Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer.
Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer.
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DOI：
10.1371/journal.pone.0007287
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发表时间：
2009-10-02
期刊：
影响因子：
3.7
通讯作者：
Siena S
中科院分区：
文献类型：
--
作者：
Sartore-Bianchi A;Di Nicolantonio F;Nichelatti M;Molinari F;De Dosso S;Saletti P;Martini M;Cipani T;Marrapese G;Mazzucchelli L;Lamba S;Veronese S;Frattini M;Bardelli A;Siena S
KRAS突变发生在35-45%的转移性结直肠癌(MCRC)中，并排除了对西妥昔单抗或Panitumumab的EGFR靶向治疗的反应性。然而，只有不到20%的患者表现出野生型KRAS肿瘤的客观反应。已经发现，EGFR下游其他效应物的改变，如BRAF，以及PIK3CA/PTEN通路的放松调控，都独立地引起了耐药性。我们对接受西妥昔单抗或帕尼单抗治疗的mCRC患者的KRAS、BRAF、PIK3CA突变和PTEN表达进行了全面的分析，目的是阐明这些分子变化对耐药性的相对贡献。我们回顾分析了132例西妥昔单抗或帕尼单抗治疗的mCRC患者的客观肿瘤疗效、无进展(PFS)和总生存期(OS)，以及KRAS、BRAF、PIK3CA和PTEN的突变情况。在106名无反应的患者中，74名(70%)的肿瘤在四个标志物中至少有一个分子改变。在无改变的患者中，有效率为51%(22/43)，在1个改变的患者中为4%(2/47)，在≥2改变的患者中为0%(0/24)(p<；0.0001)。相应地，对于没有、1或≥2分子改变的肿瘤患者，PFS和OS越来越差(S)(p<；0.001)。当同时确定PTEN的表达以及KRAS、BRAF和PIK3CA的突变时，高达70%的对抗EGFR治疗无效的mCRC患者可以被确定。我们建议将KRAS、BRAF、PTEN和PIK3CA缺乏改变的癌定义为“四重阴性”。应该考虑对EGFR信号通路进行全面的分子解剖，以选择接受西妥昔单抗或帕尼单抗治疗的mCRC患者。
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. 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<0.0001). Accordingly, PFS and OS were increasingly worse for patients with tumors harboring none, 1, or ≥2 molecular alteration(s) (p<0.001). When expression of PTEN and mutations of KRAS, BRAF and PIK3CA are concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to anti-EGFR therapies can be identified. We propose to define as ‘quadruple negative’, the CRCs lacking alterations in KRAS, BRAF, PTEN and PIK3CA. Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients for cetuximab- or panitumumab-based therapies.
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影响因子：
51.1
作者：
Moroni, M;Veronese, S;Bardelli, A
通讯作者：
Bardelli, A
人类癌症中PIK3CA癌基因的突变。
影响因子：
8.8
作者：
Karakas, B;Bachman, KE;Park, BH
通讯作者：
Park, BH
影响因子：
8.8
作者：
Frattini, M;Saletti, P;Romagnani, E;Martin, V;Molinari, F;Ghisletta, M;Camponovo, A;Etienne, L L;Cavalli, F;Mazzucchelli, L
通讯作者：
Mazzucchelli, L
DOI：
10.1200/jco.2008.18.6544
发表时间：
2009-03-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Ogino S;Nosho K;Kirkner GJ;Shima K;Irahara N;Kure S;Chan AT;Engelman JA;Kraft P;Cantley LC;Giovannucci EL;Fuchs CS
通讯作者：
Fuchs CS
影响因子：
51.1
作者：
Linardou, Helena;Dahabreh, Issa J.;Murray, Samuel
通讯作者：
Murray, Samuel