TY - JOUR
T1 - Validation of HER2 amplification as a predictive biomarker for anti- epidermal growth factor receptor antibody therapy in metastatic colorectal cancer
AU - Raghav, Kanwal
AU - Loree, Jonathan Michael
AU - Morris, Jeffrey
AU - Overman, Michael J.
AU - Yu, Ruoxi
AU - Meric-Bernstam, Funda
AU - Menter, David
AU - Korphaisarn, Krittiya
AU - Kee, Brian
AU - Muranyi, Andrea
AU - Singh, Shalini
AU - Routbort, Mark
AU - Chen, Ken
AU - Shaw, Kenna R.M.
AU - Katkhuda, Riham
AU - Shanmugam, Kandavel
AU - Maru, Dipen
AU - Fakih, Marwan
AU - Kopetz, Scott
N1 - Publisher Copyright:
© 2019 American Society of Clinical Oncology.
PY - 2019
Y1 - 2019
N2 - Purpose HER2 amplification has been implicated in resistance to therapy with anti- epidermal growth factor receptor antibodies (anti-EGFRabs) in metastatic colorectal cancer (mCRC). The purpose of the study was to validate the predictive impact of HER2 amplification in mCRC. Patients and Methods We analyzed patients with RAS/BRAF wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), HER2 amplification was tested in tumor tissue using dual in situ hybridization (HER2 amplification: HER2/CEP17 ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with HER2 amplification and 54 HER2 nonamplified controls identified by next-generation sequencing (HER2 amplification: four or more copies) who had received prior anti-EGFRabs. The primary end point was progression-free survival (PFS) on treatment with anti-EGFRab therapy, which was estimated and compared using the Kaplan-Meier method and log-rank test. Results Median PFS in cohort 1 on anti-EGFRab-based therapy was significantly shorter in patients with HER2 amplification compared with HER2 nonamplified patients (2.8 v 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; P < .001). These findings were validated in cohort 2 (median PFS for HER2 amplified v nonamplified: 2.8 v 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; P < .001). The median PFS on therapy without anti-EGFRabs was similar among HER2-amplified and nonamplified patients in both cohort 1 (9.7 v 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; P = .97) and cohort 2 (9.6 v 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; P = .66). In multivariable analyses, HER2 amplification emerged as a single independent predictor of poor PFS on anti-EGFRab therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1 to 13.6; P < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; P < .001). Conclusion HER2 amplification in RAS/RAF wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with RAS/ BRAF wild-type mCRC for HER2 amplification should be considered before anti- EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.
AB - Purpose HER2 amplification has been implicated in resistance to therapy with anti- epidermal growth factor receptor antibodies (anti-EGFRabs) in metastatic colorectal cancer (mCRC). The purpose of the study was to validate the predictive impact of HER2 amplification in mCRC. Patients and Methods We analyzed patients with RAS/BRAF wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), HER2 amplification was tested in tumor tissue using dual in situ hybridization (HER2 amplification: HER2/CEP17 ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with HER2 amplification and 54 HER2 nonamplified controls identified by next-generation sequencing (HER2 amplification: four or more copies) who had received prior anti-EGFRabs. The primary end point was progression-free survival (PFS) on treatment with anti-EGFRab therapy, which was estimated and compared using the Kaplan-Meier method and log-rank test. Results Median PFS in cohort 1 on anti-EGFRab-based therapy was significantly shorter in patients with HER2 amplification compared with HER2 nonamplified patients (2.8 v 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; P < .001). These findings were validated in cohort 2 (median PFS for HER2 amplified v nonamplified: 2.8 v 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; P < .001). The median PFS on therapy without anti-EGFRabs was similar among HER2-amplified and nonamplified patients in both cohort 1 (9.7 v 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; P = .97) and cohort 2 (9.6 v 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; P = .66). In multivariable analyses, HER2 amplification emerged as a single independent predictor of poor PFS on anti-EGFRab therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1 to 13.6; P < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; P < .001). Conclusion HER2 amplification in RAS/RAF wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with RAS/ BRAF wild-type mCRC for HER2 amplification should be considered before anti- EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.
UR - http://www.scopus.com/inward/record.url?scp=85063563873&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063563873&partnerID=8YFLogxK
U2 - 10.1200/PO.18.00226
DO - 10.1200/PO.18.00226
M3 - Article
C2 - 35100667
AN - SCOPUS:85063563873
SN - 2473-4284
VL - 3
SP - 1
EP - 13
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -