostic value of somatic mutations specifically in rectal cancer liver metastases.

Interestingly, some studies suggest that the interaction of somatic mutations and other prognostic factors are far from linear. In turn, some somatic mutations gain or lose significance due to the absence or presence of other variables. For example, our group has demonstrated that KRAS status has a variable prognostic impact after hepatic resection for CRLMs depending on the site of the primary CRC, while others have shown that the prognostic value of RAS mutations depends on the presence or absence of other somatic mutations such as TP53 and SMAD4.  Further studies that will elucidate the interaction of somatic mutations and other prognostic factors (including other somatic mutations) are warranted.

In addition to their prognostic value, somatic gene alterations can potentially impact the surgical management of CRLMs by informing: I) patient selection for surgery (i.e., there is a need to define “biological contraindications”), II) patient selection and surgical strategy in those with bilobar CLM that is not resectable in one operation and who are candidates for 2-stage hepatectomy or ALPPS (KRAS mutation has been demonstrated to be an independent predictor of poor survival after ALPPS, although the study was very small), III) patient selection for liver transplantation (unexplored topic), IV) selection of optimal margin width (a long-lasting debate), V) post-hepatectomy surveillance (only one study has addressed this to date), and VI) selection of patients for repeat hepatectomy for recurrent disease (similarly, only a few studies have addressed the role of RAS mutations in this context). Further studies to address these aims are needed.

Dr. Georgios Antonios Margonis
Prof. Dr. Katharina Beyer
Dr. Carsten Kamphues
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • colorectal liver metastases
  • somatic mutations
  • tumor biology
  • prognosis
  • surgery
  • gene alterations
  • two-stage hepatectomy
  • ALPPS
  • RAS mutations
  • margin

Published Papers (9 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review, Other

4 pages, 185 KiB  
Editorial
Prognostic and Therapeutic Implications of Tumor Biology in Colorectal Liver Metastases
by Carsten Kamphues, Katharina Beyer and Georgios Antonios Margonis
Cancers 2022, 14(1), 88; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010088 - 24 Dec 2021
Cited by 1 | Viewed by 1655
Abstract
Prognostic models allow clinicians to predict survival outcomes, facilitate patient–physician discussions, and identify subgroups with potentially distinct prognoses [...] Full article

Research

Jump to: Editorial, Review, Other

11 pages, 711 KiB  
Article
PET-Uptake in Liver Metastases as Method to Predict Tumor Biological Behavior in Patients Transplanted for Colorectal Liver Metastases Developing Lung Recurrence
by Svein Dueland, Tor Magnus Smedman, Harald Grut, Trygve Syversveen, Lars Hilmar Jørgensen and Pål-Dag Line
Cancers 2022, 14(20), 5042; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14205042 - 14 Oct 2022
Cited by 2 | Viewed by 1173
Abstract
The objective of the study was to determine the impact of PET uptake on liver metastases on overall survival (OS) after resection of pulmonary metastases in patients who had received liver transplantation (LT) due to unresectable colorectal liver-only metastases. Resection of pulmonary colorectal [...] Read more.
The objective of the study was to determine the impact of PET uptake on liver metastases on overall survival (OS) after resection of pulmonary metastases in patients who had received liver transplantation (LT) due to unresectable colorectal liver-only metastases. Resection of pulmonary colorectal metastases is controversial. Some hospitals offer this treatment to selected patients, whereas other hospitals do not perform the procedure in colorectal cancer patients who develop pulmonary metastases. All patients included in the LT studies who developed pulmonary metastases as first site of relapse, and had resection of these as first treatment, were included in this report. Metabolic tumor volume (MTV) in liver was derived from the pre-transplant PET examinations. OS from time of resection was calculated by the Kaplan–Meier method. Patients with low MTV (<70 cm3) had significantly longer OS from time of resection of pulmonary metastases compared to patients with high MTV (>70 cm3). Patients with low MTV in the liver had 10-year OS from time of pulmonary resections of 86%. Liver MTV values from pre-transplant PET examinations may predict long OS in colorectal cancer patients with a resection of pulmonary metastases developing after LT. Thus, in selected colorectal cancer patients developing pulmonary metastases resection of these metastases should be the treatment of choice. Full article
Show Figures

