Metastatic disease is responsible for the vast majority of cancer-related deaths. Patterns of metastatic spread and colonization are, however, not random: routes of metastatic dissemination are cancer-type specific, and different cancer types exhibit varying levels of affinity for specific organs as metastatic target sites.

We analyzed a cohort of more than 30,000 patients that were treated at Memorial Sloan Kettering Cancer Center (MSK) and had their tumors sequenced using the clinical MSK-IMPACT test, a targeted next-generation sequencing assay that identifies mutations, copy number changes and structural rearrangements in 468 genes. By querying the electronic medical record, we catalogued all metastatic events in the clinical history of these patients and mapped them to a set of 32 tissue sites. The primary diagnoses spanned 30 different cancer types, which were further stratified into >50 relevant molecular subtypes, based on a combination of molecular and histopathological features. Observed patterns of metastatic dissemination were cancer type specific and, in some cases, exhibited strong differences across molecular subtypes of the same cancer type. For example, HER2+ subtypes of breast cancer exhibited increased rates of brain (34% vs. 18%, p<0.0001) and lung (31% vs. 19%, p=0.006) metastasis when compared to HER2- subtypes.

The median number of organs affected by metastatic disease per patient was 4 (range 1-14). The number of affected organs exhibited a strong positive correlation with the overall level of aneuploidy, as measured by the total fraction of genome altered by copy number changes (P<0.0001, Spearman correlation), but not with overall mutational burden. We identified genomic alterations that were significantly enriched in tumors from patients with metastasis to specific organs in a cancer-type dependent manner. For example, 244/556 (44%) of lung adenocarcinoma patients with EGFR amplification or activating mutations presented bone metastasis at some point of their clinical history, as opposed to only 400/1,124 (36%) of EGFR wild type patients (p=0.001, Fisher’s exact test). In the case of HR+/ER- breast adenocarcinoma patients, bone metastases were reported in 22/30 (73%) of patients with NF1 inactivated tumors, as opposed to only 330/745 (44%) of patients with NF1 wild-type (p=0.002, Fisher’s exact test).

We present the first pan-cancer study that combines molecular and histopathological features to draw a comprehensive atlas of tumor metastasis. Our results provide novel insights into the biology of metastatic tumors and can have a direct impact on patient management and care by optimizing the use and frequency of specific imaging studies for metastasis surveillance.

Citation Format: Francisco Sanchez-Vega, Christopher Fong, Walid Chatila, Philip Jonsson, Alexander V. Penson, Renzo G. DiNatale, Michael F. Berger, Ahmet Zehir, Ed Reznik, Jianjiong Gao, Karuna Ganesh, Barry S. Taylor, Nikolaus Schultz. A molecular and histopathologic map of cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2736.