Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis

Abstract

The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.

Multidisciplinary Tumor Board Recommendations for Oligometastatic Malignancies: A Prospective Single-Center Analysis

“…For these recommendations, a biologically proven concept does not exist and only in a few cases are these recommendations supported by prospective trials [36,39,40]. Both translational and prospective clinical trials are urgently needed to validate this clinical practice, supported by further advancements in molecular cancer subtyping that will help to define curable oligometastatic disease states [41]. For reasons of therapeutic complexity, oligometastatic patients should be treated at tertiary referral centers.…”

Hepatobiliary surgeons meet immunologists: the case of colorectal liver metastases patients

“…Many different genes were identified, but interestingly, most of them were linked to the host immune functionality (T and B cell activation, inflammatory response, T and B cell differentiation, adhesion-and migration-associated chemokines and activation of NK cells), which convincingly suggest that the immune system deserves further attention. Consistent with this, Pitroda et al (59) recently reported an elegant classification on 134 consecutive resections for CLM that integrated three molecular subtypes matched with the clinical risk stratification. The most favorable subtype was the so-called immune type, which corresponded to those metastases with a high density of CD3+ and CD8+ cells in the peritumor and intratumor compartments with minimal fibrosis.…”

Oligometastatic prostate cancer: Reality or figment of imagination?

“…Similarly, an exploratory analysis of tumors from patients who had clinically oligometastatic disease of mixed histologies and received stereotactic body radiotherapy (SBRT) to all known sites indicated that a candidate classifier using expression of miR‐23b, miR‐449a, and miR‐449b predicted survival for 17 patients who had available expression data . More recently, integrated molecular analysis was used to risk stratify patients with de novo colorectal liver metastasis . Specifically, a low‐risk group with a 10‐year overall survival (OS) rate of approximately 95% was identified that had favorable clinical features in concert with metastases primarily enriched for innate and adaptive immune activation independent of microsatellite instability status.…”

“…75 More recently, integrated molecular analysis was used to risk stratify patients with de novo colorectal liver metastasis. 76 Specifically, a low-risk group with a 10-year overall survival (OS) rate of approximately 95% was identified that had favorable clinical features in concert with metastases primarily enriched for innate and adaptive immune activation independent of microsatellite instability status. It is hypothesized that this subtype is most representative of a true oligometastatic state, and its elucidation illustrates that tumor biology and host factors like immune contexture may augment the more traditional indicators of limited metastasis.…”

“…78 In addition, a novel subtype of castration-resistant disease characterized by biallelic CDK12 loss, immune activation, and the absence of hypermutation also was detected by performing integrative genomic analysis. 79 It is noteworthy that CDK12 mutations also were detected in the previously mentioned immune subtype of de novo colorectal cancer metastases in which patients experience favorable survival, 76 suggesting that CDK12 inactivation may associate with an altered tumor immunophenotype and have implications for curability after metastasis-directed therapy and sensitivity to immune-checkpoint blockade. Taken together, these data form a foundation for the molecular characterization of unselected patients with metastatic prostate cancer and support similar efforts focused exclusively on defining molecular subtypes of oligometastatic prostate cancer.…”