Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer

被引：25

作者：

Shitara, Kohei ^{[1
,2
]}

Muro, Kei ^{[3
]}

Watanabe, Jun ^{[4
]}

Yamazaki, Kentaro ^{[5
]}

Ohori, Hisatsugu ^{[6
]}

Shiozawa, Manabu ^{[7
]}

Takashima, Atsuo ^{[8
]}

Yokota, Mitsuru ^{[9
]}

Makiyama, Akitaka ^{[10
,11
,12
]}

Akazawa, Naoya ^{[13
]}

Ojima, Hitoshi ^{[14
]}

Yuasa, Yasuhiro ^{[15
]}

Miwa, Keisuke ^{[16
]}

Yasui, Hirofumi ^{[5
]}

Oki, Eiji ^{[17
]}

Sato, Takeo ^{[18
]}

Naitoh, Takeshi ^{[19
]}

Komatsu, Yoshito ^{[20
]}

Kato, Takeshi ^{[21
]}

Mori, Ikuo ^{[22
]}

Yamanaka, Kazunori ^{[23
]}

Hihara, Masamitsu ^{[22
]}

Soeda, Junpei ^{[22
]}

Misumi, Toshihiro ^{[24
]}

Yamamoto, Kouji ^{[24
]}

Yamashita, Riu ^{[25
]}

Akagi, Kiwamu ^{[26
]}

Ochiai, Atsushi ^{[27
]}

Uetake, Hiroyuki ^{[28
]}

Tsuchihara, Katsuya ^{[25
]}

Yoshino, Takayuki ^{[1
]}

机构：

[1] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Kashiwa, Japan

[2] Nagoya Univ, Dept Immunol, Grad Sch Med, Nagoya, Aichi, Japan

[3] Aichi Canc Ctr Hosp, Dept Clin Oncol, Nagoya, Japan

[4] Yokohama City Univ, Gastroenterol Ctr, Dept Surg, Med Ctr, Yokohama, Japan

[5] Shizuoka Canc Ctr, Div Gastrointestinal Oncol, Shizuoka, Japan

[6] Japanese Red Cross Ishinomaki Hosp, Div Med Oncol, Ishinomaki, Miyagi, Japan

[7] Kanagawa Canc Ctr, Dept Gastrointestinal Surg, Yokohama, Kanagawa, Japan

[8] Natl Canc Ctr, Dept Gastrointestinal Med Oncol, Tokyo, Japan

[9] Kurashiki Cent Hosp, Dept Gen Surg, Okayama, Japan

[10] Japan Community Healthcare Org, Dept Hematol Oncol, Fukuoka, Japan

[11] Gifu Univ Hosp, Canc Ctr, Gifu, Japan

[12] Ctr One Med Innovat Translat Res, Div Anim Med Sci, Gifu, Japan

[13] Sendai Open Hosp, Sendai City Med Ctr, Dept Gastroenterol Surg, Sendai, Miyagi, Japan

[14] Gunma Prefectural Canc Ctr, Dept Gastroenterol Surg, Gunma, Japan

[15] Japanese Red Cross Tokushima Hosp, Dept Gastroenterol Surg, Yoshinogawa, Tokushima, Japan

[16] Kurume Univ Hosp, Multidisciplinary Treatment Canc Ctr, Kurume, Japan

[17] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka, Japan

[18] Kitasato Univ, Res & Dev Ctr Med Educ, Dept Clin Skills Educ, Sch Med, Sagamihara, Japan

[19] Kitasato Univ, Dept Lower Gastrointestinal Surg, Sch Med, Sagamihara, Japan

[20] Hokkaido Univ, Div Canc Chemotherapy, Hosp Canc Ctr, Sapporo, Japan

[21] Osaka Natl Hosp, Dept Surg, Natl Hosp Org, Osaka, Japan

[22] Takeda Pharmaceut Co Ltd, Japan Med Affairs, Japan Oncol Business Unit, Tokyo, Japan

[23] Takeda Pharmaceut Co Ltd, Pharmaceut Res Div, Fujisawa, Kanagawa, Japan

[24] Yokohama City Univ, Dept Biostat, Sch Med, Yokohama, Japan

[25] Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Div Translat Informat, Chiba, Japan

