Prediction of response to anti-EGFR antibodies in metastatic colorectal cancer: looking beyond EGFR inhibition

摘要: A commentary on The evolving role of monoclonal antibodies in colorectal cancer: early presumptions and impact on clinical trial development by Eng, C. (2010). Oncologist 15, 73–84. One the most successfully approach treatment metastatic cancer (mCRC) is inhibition Epidermal Growth Factor Receptor (EGFR) pathway by (cetuximab panitumumab). Notably, randomized trials with anti-EGFR have shown a significant KRAS [wild type (wt) vs. mutated (mut)] response prognosis: presence activating mutations was found to be associated reduced biological activity for (response rate mut 50%). Thus, mutational status now widely accepted criteria selection patients who would likely respond these treatments. In next future, other genes involved EGFR could prediction (BRAF, PIK3CA, PTEN, etc.) (De Roock et al., 2011). Cetuximab an IgG1 antibody, it binds specifically extracellular domain inhibiting downstream proliferative, anti-apoptotic neoangiogenetic signals kras wt tumors has efficacy mCRC (Eng, 2010). However, one anti-tumor mechanism antibody-dependent cell-mediated cytotoxicity (ADCC) which Fc region antibody FcγRs (Fragment c Gamma Receptors) expressed immune effector cells (Natural Killer cells, macrophages, (Kohrt 2012). scenario very complex result not simple sum above phenomena. Very recently, been demonstrated that immunologic mechanisms can cooperate but also antagonize EGFR/kras signal. fact, CD163+ “tumor-promoting” M2 macrophages abundant microenvironment carcinomas are activated cetuximab turn they release anti-inflammatory tumor-promoting mediators, including IL-10 VEGF (Pander 2011). Furthermore, both ADCC cetuximab-induced macrophage responses more pronounced FcγRIIIa 158-Val (high-affinity receptor Fc) carriers (Tsuchiya 2007; Pander The different abundance CD163 + tumor environment explain contrasting results reported literature FcγR polymorphisms (Zhang Bibeau 2009). Very we homozygous 158V allele show high significantly improved prognosis (Calemma This consistent hypothesis variants human IgG-receptors influence extent and, thus, therapy. We made, however, intriguing observation had prognostic power entire series, did receive therapy (data shown). To confirm this observation, extending analysis all referring our center. Our speculation triggered “endogenous” binding “high-affinity” Fcγ R might capable mediating clinically relevant activity. Such present work mutant patients. rather than “therapeutic” trigger such fascinating difficult demonstrate responsible long-term stabilizations after surgery and/or radio chemotherapy see practice. Indirectly, increased rates antibody-mediated autoimmune diseases suggest polymorphism plays endogenous (Matsumoto 2005). ADCC seen tumors. Ashraf al. (2012) higher expression predict susceptibility killing CRC occurring independently KRAS/BRAF/PIK3CA (in press Proc. Natl. Acad. Sci. U.S.A.). Therefore, administration may considered target favorable polymorphisms. context factors antibodies: previous concomitant therapies, HLA expression, cytokines production, cell receptors repertoire, etc. Study interactions between host should urgently optimize therapeutic mCRC.