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.
Highlights
Metastases are the leading cause of cancer-related deaths and frequently are widely disseminated, which has led to the prevailing view that metastases are always widespread
Our findings indicate a molecular basis for oligometastasis that is predictive of clinical outcome and complementary to established clinical risk factors associated with long-term survival following hepatic resection
Given that mismatch repair deficiency leading to microsatellite instability (MSI) contributes to tumor hypermutation in association with cytotoxic immune infiltration[25], we investigated whether MSI explained the immune subtype 2
Summary
Metastases are the leading cause of cancer-related deaths and frequently are widely disseminated, which has led to the prevailing view that metastases are always widespread. The oligometastasis hypothesis suggests that metastatic spread is a spectrum of virulence where some metastases are limited both in number and organ involvement and potentially curable with surgical resection or other loco-regional therapies[1,2]. This paradigm is in stark contrast to the outcomes of patients with solid tumors where widespread metastases are largely fatal despite recent advances in systemic therapy. Our findings may have important clinical implications in the selection of local therapy for those patients with potentially curable oligometastatic disease from those whose few metastases are a part of a large cascade of widespread disease These concepts may be applicable to many histological types of cancer
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