Abstract 1109: Integrative analysis of clinical and genomic information identifies predictive markers of metastatic risk
Authors: Fong Christopher J. , Sanchez-Vega Francisco , Ngyuen Bastien , Luthra Anisha , Nandakumar Subhiksha , Walch Henry , Chatila Walid , Rajanna Arjun , Zehir Ahmet , Berger Michael , Gao Jianjiong , Schultz Nikolaus 
Published: September 2020

Despite the fact that the majority of cancer related deaths are due to metastatic disease, existing large-scale cancer sequencing projects such as The Cancer Genome Atlas have so far focused mainly on primary tumors. Moreover, most publicly available datasets in cancer genomics lack information about spatiotemporal patterns of metastatic spread.

We have developed new clinical data extraction methods and performed an integrative analysis of clinical and genomic features from 34,836 patients treated at Memorial Sloan Kettering Cancer Center (MSK), stratified into 45 cancer subtypes. Tumors were sequenced with MSK-IMPACT, a targeted next-generation sequencing assay that identifies genomic alterations in 468 genes. Indications of metastatic events, including affected organs and detailed timeline annotations, were extracted from the electronic medical records. This allowed us to distinguish not only sequenced primaries (58%) from sequenced metastases (42%), but also primaries in patients with evidence of metastatic disease (33%) from patients without evidence of metastatic disease (25%) at the time of sequencing.

Tumors from patients with evidence of metastatic disease exhibited increased copy-number alterations, measured as fraction of genome altered (FGA) in multiple cancer types, including prostate adenocarcinoma, endometrial endometrioid, HR+/HER2- breast invasive carcinoma and lung adenocarcinoma (all p &lt; 0.001). This supports the existence of a positive correlation between disease burden and chromosomal instability, although this effect is weaker or non-existent in some cancer types, including hepatocellular carcinoma, ovarian serous, and cholangiocarcinoma.

We investigated associations between somatic alterations and metastatic organotropisms. For example, among patients with microsatellite stable colorectal cancer, tumors that metastasized exclusively to the peritoneum were enriched in BRAF alterations when compared to patients that never metastasized to that site (21% vs. 6%; p=0.003), while tumors that metastasized exclusively to the lung were enriched in KRAS alterations (69% vs. 41%; p=0.002). By analyzing primary tumors in patients with no evidence of metastatic disease at the time of sequencing, and comparing those that would eventually metastasize with those that would not, we identified predictive markers of metastatic risk. For example, in bladder cancer, tumors with altered TP53 were twice as likely to metastasize (54% vs. 27%; p&lt;0.001), while tumors with FGFR3 alterations exhibited the opposite trend (24% vs. 43%; p&lt;0.001).

We present a comprehensive, spatiotemporal map of metastasis that integrates clinical and molecular information and can be used to build personalized risk models of metastatic spread at target-organ resolution based on individual molecular profiles, which can enhance precision medical care and optimize clinical outcomes.

Citation Format: Christopher J. Fong, Francisco Sanchez-Vega, Bastien Ngyuen, Anisha Luthra, Subhiksha Nandakumar, Henry Walch, Walid Chatila, Arjun Rajanna, Ahmet Zehir, Michael Berger, Jianjiong Gao, Nikolaus Schultz. Integrative analysis of clinical and genomic information identifies predictive markers of metastatic risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1109.