Radiation and Cancer Biology

SS 03 - Biology 1 - Innovative Biologic Approaches to Improve Risk Stratification and Treatment Outcomes

22 - Integrated Molecular Subtyping of Clinical Metastasis: Implications for Defining a Curable Oligometastatic State

Sunday, October 21
1:15 PM - 1:25 PM
Location: Room 008

Integrated Molecular Subtyping of Clinical Metastasis: Implications for Defining a Curable Oligometastatic State
S. Pitroda1, N. Khodarev1, L. Huang1, A. Uppal1, S. Wightman1, S. Ganai2, N. Joseph3, L. Xue1, C. Weber1, J. Segal1, M. Stack1, S. Khan4, P. Paty5, K. Kaul3, J. Andrade1, K. White1, M. Talamonti3, M. Posner1, S. Hellman1, and R. R. Weichselbaum1; 1University of Chicago, Chicago, IL, 2Southern Illinois University, Springfield, IL, 3NorthShore University Hospital, Evanston, IL, 4Department of Surgical Oncology, Yale University School of Medicine, New Haven, CT, 5Memorial Sloan-Kettering Cancer Center, New York, NY

Purpose/Objective(s): The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in number and organ involvement and potentially curable with focal therapies. A subset of patients with metastatic colorectal cancer (CRC) achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here, we characterized the molecular determinants of CRC liver metastases (CRCLM) as they relate to clinical outcomes following resection.

Materials/Methods: We integrated next-generation DNA and RNA Sequencing, microRNA expression, and microsatellite instability (MSI) analysis of 121 clinically annotated de novo CRCLM. Molecular data were incorporated with clinicopathological variables to identify patients who achieved favorable outcomes following hepatic resection.

Results: Molecular features of primary CRC are reflected in liver metastases, but are not predictive of clinical outcomes. By contrast, integrative transcriptional analysis revealed three robust molecular subtypes of CRCLM associated with distinct outcomes. Metastases exhibiting MSI-independent immune activation predicted the most favorable survival. Subtypes with adverse clinical outcomes demonstrated VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. An expression-based classifier independently validated to identify patients with favorable clinical outcomes following resection of limited CRCLM. Integration of molecular subtypes and clinicopathologic risk stratification distinguished low-, intermediate-, and high-risk patients with 10-year overall survivals of 94%, 45% and 19%, respectively.

Conclusion: This is the first integrated analysis to define the molecular subtypes of metastasis as they relate to clinical outcomes. Molecular subtypes of CRCLM complement clinical risk stratification to provide a framework for integrated classification and treatment of metastatic disease and support the biological basis of curable oligometastatic CRC. These concepts may be applicable to many patients with metastatic cancer.

Author Disclosure: S. Pitroda: None. N. Khodarev: None. L. Huang: None. N. Joseph: None. L. Xue: None. J. Segal: Research Grant; Abbvie. Honoraria; Bristol-Myers Squibb, Abbvie. S. Khan: None. K. White: President; Tempus. M. Talamonti: None. M. Posner: Consultant; Sirtex Medical. R.R. Weichselbaum: Research Grant; Regeneron, Varian Medical Systems. Honoraria; Merck, AstraZeneca. Travel Expenses; AstraZeneca, Immunovir. Stock Options; Immunovir. Patent/License Fees/Copyright; Tvec.

Sean Pitroda, MD

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