Abstract
Background: KRAS mutations occur in 35-45% of metastatic colorectal cancers (mCRC) and preclude responsiveness to EGFR-targeted therapy with cetuximab or panitumumab. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been found to give rise to resistance. We present a comprehensive analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression in mCRC patients treated with cetuximab or panitumumab, with the aim of clarifying the relative contribution of these molecular alterations to resistance. Methodology/Principal Findings: We retrospectively analyzed objective tumor response, progression-free (PFS) and overall survival (OS) together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non-responsive patients, 74 (70%) had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43) among patients with no alterations, 4% (2/47) among patients with 1 alteration, and 0% (0/24) for patients with ≥2 alterations (p
| Original language | English |
|---|---|
| Article number | e7287 |
| Journal | PLoS One |
| Volume | 4 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Oct 2 2009 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. / Sartore-Bianchi, Andrea; Di Nicolantonio, Federica; Nichelatti, Michele; Molinari, Francesca; De Dosso, Sara; Saletti, Piercarlo; Martini, Miriam; Cipani, Tiziana; Marrapese, Giovanna; Mazzucchelli, Luca; Lamba, Simona; Veronese, Silvio; Frattini, Milo; Bardelli, Alberto; Siena, Salvatore.
In: PLoS One, Vol. 4, No. 10, e7287, 02.10.2009.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer
AU - Sartore-Bianchi, Andrea
AU - Di Nicolantonio, Federica
AU - Nichelatti, Michele
AU - Molinari, Francesca
AU - De Dosso, Sara
AU - Saletti, Piercarlo
AU - Martini, Miriam
AU - Cipani, Tiziana
AU - Marrapese, Giovanna
AU - Mazzucchelli, Luca
AU - Lamba, Simona
AU - Veronese, Silvio
AU - Frattini, Milo
AU - Bardelli, Alberto
AU - Siena, Salvatore
PY - 2009/10/2
Y1 - 2009/10/2
N2 - Background: KRAS mutations occur in 35-45% of metastatic colorectal cancers (mCRC) and preclude responsiveness to EGFR-targeted therapy with cetuximab or panitumumab. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been found to give rise to resistance. We present a comprehensive analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression in mCRC patients treated with cetuximab or panitumumab, with the aim of clarifying the relative contribution of these molecular alterations to resistance. Methodology/Principal Findings: We retrospectively analyzed objective tumor response, progression-free (PFS) and overall survival (OS) together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non-responsive patients, 74 (70%) had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43) among patients with no alterations, 4% (2/47) among patients with 1 alteration, and 0% (0/24) for patients with ≥2 alterations (p
AB - Background: KRAS mutations occur in 35-45% of metastatic colorectal cancers (mCRC) and preclude responsiveness to EGFR-targeted therapy with cetuximab or panitumumab. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been found to give rise to resistance. We present a comprehensive analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression in mCRC patients treated with cetuximab or panitumumab, with the aim of clarifying the relative contribution of these molecular alterations to resistance. Methodology/Principal Findings: We retrospectively analyzed objective tumor response, progression-free (PFS) and overall survival (OS) together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non-responsive patients, 74 (70%) had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43) among patients with no alterations, 4% (2/47) among patients with 1 alteration, and 0% (0/24) for patients with ≥2 alterations (p
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U2 - 10.1371/journal.pone.0007287
DO - 10.1371/journal.pone.0007287
M3 - Article
C2 - 19806185
AN - SCOPUS:70350028742
VL - 4
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e7287
ER -