Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.
Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of 2 ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤ 19) / long (L; ≥ 20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n = 28/57, UMIN000004197) or SOX (n = 49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 66 months, HR 0.52, P = 0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P = 0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P = 0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P = 0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P = 0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.
a Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA.|b Division of Medical Oncology, Department of Internal Medicine, Showa University Northern Yokohama Hospital , Yokohama , Kanagawa , Japan.
Yu
Y
Sunakawa
c Department of Preventive Medicine , Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA.
Dongyun
D
Yang
d Response Genetics, Inc. , Los Angeles , CA , USA.
Miriana
M
Moran
d Response Genetics, Inc. , Los Angeles , CA , USA.
Stephanie H
SH
Astrow
e Department of Clinical Oncology , Kagawa University Faculty of Medicine Cancer Center, Kagawa University Hospital , Kita-gun , Kagawa , Japan.
Akihito
A
Tsuji
d Response Genetics, Inc. , Los Angeles , CA , USA.
Craig
C
Stephens
a Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA.
Wu
W
Zhang
c Department of Preventive Medicine , Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA.
Shu
S
Cao
f Division of Medical Oncology, Showa University Hospital , Shinagawa-ku, Tokyo , Japan.
Takehiro
T
Takahashi
g Division of Gastroenterology, Chiba Cancer Center , Chuo-ku, Chiba , Japan.
Tadamichi
T
Denda
h Division of Medical Oncology, Department of Internal Medicine, Showa University Koto Hospital , Toyosu, Koto-ku, Tokyo , Japan.
Ken
K
Shimada
i Department of Digestive Surgery , Nihon University School of Medicine , Itabashi-ku, Tokyo , Japan.
Mitsugu
M
Kochi
j Aizawa Comprehensive Cancer Center, Aizawa Hospital , Matsumoto , Nagano , Japan.
Masato
M
Nakamura
k Gastrointestinal Center, Sano Hospital , Kobe , Hyogo , Japan.
Masahito
M
Kotaka
l Division of Medical Oncology, Saitama Medical University International Medical Center , Hidaka , Saitama , Japan.
Yoshihiko
Y
Segawa
m Division of Gastroenterology, Tsuchiura Kyodo General Hospital , Tsuchiura , Ibaraki , Japan.
Toshiki
T
Masuishi
n Department of Clinical Medicine (Biostatistics) , Kitasato University School of Pharmacy , Shirokane, Minato-ku, Tokyo , Japan.
Masahiro
M
Takeuchi
i Department of Digestive Surgery , Nihon University School of Medicine , Itabashi-ku, Tokyo , Japan.
Masashi
M
Fujii
o Japan Clinical Cancer Research Organization , Chuo-ku, Tokyo , Japan.
Toshifusa
T
Nakajima
p Division of Medical Oncology, Showa University Fujigaoka Hospital , Yokohama , Kanagawa , Japan.
Wataru
W
Ichikawa
a Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California , Los Angeles , CA , USA.
Heinz-Josef
HJ
Lenz
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab
Amphiregulin; EGFR; EGFR gene copy number; cetuximab; colorectal cancer