<i>RAS/RAF</i> Comutation and <i>ERBB2</i> Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer-Reference-Cited by-同舟云学术

RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer

Published:2024-02-12 Issue:8 Volume:30 Page:1669-1684
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Singh Harshabad¹^ORCID,Sahgal Pranshu¹²^ORCID,Kapner Kevin¹^ORCID,Corsello Steven M.³^ORCID,Gupta Hersh¹²^ORCID,Gujrathi Rahul⁴^ORCID,Li Yvonne Y.¹²^ORCID,Cherniack Andrew D.¹²^ORCID,El Alam Raquelle⁵^ORCID,Kerfoot Joseph⁶^ORCID,Andrews Elizabeth¹^ORCID,Lee Annette¹^ORCID,Nambiar Chetan¹^ORCID,Hannigan Alison M.¹^ORCID,Remland Joshua¹^ORCID,Brais Lauren¹^ORCID,Leahy Meghan E.¹^ORCID,Rubinson Douglas A.¹^ORCID,Schlechter Benjamin L.¹^ORCID,Meyerson Matthew¹²⁷^ORCID,Kuang Yanan⁸^ORCID,Paweletz Cloud P.⁸^ORCID,Lee Jessica K.⁹^ORCID,Quintanilha Julia C.F.⁹^ORCID,Aguirre Andrew J.¹²^ORCID,Perez Kimberly J.¹^ORCID,Huffman Brandon M.¹^ORCID,Rossi Humberto¹^ORCID,Abrams Thomas A.¹^ORCID,Kabraji Sheheryar¹^ORCID,Trusolino Livio¹⁰¹¹^ORCID,Bertotti Andrea¹⁰¹¹^ORCID,Sicinska Ewa T.⁶^ORCID,Parikh Aparna R.¹²^ORCID,Wolpin Brian M.¹^ORCID,Schrock Alexa B.⁹^ORCID,Giannakis Marios¹^ORCID,Ng Kimmie¹^ORCID,Meyerhardt Jeffrey A.¹^ORCID,Hornick Jason L.¹³^ORCID,Sethi Nilay S.¹^ORCID,Cleary James M.¹^ORCID

Affiliation:

1. 1Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

2. 2Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

3. 3Department of Medicine, Stanford University, Palo Alto, California.

4. 4Department of Radiology, Boston Medical Center and Boston University, Boston, Massachusetts.

5. 5Department of Radiology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

6. 6Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

7. 7Department of Genetics, Harvard Medical School, Boston, Massachusetts.

8. 8Belfer Center for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

9. 9Foundation Medicine, Inc., Cambridge, Massachusetts.

10. 10Candiolo Cancer Institute FPO IRCCS, Candiolo, Torino, Italy.

11. 11Department of Oncology, University of Torino, Candiolo, Torino, Italy.

12. 12Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

13. 13Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Abstract

Abstract Purpose: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. Experimental Design: Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts. Results: ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer. Conclusions: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted.

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

Link

https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-23-2581/3415084/ccr-23-2581.pdf

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