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

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