Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer
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 (panitumuma...
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| Veröffentlicht in: | Nature medicine 2024-03, Vol.30 (3), p.730-739 |
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| creator | Shitara, Kohei Muro, Kei Watanabe, Jun Yamazaki, Kentaro Ohori, Hisatsugu Shiozawa, Manabu Takashima, Atsuo Yokota, Mitsuru Makiyama, Akitaka Akazawa, Naoya Ojima, Hitoshi Yuasa, Yasuhiro Miwa, Keisuke Yasui, Hirofumi Oki, Eiji Sato, Takeo Naitoh, Takeshi Komatsu, Yoshito Kato, Takeshi Mori, Ikuo Yamanaka, Kazunori Hihara, Masamitsu Soeda, Junpei Misumi, Toshihiro Yamamoto, Kouji Yamashita, Riu Akagi, Kiwamu Ochiai, Atsushi Uetake, Hiroyuki Tsuchihara, Katsuya Yoshino, Takayuki |
| description | 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. |
| doi_str_mv | 10.1038/s41591-023-02791-w |
| format | Article |
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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.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-023-02791-w</identifier><identifier>PMID: 38347302</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/67/68 ; 692/53/2422 ; Bevacizumab ; Biomarkers ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Cancer Research ; Chemotherapy ; Colorectal cancer ; Colorectal carcinoma ; Deoxyribonucleic acid ; DNA ; Epidermal growth factor receptors ; ErbB-2 protein ; Growth factors ; Infectious Diseases ; Metabolic Diseases ; Metastases ; Metastasis ; Molecular Medicine ; Monoclonal antibodies ; Neurosciences ; PTEN protein ; Survival ; Targeted cancer therapy ; Tumors</subject><ispartof>Nature medicine, 2024-03, Vol.30 (3), p.730-739</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c419t-2310c0bf4a01e0fcd6de130eeec9c3e891e4277658ee687b14cf48defa06305a3</citedby><cites>FETCH-LOGICAL-c419t-2310c0bf4a01e0fcd6de130eeec9c3e891e4277658ee687b14cf48defa06305a3</cites><orcidid>0000-0002-0489-4756 ; 0000-0003-4169-6334 ; 0000-0003-3753-0999 ; 0000-0002-9763-9366 ; 0000-0002-1570-6802 ; 0000-0001-5196-3630 ; 0000-0001-8688-7295 ; 0000-0001-7507-2349</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-023-02791-w$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-023-02791-w$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38347302$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shitara, Kohei</creatorcontrib><creatorcontrib>Muro, Kei</creatorcontrib><creatorcontrib>Watanabe, Jun</creatorcontrib><creatorcontrib>Yamazaki, Kentaro</creatorcontrib><creatorcontrib>Ohori, Hisatsugu</creatorcontrib><creatorcontrib>Shiozawa, Manabu</creatorcontrib><creatorcontrib>Takashima, Atsuo</creatorcontrib><creatorcontrib>Yokota, Mitsuru</creatorcontrib><creatorcontrib>Makiyama, Akitaka</creatorcontrib><creatorcontrib>Akazawa, Naoya</creatorcontrib><creatorcontrib>Ojima, Hitoshi</creatorcontrib><creatorcontrib>Yuasa, Yasuhiro</creatorcontrib><creatorcontrib>Miwa, Keisuke</creatorcontrib><creatorcontrib>Yasui, Hirofumi</creatorcontrib><creatorcontrib>Oki, Eiji</creatorcontrib><creatorcontrib>Sato, Takeo</creatorcontrib><creatorcontrib>Naitoh, Takeshi</creatorcontrib><creatorcontrib>Komatsu, Yoshito</creatorcontrib><creatorcontrib>Kato, Takeshi</creatorcontrib><creatorcontrib>Mori, Ikuo</creatorcontrib><creatorcontrib>Yamanaka, Kazunori</creatorcontrib><creatorcontrib>Hihara, Masamitsu</creatorcontrib><creatorcontrib>Soeda, Junpei</creatorcontrib><creatorcontrib>Misumi, Toshihiro</creatorcontrib><creatorcontrib>Yamamoto, Kouji</creatorcontrib><creatorcontrib>Yamashita, Riu</creatorcontrib><creatorcontrib>Akagi, Kiwamu</creatorcontrib><creatorcontrib>Ochiai, Atsushi</creatorcontrib><creatorcontrib>Uetake, Hiroyuki</creatorcontrib><creatorcontrib>Tsuchihara, Katsuya</creatorcontrib><creatorcontrib>Yoshino, Takayuki</creatorcontrib><title>Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>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.