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Advanced NSCLC Management 혈액 종양 내과 Prof.김시영/R3 문수영 Chemotherapy for advanced NSCLC patients with performance status 2 The natural history of untreated, advanced NSCLC : - a median survival of 4–5 months & a 1-year survival rate of less than 10% - Treatment with cisplatin or carboplatin in combination with a thirdgeneration cytotoxic such as gemcitabine, paclitaxel, docetaxel, or vinorelbine median survival of 8 to 11 months & 1-year survival rate of 30–45% PS consistently - an independent prognostic parameter 1960 patients treated with cisplatin-based chemotherapy between 1981 & 1994 The median survival times : 9.4, 6.4 & 3.3 months in patients with a PS of 0, 1 and 2, respectively in the ECOG 1594 trial that compared four platinum combination regimens in over 1000 patients median survival 4.1mon. & 1 year survival rate 19% for PS 2 pt. Randomized trials of comparative standard platinum-based combination CTx regimens inferior survival rates in PS 2 pt. compared with those with PS 0 or 1 The sideeffects of treatment outweigh the benefits ? CTx has not been recommended as a standard of care. Gemcitabine, vinorelbine or taxane monotherapy, dose-attenuated platinum combination regimens, & epidermal growth factor receptor inhibitors may provide a clinical benefit with less toxicity. Potential with cytotoxic treatment to improve the palliative options for PS 2 patients with advanced NSCLC Further trials designed specifically for PS 2 patients that include measurement of symptoms, quality of life, & survival & toxicity are required. CLINICAL PROGNOSTIC CHARACTERISTICS Performance status Weight loss - Separate from performance status, an independent predictor of decreased survival Inflammatory response to the tumor - Chronic inflammation implicated in the development of airway dysplasia & lung cancer. Ethnicity Novel therapeutic approaches for advanced NSCLC Conventional treatment for patients with metastatic NSCLC - systemic chemotherapy The benefits of chemotherapy in patients with advanced NSCLC - reduction in symptoms, improvement in quality of life, prolongation of survival Chemotherapy in NSCLC Metastatic NSCLC - a uniformly fatal disease Treatment is palliative Despite being considered a relatively chemotherapy-refractory disease Some regimens (cisplatin, or non-cisplatin combinations with gemcitabine or paclitaxel) produce objective response rates in the range of 20 to 40 percent The response duration generally less than six months, & median survival is disappointingly short, usually less than 10 months the impact of chemotherapy on survival from NSCLC is modest an objective response to therapy accompanied by symptomatic improvement, an important palliative endpoint. This improvement in disease-related symptoms must be balanced against treatment-related toxicity, particularly with regimens containing cisplatin. The median survival of PS 2 patients treated with best supportive care is 2–3 months Chemotherapy regimens associated with median survivals ranging from 4 to 6 months These data provide encouragement to revisit the role of CTx in this group of patients Therapeutic approaches & the molecular pathogenesis of lung cancer Major components of cell signaling pathways - protein tyrosine kinases, protein kinase C, ras/mitogen-activated protein kinase [ras/MAPK] Components of the normal cell cycle - overexpression or mutation. Tumor-associated antigens a focus for immunotherapy approaches Angiogenesis Treatment of NSCLC & pharmacogenomics: where we are and where we are going Chemotherapy NSCLC has reached a plateau, with no evidence of substantial improvement in survival. Performance status of 0 is the most significant prognostic factor, though excision repair cross-complementing 1 (ERCC1) mRNA expression is closely linked to cisplatin resistance The economic impact of novel targeted therapies has not yet been evaluated & their overall benefit is still meager Activating mutations in tyrosine kinases have emerged as a new paradigm for predicting response and outcome. Growing evidence indicates that epidermal growth factor receptor (EGFR) deletions & L858R mutations are strong predictors of dramatic responses to gefitinib & erlotinib. the most relevant findings in lung cancer molecular biology The way for individualized treatment based on predictive markers - BRCA mRNA expression - K-ras mutations - ERCC1 & SEMA3B single nucleotide polymorphisms - mutations in tyrosine kinases - acquired resistance in sensitive EGFR mutations - erythropoietin receptor - estrogen & progesterone receptors - microRNAs (miRNAs) - Wnt signaling pathway Predictive markers for customized chemotherapy Between 1993 & 1999, 1436 patients with stage IV or IIIB NSCLC with effusion were treated with platinumbased doublets (involving either paclitaxel, docetaxel, vinorelbine or gemcitabine) The response