Review
Precision surgery for colorectal liver metastases: Opportunities and challenges of omics-based decision making

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Abstract

Precision surgery involves improving patient selection to ensure that surgical intervention that is proven to benefit on a population level is the optimal treatment for each individual patient. For patients with colorectal liver metastases (CRLM), existing prognostic scoring systems rely on well-recognised histopathological features such as size and number of lesions. Advances in preoperative imaging algorithms mean that increasingly low volume disease can be detected, improving assessment of these factors. In addition, novel imaging modalities mean that underlying tumour biology and metabolic behaviour during therapy can be assessed. Molecular analysis of tumours can provide crucial prognostic information, with the critical role of RAS/RAF mutations in prognosis well recognised. The optimal source of tissue for this level of analysis is debated, with good concordance between primary and metastatic lesions for some recognised prognostic factors but marked discrepancies for a variety of other relevant mutations. As well as mutational heterogeneity between primary and metastatic lesions, heterogeneity within tumours and dynamic changes in tumour biology over time present a significant challenge in assessing tumour for prognostic biomarkers. Circulating tumour cells offer one potential method of longitudinal tumour analysis, but are limited by current technologies.

This review article summarises some of the key advances in prognostication for patients with resectable colorectal liver metastases, as well as highlighting the potential limitations of such an approach.

Introduction

Precision (adj.) The quality of being exact

Traditionally, the term precision surgery has been used to describe technical and operative excellence. Absolute adherence to tissue planes, recognition of critical anatomy and fastidious technique all constitute part of precision surgery. However, there is growing recognition that precision surgery starts before the patient reaches the operating theatre, with the careful selection and targeting of surgical interventions in patients in whom the benefit is likely to outweigh the risk. In the field of medical oncology, this precision approach is well recognised. Patients with breast cancer undergo receptor analysis to identify HER2 mutation status, allowing targeting of appropriate therapies. Following surgery, patient's tumour genotype is assessed using Oncotype DX, a gene assay that predicts distant recurrence and allows stratification for adjuvant chemotherapy. Precision surgery follows similar concepts, and involves improving patient selection to ensure that surgical intervention that is proven to benefit on a population level is the optimal treatment for each individual patient.

For patients with resectable colorectal liver metastases (CRLM), the decision to treat with surgery remains the standard of care. However, it is clear that not all patients undergoing resection enjoy long-term benefit – around 30% will develop recurrence and 15% will succumb to their disease within a year of surgery.1 By contrast, multi-agent systemic chemotherapy offers a median survival of over 25 months,2 and so a proportion of patients undergoing surgery may have been better served by systemic chemotherapy. In contrast to systemic chemotherapy however, surgical resection offers patients the potential for long-term disease-free survival and cure with meta-analysis suggesting around 40% of patients are alive at 5 years, with 25% surviving to 10 years.3

Selecting the optimal treatment for each individual treatment remains complex. There is broad agreement over which patients with CRLM clearly should and should not be offered resection.4, 5 For a patient with a small solitary liver metastasis presenting several years after primary resection, surgery is generally accepted to offer a clear and significant long-term survival benefit. For patients with synchronous extensive large volume disseminated disease, surgery is unlikely to improve outcome. Deciding on the optimal management strategy for patients who fall into the grey area between these extremes remains one of the most challenging decisions in the management of stage IV colorectal cancer, and involves a careful assessment of both technical and oncological factors. Current consensus is that disease is technically resectable if it is possible to leave sufficient future liver volume to maintain hepatic function, whilst removing all macroscopic disease with microscopically negative margins and preserving adequate vascular inflow and outflow.6 Novel technical approaches such as 2-stage hepatectomy7 and the ALPPS procedure (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy)8 have increased the number of patients who are technically resectable. What remains less clear is how to identify patients in whom resection, whilst technically feasible, is unlikely to deliver long-term oncological benefits.

This review aims to summarise some of the key advances in prognostication for patients with colorectal liver metastases, as well as highlighting potential limitations of such an approach.

Section snippets

Existing clinico-pathological prognostic biomarkers

The list of factors associated with survival after resection of CRLM has been extensively discussed, and includes: size of metastasis,9, 10 number of lesions,9, 11 primary tumour nodal status (positive nodes and number of positive nodes),12 differentiation grade,13 margin status,9 CEA level,14 need for perioperative blood transfusion,15, 16 neutrophil to lymphocyte ratio,15 T-cell tumour infiltration,17 age and sex,14 disease-free interval (different intervals have been used),9 primary tumour

Radiomic prognostic biomarkers

One of the most critical factors in deciding whether a patient with liver-limited metastatic colorectal cancer should be considered for liver resection is accurate identification of the true burden and distribution of metastatic disease. The relatively high rates of recurrence after liver resection for CRLM reflect occult metastatic spread, and improvements in imaging techniques aim to improve the identification of this patient cohort thus preventing futile surgery. FDG PET has been widely used

Molecular prognostic biomarkers

KRAS and NRAS are proteins and downstream effectors of epidermal growth factor receptor (EGFR), with binding of the EGF ligand to the receptor triggering downstream signalling via the PI3K/AKT/MTOR and RAF/MEK/ERK cellular proliferation pathways.34 Approximately 90% of mutations occur within codon 12 and 13,35 with well characterised single base substitution point mutations.36 RAS mutations occurs in 35%–45% of all patients with metastatic colorectal cancer,37, 38, 39 and the predictive role of

Circulating prognostic biomarkers and liquid biopsies

As tumour cells proliferate, they promote angiogenesis and then invade into the bloodstream to sites of distant metastasis. Approximately 1.3 × 106 tumour cells per gram of tumour tissue are released into the circulation every day by solid tumours,68 and the presence of these circulating tumour cells (CTCs) has been associated with poor progression-free and overall survival in patients with a variety of gastrointestinal cancers,69 including patients with colorectal liver metastases.70

Challenges in assessment of prognostic biomarkers

Questions still remain about the optimal source of tissue for biomarker identification and analysis. Vakiani et al.74 performed a targeted genomic analysis of primary and resected metastatic colorectal cancer samples in 84 patients, and identified high levels of concordance in 5 prognostically relevant genes (KRAS, NRAS, BRAF, PIK3CA and TP53). The implication of this finding is that if metastatic tissue is unavailable, archival primary tumour provides an acceptable alternative given the high

Conclusions

Improved prognostic information for patients with liver-limited metastatic colorectal cancer remains essential. The ready access to improved imaging means future prognostic models will likely integrate imaging tools with clinical and molecular biomarkers. Both offer marked benefits for patient stratification. The capacity for imaging to both characterise and localise the phenotypic heterogeneity of multiple tumour locations in a longitudinal fashion offers a significant advantage, but is

Conflict of interest

GJP has attended Advisory Boards and contributed to Speaker Panels for Merck Serono; BTG; SirTex; Sanofi Aventis.

The other authors declare no conflict of interest.

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