Figure 1

15 pages, 1607 KiB  
Article
Impact of Preoperative Chemotherapy Features on Patient Outcomes after Hepatectomy for Initially Unresectable Colorectal Cancer Liver Metastases: A LiverMetSurvey Analysis
by Pasquale F. Innominato, Valérie Cailliez, Marc-Antoine Allard, Santiago Lopez-Ben, Alessandro Ferrero, Hugo Marques, Catherine Hubert, Felice Giuliante, Fernando Pereira, Esteban Cugat, Darius F. Mirza, Jose Costa-Maia, Alejandro Serrablo, Real Lapointe, Cristina Dopazo, Jose Tralhao, Gernot Kaiser, Jinn-Shiun Chen, Francisco Garcia-Borobia, Jean-Marc Regimbeau, Oleg Skipenko, Jen-Kou Lin, Christophe Laurent, Enrico Opocher, Yuichi Goto, Benoist Chibaudel, Aimery de Gramont and René Adamadd Show full author list remove Hide full author list
Cancers 2022, 14(17), 4340; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174340 - 05 Sep 2022
Cited by 2 | Viewed by 1897
Abstract
Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within [...] Read more.
Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes. Full article
Show Figures

Figure 1

Review

Jump to: Editorial, Research, Other

14 pages, 2509 KiB  
Review
Histopathological Growth Pattern in Colorectal Liver Metastasis and The Tumor Immune Microenvironment
by Claudia Zaharia, Torhild Veen, Dordi Lea, Arezo Kanani, Marina Alexeeva and Kjetil Søreide
Cancers 2023, 15(1), 181; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010181 - 28 Dec 2022
Cited by 5 | Viewed by 2719
Abstract
Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological growth patterns and tumor immune microenvironment of colorectal liver metastases may help determine treatment strategies and assess prognosis. A literature search [...] Read more.
Almost half of all patients with colorectal cancer present with or eventually develop metastasis, most frequently in the liver. Understanding the histopathological growth patterns and tumor immune microenvironment of colorectal liver metastases may help determine treatment strategies and assess prognosis. A literature search was conducted to gather information on cancer biology, histopathological growth patterns, and the tumor immune microenvironment in colorectal liver metastases, including their mechanisms and their impact on clinical outcomes. A first consensus on histopathological growth patterns emerged in 2017, identifying five growth patterns. Later studies found benefits from a two-tier system, desmoplastic and non-desmoplastic, incorporated into the updated 2022 consensus. Furthermore, the tumor immune microenvironment shows additional characteristic features with relevance to cancer biology. This includes density of T-cells (CD8+), expression of claudin-2, presence of vessel co-option versus angiogenesis, as well as several other factors. The relation between histopathological growth patterns and the tumor immune microenvironment delineates distinct subtypes of cancer biology. The distinct subtypes are found to correlate with risk of metastasis or relapse, and hence to clinical outcome and long-term survival in each patient. In order to optimize personalized and precision therapy for patients with colorectal liver metastases, further investigation into the mechanisms of cancer biology and their translational aspects to novel treatment targets is warranted. Full article
Show Figures

Figure 1

12 pages, 656 KiB  
Review
BRAF Mutations in Colorectal Liver Metastases: Prognostic Implications and Potential Therapeutic Strategies
by Pei-Pei Wang, Chen Lin, Jane Wang, Georgios Antonios Margonis and Bin Wu
Cancers 2022, 14(17), 4067; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174067 - 23 Aug 2022
Cited by 6 | Viewed by 1637
Abstract
Surgery combined with chemotherapy and precision medicine is the only potential treatment for patients with colorectal cancer liver metastases (CRLM). The use of modern molecular biotechnology to identify suitable biomarkers is of great significance for predicting prognosis and formulating individualized treatment plans for [...] Read more.
Surgery combined with chemotherapy and precision medicine is the only potential treatment for patients with colorectal cancer liver metastases (CRLM). The use of modern molecular biotechnology to identify suitable biomarkers is of great significance for predicting prognosis and formulating individualized treatment plans for these patients. BRAF mutations, particularly V600E, are widely believed to be associated with poor prognosis in patients with metastatic CRC (mCRC). However, it is unclear which specific factors affect the prognosis of CRLM patients with BRAF mutations. It is also unknown whether patients with resectable CRLM and BRAF mutations should undergo surgical treatment since there is an increased recurrence rate after surgery in these patients. In this review, we combined the molecular mechanism and clinical characteristics of BRAF mutations to explore the prognostic significance and potential targeted therapy strategies for patients with BRAF-mutated CRLM. Full article
Show Figures