[26] Saitama Canc Ctr, Div Mol Diag & Canc Prevent, Saitama, Japan

[27] Tokyo Univ Sci, Res Inst Biomed Sci, Tokyo, Japan

[28] Natl Hosp Org, Disaster Med Ctr, Tokyo, Japan

来源：

NATURE MEDICINE | 2024年 / 30卷 / 03期

关键词：

RAS MUTATIONS; WILD-TYPE; RESISTANCE; BEVACIZUMAB; EVOLUTION; BRAF;

D O I：

10.1038/s41591-023-02791-w

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS,PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795. In an exploratory preplanned biomarker analysis of the phase 3 PARADIGM trial, a lack of resistance gene alterations in baseline circulating tumor DNA (negative hyperselection) was associated with prolonged overall survival after first-line panitumumab with chemotherapy in patients with RAS wild-type metastatic colorectal cancer.

引用

页码：730 / 739

页数：10

共 50 条

[21] Panitumumab for the treatment of metastatic colorectal cancer: a review
Del Prete, M.
Giampieri, R.
Faloppi, L.
Bianconi, M.
Bittoni, A.
Andrikou, K.
Cascinu, S.
IMMUNOTHERAPY, 2015, 7 (07) : 721 - 738
[22] Chemotherapy plus Panitumumab Versus Chemotherapy plus Bevacizumab in Metastatic Colorectal Cancer: A Meta-analysis
Li, Zhigui
Huang, Yuqian
Zhao, Rui
Cui, Yaping
Zhou, Yong
Wu, Xiaoting
SCIENTIFIC REPORTS, 2018, 8
[23] Cost-effectiveness of cetuximab and panitumumab for chemotherapy-refractory metastatic colorectal cancer
Carvalho, Adriana Camargo
Leal, Frederico
Sasse, Andre Deeke
PLOS ONE, 2017, 12 (04):
[24] Role of panitumumab in the management of metastatic colorectal cancer
Saif, Muhammad Wasif
Cohenuram, Michael
CLINICAL COLORECTAL CANCER, 2006, 6 (02) : 118 - 124
[25] Chemotherapy plus Panitumumab Versus Chemotherapy plus Bevacizumab in Metastatic Colorectal Cancer: A Meta-analysis
Zhigui Li
Yuqian Huang
Rui Zhao
Yaping Cui
Yong Zhou
Xiaoting Wu
Scientific Reports, 8
[26] Panitumumab in Combination With Cytotoxic Chemotherapy for the Treatment of Metastatic Colorectal Carcinoma
Peeters, Marc
Cohn, Allen
Koehne, Claus-Henning
Douillard, Jean-Yves
CLINICAL COLORECTAL CANCER, 2012, 11 (01) : 14 - 23
[27] Biomarker alterations associated with distinct patterns of metastatic spread in colorectal cancer
Michl, M.
Taverna, F.
Kumbrink, J.
Schiergens, T. S.
Heinemann, V.
Engel, J.
Kirchner, T.
Neumann, Jens
VIRCHOWS ARCHIV, 2021, 478 (04) : 695 - 705
[28] Panitumumab significantly improves progression-free survival in patients with metastatic colorectal cancer
Van Cutsem, E.
Peeters, M.
Siena, S.
Humblet, Y.
Hendisz, A.
Neyns, B.
Canon, J.
Van Laethem, J.
Maurel, J.
Richardson, G.
ANNALS OF ONCOLOGY, 2006, 17 : 27 - 27
[29] Therapeutic Response of Metastatic Colorectal Cancer Harboring a KRAS Missense Mutation After Combination Chemotherapy With the EGFR Inhibitor Panitumumab
Lou, Emil
D'Souza, Donna
Nelson, Andrew C.
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK, 2017, 15 (04): : 427 - 432
[30] Biomarker alterations associated with distinct patterns of metastatic spread in colorectal cancer
M. Michl
F. Taverna
J. Kumbrink
T. S. Schiergens
V. Heinemann
J. Engel
T. Kirchner
Jens Neumann
Virchows Archiv, 2021, 478 : 695 - 705

← 1 2 3 4 5 →