rates & median survival times were 20% & 8.2 months. One & two-year survivals were 33% and 11%, respectively In a multivariate analysis, lower performance status 1 versus 0 was identified as one prognostic factor. Cisplatin resistance is associated with increased expression of the ERCC1 gene. Cancer tissues from ovarian cancer patients whose tumors were clinically resistant therapy showed greater levels of ERCC1 mRNA BRCA1 levels and cisplatin resistance BRCA1 overexpressed in the cisplatin-resistant breast cancer cell line MCF7 BRCA1 - a component of multiple DNA repair pathways & functions as a molecular determinant of response to a range of cytotoxic chemotherapeutic agents. BRCA1 abrogates the apoptotic phenotype induced by a range of DNA-damaging agents, including cisplatin, etoposide & bleomycin, induces dramatic responses to a range of antimicrotubule agents, paclitaxel & vinorelbine. BRCA1 mRNA expression closely correlates with ERCC1 mRNA expression BRCA1 mRNA expression predicts outcome in locally advanced NSCLC patients treated with neoadjuvant gemcitabine plus cisplatin followed by surgery. Median survival has not been reached in patients with the lowest BRCA1 mRNA levels, while survival was very poor in patients with the highest levels. K-ras mutations Adjuvant vinorelbine plus cisplatin increased survival in patients with stage II NSCLC Adjuvant Chemotherapy , did not confer survival advantage in patients whose tumors had ras mutations Pooled data on K-ras mutations indicate that it is mutated in 20% of NSCLC, mainly in adenocarcinoma & linked to poor prognosis Single nucleotide polymorphisms in ERCC1 & SEMA3B Single nucleotide polymorphisms (SNPs) found in nearly all human DNA repair genes that have been investigated. The repair genotype can be very complex in an individual, resulting in several variant peptides between the respective repair complexes. DNA repair function & cancer risk are significantly modulated by additive & even multiplicative effects of various variant allele Two common SNPs of ERCC1, codon 118 C/T & C8092A, The codon 118 C/T SNP - associated with differential mRNA levels. The C8092A SNP - may affect ERCC1 mRNA stability A significant observation has been observed between C8092A SNP & survival in cisplatin-treated NSCLC patients. Median survival was 22.3 months for patients with the C/C genotype versus 13.4 months for those with C/A or A/A (P ¼ 0.006) any copy of the A allele is associated with poor outcome SEMA3B belongs to a large family of secreted, transmembrane & membrane-associated semaphoring proteins characterized by a conserved, cysteine-rich, 500 amino-acid ‘sema’ domain. SEMA3B is located in the LUCA region of chromosome 3p21.3, which is frequently deleted in human lung cancer. Protein homology between the sema domain of SEMA3B & the MET and RON oncogenes SEMA3B can antagonize the VEGF pathway. An SNP has been reported at codon 415 of SEMA3B, leading to a substitution of Thr Ile (T415I). The variant Ile allele occurs in African-American and LatinoAmerican control subjects but not in Caucasian subjects Possessing either the heterozygous or homozygous variant genotype greater than 40% reduced relative risk of lung cancer in Latino-Americans, controlling for other lung cancer risk factors CELL SIGNALING PATHWAYS: TYROSINE KINASES the largest family of dominant oncogenes that are altered in lung Two major types: receptor tyrosine kinases (RTKs) & nonreceptor TKs Tumor growth & progression depends largely upon the activity of cell surface membrane receptors ( control the intracellular signal transduction pathways regulating proliferation, apoptosis, angiogenesis, adhesion, & motility) RTKs EGFR (HER1 or erbB-1), erbB-2 ( HER-2/neu) erbB-3 (HER-3) erbB-4 (HER-4). Gene mutations as predictive markers for molecular therapy Inhibition of tyrosine kinases by selective small molecule inhibitors emerging as a new strategy for treatment of hematologic malignancies & solid tumors, including leukemias, gastrointestinal stromal cell tumors & NSCLC. The identification of somatic mutations in the tyrosine kinase domain of the EGFR gene represents the most important molecular marker of sensitivity to EGFR tyrosine kinase inhibitors The EGFR is overexpressed in a variety of solid tumors, including NSCLC - EGFR overexpression correlates with advanced disease stage poor prognosis in many but not all studies The protein phosphorylation activation of the EGFR promotes pathways tumor growth and progression, including cell proliferation, inhibition of apoptosis, invasion/metastasis, and upregulation of angiogenesis Mutations in the EGFR observed in some tumors (eg, brain, lung, breast, prostate &stomach cancers) a constitutively activated TK with a truncated ligand binding domain, whose activation is independent of ligand binding Several agents that block the activation of EGFR potential therapies for