Figure 1

21 pages, 343 KiB  
Review
Prognostic Models Incorporating RAS Mutation to Predict Survival in Patients with Colorectal Liver Metastases: A Narrative Review
by Geoffrey Yuet Mun Wong, Connie Diakos, Mark P. Molloy and Thomas J. Hugh
Cancers 2022, 14(13), 3223; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133223 - 30 Jun 2022
Cited by 2 | Viewed by 1505
Abstract
Recurrence and survival vary widely among patients who undergo curative-intent resection of colorectal liver metastases (CRLM). Prognostic models provide estimated probabilities of these outcomes and allow the effects of multiple potentially interacting variables to be adjusted and assessed simultaneously. Although many prognostic models [...] Read more.
Recurrence and survival vary widely among patients who undergo curative-intent resection of colorectal liver metastases (CRLM). Prognostic models provide estimated probabilities of these outcomes and allow the effects of multiple potentially interacting variables to be adjusted and assessed simultaneously. Although many prognostic models based on clinicopathologic factors have been developed since the 1990s to predict survival after resection of CRLM, these models vary in their predictive performance when applied to contemporary cohorts. Rat sarcoma viral oncogene homolog (RAS) mutation status is routinely tested in patients with metastatic colorectal cancer to predict response to anti-epidermal growth factor therapy. In addition, mutations in RAS predict survival and recurrence in patients undergoing hepatectomy for CRLM. Several recent prognostic models have incorporated RAS mutation status as a surrogate of tumor biology and combined revised clinicopathologic variables to improve the prediction of recurrence and survival. This narrative review aims to evaluate the differences between contemporary prognostic models incorporating RAS mutation status and their clinical applicability in patients considered for curative-intent resection of CRLM. Full article

Other

9 pages, 1166 KiB  
Opinion
Staged or Simultaneous Surgery for Colon or Rectal Cancer with Synchronous Liver Metastases: Implications for Study Design and Clinical Endpoints
by Sheraz Yaqub, Georgios Antonios Margonis and Kjetil Søreide
Cancers 2023, 15(7), 2177; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072177 - 06 Apr 2023
Cited by 1 | Viewed by 1501
Abstract
In patients presenting with colorectal cancer and synchronous liver metastases, the disease burden related to the liver metastasis is the driving cause of limited longevity and, eventually, risk of death. Surgical resection is the potentially curative treatment for colorectal cancer liver metastases. In [...] Read more.
In patients presenting with colorectal cancer and synchronous liver metastases, the disease burden related to the liver metastasis is the driving cause of limited longevity and, eventually, risk of death. Surgical resection is the potentially curative treatment for colorectal cancer liver metastases. In the synchronous setting where both the liver metastases and the primary tumor are resectable with a relative low risk, the oncological surgeon and the patient may consider three potential treatment strategies. Firstly, a “staged” or a “simultaneous” surgical approach. Secondly, for a staged strategy, a ‘conventional approach’ will suggest removal of the primary tumor first (either colon or rectal cancer) and plan for liver surgery after recovery from the first operation. A “Liver first” strategy is prioritizing the liver resection before resection of the primary tumor. Planning a surgical trial investigating a two-organ oncological resection with highly variable extent and complexity of resection as well as the potential impact of perioperative chemo(radio)therapy makes it difficult to find the optimal primary endpoint. Here, we suggest running investigational trials with carefully chosen composite endpoints as well as embedded risk-stratification strategies to identify subgroups of patients who may benefit from simultaneous surgery. Full article
Show Figures