</description><subject>631/67/68</subject><subject>692/53/2422</subject><subject>Bevacizumab</subject><subject>Biomarkers</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Chemotherapy</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB-2 protein</subject><subject>Growth factors</subject><subject>Infectious Diseases</subject><subject>Metabolic Diseases</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Molecular Medicine</subject><subject>Monoclonal antibodies</subject><subject>Neurosciences</subject><subject>PTEN protein</subject><subject>Survival</subject><subject>Targeted cancer 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shitara, Kohei</au><au>Muro, Kei</au><au>Watanabe, Jun</au><au>Yamazaki, Kentaro</au><au>Ohori, Hisatsugu</au><au>Shiozawa, Manabu</au><au>Takashima, Atsuo</au><au>Yokota, Mitsuru</au><au>Makiyama, Akitaka</au><au>Akazawa, Naoya</au><au>Ojima, Hitoshi</au><au>Yuasa, Yasuhiro</au><au>Miwa, Keisuke</au><au>Yasui, Hirofumi</au><au>Oki, Eiji</au><au>Sato, Takeo</au><au>Naitoh, Takeshi</au><au>Komatsu, Yoshito</au><au>Kato, Takeshi</au><au>Mori, Ikuo</au><au>Yamanaka, Kazunori</au><au>Hihara, Masamitsu</au><au>Soeda, Junpei</au><au>Misumi, Toshihiro</au><au>Yamamoto, Kouji</au><au>Yamashita, Riu</au><au>Akagi, Kiwamu</au><au>Ochiai, Atsushi</au><au>Uetake, Hiroyuki</au><au>Tsuchihara, Katsuya</au><au>Yoshino, Takayuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2024-03-01</date><risdate>2024</risdate><volume>30</volume><issue>3</issue><spage>730</spage><epage>739</epage><pages>730-739</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>38347302</pmid><doi>10.1038/s41591-023-02791-w</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-0489-4756</orcidid><orcidid>https://orcid.org/0000-0003-4169-6334</orcidid><orcidid>https://orcid.org/0000-0003-3753-0999</orcidid><orcidid>https://orcid.org/0000-0002-9763-9366</orcidid><orcidid>https://orcid.org/0000-0002-1570-6802</orcidid><orcidid>https://orcid.org/0000-0001-5196-3630</orcidid><orcidid>https://orcid.org/0000-0001-8688-7295</orcidid><orcidid>https://orcid.org/0000-0001-7507-2349</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2024-03, Vol.30 (3), p.730-739 |
| issn | 1078-8956 1546-170X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2926078428 |
| source | SpringerLink Journals; Nature Journals Online |
| subjects | 631/67/68 692/53/2422 Bevacizumab Biomarkers Biomedical and Life Sciences Biomedicine Cancer Cancer Research Chemotherapy Colorectal cancer Colorectal carcinoma Deoxyribonucleic acid DNA Epidermal growth factor receptors ErbB-2 protein Growth factors Infectious Diseases Metabolic Diseases Metastases Metastasis Molecular Medicine Monoclonal antibodies Neurosciences PTEN protein Survival Targeted cancer therapy Tumors |
| title | Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T01%3A13%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Baseline%20ctDNA%20gene%20alterations%20as%20a%20biomarker%20of%20survival%20after%20panitumumab%20and%20chemotherapy%20in%20metastatic%20colorectal%20cancer&rft.jtitle=Nature%20medicine&rft.au=Shitara,%20Kohei&rft.date=2024-03-01&rft.volume=30&rft.issue=3&rft.spage=730&rft.epage=739&rft.pages=730-739&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/s41591-023-02791-w&rft_dat=%3Cproquest_cross%3E2972994744%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2972994744&rft_id=info:pmid/38347302&rfr_iscdi=true |