NSCLC, including small molecule TK inhibitors, monoclonal antibodies, & antisense oligonucleotides MicroRNAs MiRNAs & short interfering RNAs (siRNAs) - processed by the type III double-stranded RNase Dicer function in an RNA-based mechanism of gene silencing MiRNA genes expressed as primary transcripts (pri-miRNAs) PrimiRNAs trimmed into 70 nucleotide pre-miRNA forms, mainly in the nucleus. After this initial processing, the pre-miRNAs are exported to the cytoplasm and are cleaved to generate the final products of 22 nucleotides by Dicer. The miRNAs originally described as miR-1 to miR-33 miR-15 and miR-16 : commonly downregulated in CLL The Caenorhabditis elegans let-7 miRNA is highly preserved through the species, and reduced let-7 expression has been associated with shorter survival in resected NSCLCs Dicer expression levels were reduced in a fraction of NSCLCs, especially in non-squamous histologies, conferring poor prognosis in completely resected patients Small molecule TK inhibitors gefitinib (Iressa®) & erlotinib (Tarceva®) approved for use in NSCLC by the FDA as salvage therapy ISEL: no advantage for gefitinib compared with best surpportive care in Pt with advanced NSCLC with one or two CTx Subgrup analysis : Female , Asian, never smoker survival advantage The international TALENT and TRIBUTE trials assessing the effects of erlotinib, confirmed the negative results for the combination of chemotherapy & EGFR inhibitors. Unlike gefitinib, however, erlotinib showed a survival advantage in previously treated patients with NSCLC as compared with best supportive care alone (6.7 months compared with 4.7 months for erlotinib and placebo respectively; P ¼ 0.001) in a large phase III randomized trial Biological markers predictive of response for the EGFR inhibitors gefitinib & erlotinib - EGFR protein expression by immunohistochemistry, - EGFR gene copy detected by fluorescence in situ hybridization - EGFR mutation - pAkt expression Anti-EGFR MoAb Monoclonal antibodies (MoAbs) bind to the extracellular domain of EGFR. The MoAb prevents the receptor from interacting with its ligand EGF blocks the dimerization of receptors on the cell surface, block initiation of the intracellular signal transduction pathways involved in tumorigenesis Cetuximab, the prototype MoAb targeted against EGFR - synergistic with CTx & small molecule TK inhibitors in human lung cancer cell lines In a study of 31 patients treated with cetuximab plus the combination of paclitaxel & carboplatin treatment was well tolerated & a slight improvement in response rate & median survival suggested compared to historical controls Estrogen and progesterone receptors in NSCLC significant number of NSCLCs overexpress estrogen & progesterone receptors and that crosstalk between estrogen receptors & EGFR pathways is common EGFR protein expression was downregulated in response to estrogen and upregulated in response to fulvestrant (an estrogen receptor antagonist) the EGFR pathway is activated when estrogen is depleted in NSCLC Clinical trials of EGFR tyrosine kinase inhibitors with aromatase inhibitors. Wnt signaling in NCLC Ectopic wingless (Wnt) signaling is involved in breast cancer stem cells Wnt signaling is required for stem cell maintenance emerging as a critical pathway in lung carcinogenesis. In NSCLC, the Wnt pathway is activated upstream of b-catenin. Overexpression of Wnt effectors such as disheveled & repression of Wnt antagonists like Wnt inhibitory factor 1 play a crucial role The components of the Wnt pathway have been characterized & represent key targets for potential therapeutic agents. Recently, overexpression of Wnt-1 observed in NSCLC cell lines & primary cancer tissues Blockade of Wnt signaling with siRNA or a specific monoclonal antibody induced apoptosis in vitro. The monoclonal anti-Wnt-1 antibody suppressed tumor growth in vivo Vascular endothelial growth factor (VEGF) an endothelial-specific mitogen & a potent angiogenic factor - expressed in wide array of tumors - In NSCLC, high levels of VEGF associated with a poor prognosis Anti VEGF monoclonal antibodies Inhibiting VEGF : bevacizumab (Avastin®), a recombinant humanized monoclonal antibody binds VEGF Phase III trial : docetaxel + carboplatin vs same CTx + avastin as first-line Tx in patients with advanced or metastatic NSCLC adding avastin significant improvement in survival small-molecule inhibitors of VEGF signalling Interesting new oral drugs, currently unde investigation ZD6474, ZD2171 shows some activity against EGFR thymidine kinase promising results Novel vaccine Targeting the exposed core peptide of the MUC1 tumour-associated mucin, which is overexpressed in NSCLC Prolonged survival for patients with stage IIIB NSCLC treated with the vaccine & combined chemo-radiotherapy has been reported. A large phase III randomized trial to define the role of this new therapeutic approach is ongoing.