Figure 1

10 pages, 921 KiB  
Systematic Review
Precision Surgery of Colorectal Liver Metastases in the Current Era: A Systematic Review
by Dimitrios Papaconstantinou, Nikolaos Pararas, Anastasia Pikouli, Constantinos Nastos, Anestis Charalampopoulos, Dionysios Dellaportas, George Bagias and Emmanouil Pikoulis
Cancers 2023, 15(7), 2083; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072083 - 31 Mar 2023
Viewed by 1109
Abstract
Liver resection for colorectal liver metastases (CRLM) is widely considered the treatment with the highest curative potential. However, not all patients derive the same oncological benefit, underlining the need for better patient stratification and treatment allocation. In this context, we performed a systematic [...] Read more.
Liver resection for colorectal liver metastases (CRLM) is widely considered the treatment with the highest curative potential. However, not all patients derive the same oncological benefit, underlining the need for better patient stratification and treatment allocation. In this context, we performed a systematic review of the literature to determine the role of RAS status in selecting the optimal surgical strategy. Evidence comparing anatomical with non-anatomical resections depending on RAS mutational status was scarce and conflicting, with two studies reporting superiority in mutated RAS (mutRAS) patients and two studies reporting equivalent outcomes. The rate of incomplete microscopic resection (R1) was found to be increased among mutRAS patients, possibly due to higher micrometastatic spread lateral to the primary lesion. The impact of R1 resection margins was evaluated separately for mutRAS and wild-type patients in three studies, of which, two indicated an additive detriment to long-term survival in the former group. In the current era of precision surgery, RAS status can be utilized to predict the efficacy of liver resection in the treatment of CRLM, avoiding a potentially morbid operation in patients with adverse tumor profiles. Full article
Show Figures

Figure 1

14 pages, 2899 KiB  
Systematic Review
Is Laterality Prognostic in Resected KRAS-Mutated Colorectal Liver Metastases? A Systematic Review and Meta-Analysis
by Michail Belias, Kazunari Sasaki, Jane Wang, Nikolaos Andreatos, Carsten Kamphues, Georgios Kyriakos, Hendrik Seeliger, Katharina Beyer, Martin E. Kreis and Georgios Antonios Margonis
Cancers 2022, 14(3), 799; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030799 - 04 Feb 2022
Cited by 3 | Viewed by 1813
Abstract
Background: It is debated whether primary tumor laterality (PTL) is prognostic in all patients with colorectal liver metastases (CRLM) or only those with KRAS wild-type or KRAS-mutated tumors; Methods: We systematically reviewed PubMed for studies reporting on resected CRLM originating from left-sided (LS) [...] Read more.
Background: It is debated whether primary tumor laterality (PTL) is prognostic in all patients with colorectal liver metastases (CRLM) or only those with KRAS wild-type or KRAS-mutated tumors; Methods: We systematically reviewed PubMed for studies reporting on resected CRLM originating from left-sided (LS) versus right-sided (RS) colon cancer stratified by KRAS status. Individual participant data (IPD) were used if available. Given that there are two definitions of PTL, we performed two meta-analyses for KRAS-mutated and two for wild-type patients. To assess if an interaction underlies the possible difference between the effects of PTL in KRAS-mutated vs. wild-type CRLM, we similarly performed two meta-analyses of interaction terms; Results: The meta-analyses included eight studies and 7475 patients. PTL had a prognostic association with OS in patients with wild-type tumors (HR for LS: 0.71 [0.60–0.84]), but not in those with KRAS-mutated tumors (HR: 0.99 [0.82–1.19]). This difference stemmed from a truly variable effect of PTL for each KRAS status (mutated vs. wild-type) as the meta-analysis of interaction terms showed a significant interaction between them (HR:1.38 [1.24–1.53]). Similar results were obtained when the second definition of PTL (LS to not include the rectum) was used; Conclusions: KRAS status modifies the association of tumor site with survival. Right-sided tumors are associated with worse OS only in patients with wild-type CRLM. Full article
Show Figures

Figure 1

Back to TopTop