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Degenerative Diseases Program, Center for Cancer Research, Sanford-Burnham Medical Research Institute, 10901 N. Miao WangMiao Wang currently works as a senior postdoctoral researcher in the laboratory of Randal J. A process in which endoplasmic reticulum (ER) transmembrane transcription factors are cleaved within the plane of the membrane to release cytosolic fragments that enter the nucleus to regulate gene transcription. A large intracellular multiprotein oligomeric complex that is activated by pattern recognition receptors to initiate an innate immune response by maturation of the inflammatory cytokines interleukin-1 (IL-1) and IL-18. A subset of activated macrophages that are involved in immunosuppression and tissue repair. The epidermal growth factor receptor (EGFR) signaling pathway is importantly implicated in tumor cell growth, local invasion, angiogenesis, metastasis, protein translation and cell metabolism. Figure 1: Epidermal Growth Factor Receptor (EGFR) pathway and anti-EGFR therapy in clinical use. NSCLC is associated with EGFR overexpression in up to 80% of the patients and a high EGFR gene copy number is found in nearly 60% of the cases [4-6]. The EGFR kinase domain can be targeted with tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib.
Differences in the design of the clinical studies and technical approaches have led to some confusion about the role of molecular diagnostics in guiding the use of EGFR-targeted therapy in NSCLC. Table 1: Response rate to EGFR tyrosine kinase inhibitors according to EGFR mutation status. The early trials that evaluated EGFR TKIs for the second- and third-line settings of advanced NSCLC did not select patients on the basis of any EGFR marker [28, 29]. Another study with relevant molecular data is the SATURN trial, which randomly assigned 889 patients with advanced NSCLC who had response or stable disease after four cycles of platinum-based chemotherapy to erlotinib or placebo as maintenance treatment [39]. In the FLEX trial, 1,125 patients with advanced NSCLC and EGFR-positive tumors by IHC were randomly assigned to chemotherapy plus cetuximab or chemotherapy alone [40]. A similar trial was carried out in the USA in 676 nonselected patients with advanced NSCLC (BMS099) [42]. Recently, results of the phase II randomized trial of erlotinib compared to erlotinib in combination with paclitaxel-carboplatin chemotherapy in treatment-naïve, never or light former smokers with advanced lung adenocarcinoma [47].
Table 2: Prospective randomized studies of first-line EGFR TKIs versus standard chemotherapy in clinically-enriched and biomarker-selected patient populations.
Preliminary results of other phase III trials that randomized patients with metastatic NSCLC and EGFR mutations at baseline to receive EGFR TKIs or standard first-line platinum-based regimens are presented in Table 2. Tumors become resistant when they reactivate downstream signaling despite the presence of the EGFR inhibitor. The most commonly identified mechanism of resistance is an EGFR mutation at position 790 (T790M), resulting in substitution of a threonine residue with methionine, which abrogates the ability of gefitinib or erlotinib to inhibit EGFR [55, 56]. Based on data from KRAS mutation status and benefit of cetuximab in advanced colon cancer, molecular analysis of FLEX trial was conducted.
A fusion gene between echinoderm microtubule-associated protein like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has recently been identified in NSCLC [82]. Among 266 resected NSCLCs in an East Asian population, the EML4-ALK fusion gene was found in about 5% of cases, as assessed by reverse transcriptase-PCR and posterior sequencing [85].
Impressive clinical activity was demonstrated in a phase I trial of an oral ATP- competitive TKI of ALK and c-MET, crizotinib (PF-02341066), in patients with advanced NSCLC and whose tumors harbored ALK rearrangement by FISH analysis [87].
Identifying the patients who are most likely to obtain clinical benefit from targeted therapies in NSCLC is of paramount importance.
In conclusion, EGFR TKI therapy should be recommended to patients with activating EGFR mutations in the course of the disease. A process by which misfolded proteins in the endoplasmic reticulum (ER) are targeted by retrotranslocation and ubiquitylation for subsequent degradation by the proteasome. A specialized endoplasmic reticulum (ER) membrane is directly juxtaposed to the mitochondrion to coordinate efficient communication between these two organelles.
A process in which activated inositol-requiring protein 1 (IRE1) induces cleavage and degradation of microRNAs and of mRNAs encoding membrane and secreted proteins. Intratumoral heterogeneity of HER2 expression may potentially contribute to inaccurate assessment of HER2 status.
Based on laboratory and clinical observations, investigators have anticipated that these mutations could be predictive of response to EGFR TKIs and numerous studies have confirmed that the presence of mutation was associated with longer survival in patients receiving targeted therapy. Mutation of the EGFR proto-oncogene is found in 10% to 20% of lung carcinomas (mostly adenocarcinomas) and nearly 90% of lung cancer-specific EGFR mutations comprise a leucine-to-arginine substitution at position 858 (L858R) and deletion mutations in exon 19 (delE746-A750) [7-10].
In addition, another strategy to inhibit EGFR activity is with monoclonal antibodies such as cetuximab, a human-mouse chimeric IgG1 agent.
Most information regarding clinical benefit with these agents comes from retrospective analysis of large studies. A phase II trial in patients with refractory NSCLC confirmed RR of approximately 12% and survival outcomes similar to gefitinib [34].
Progression-free survival was significantly improved in the erlotinib maintenance arm (HR = 0.71).
There was no survival benefit with the addition of cetuximab to paclitaxel-carboplatin combination chemotherapy. The first study was conducted in Asian patients and examined EGFR status in 75 patients [43].
The first study screened chemotherapy-naïve patients with advanced NSCLC and clinical characteristic associated with EGFR mutations [45].
The North-East Japan trial (prematurely interrupted after interim analysis) and the WJTOG3405 trial demonstrated that treatment with gefitinib doubles the RR and significantly improves PFS as compared to chemotherapy [20, 21]. This mutation can be found in 50% of the tissue samples from patients with acquired gefitinib resistance [57]. Phase II trials have shown very small or absent response rates to erlotinib in patients with KRAS mutations [79]. Of the 1,125 patients enrolled, 395 had tumor samples available and KRAS mutation was detected in 19%. Although more frequent in hematological malignancies, recurrent chromosome translocations may play a role in the molecular pathogenesis of solid tumors. Patients enrolled shared several key clinical features with EGFR-mutated patients (adenocarcinoma histology and nonsmoking history). To make rational clinical decisions, in addition to understanding the biology of the disease, oncologists need to rely on standardized and validated methods of molecular assessment. Josep Tabernero for critical review and Vall d’Hebron Institute of Oncology for financial support of graphic design (Figure 1). Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Rusch V, Baselga J, Cordon-Cardo CV, Orazem J, Zaman M, Hoda S, McIntosh J, Kurie J, Dmitrovsky E. Hirsch FR, Dziadziuszko R, Thatcher N, Mann H, Watkins C, Parums DV, Speake G, Holloway B, Bunn PA Jr, Franklin WA. Lynch TJ, Bell DW, Sordell R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M.
Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA.
Carey KD, Garton AJ, Romero MS, Kahler J, Thomson S, Ross S, Park F, Haley JD, Gibson N, Sliwkowski MX. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, et al.
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Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, et al. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, et al.
Ranson M, Hammond LA, Ferry D, Kris M, Tullo A, Murray PI, Miller V, Averbuch S, Ochs J, Morris C, Feyereislova A, Swaisland H, Rowinsky EK. Herbst RS, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Baselga J, Rojo F, Hong WK, Swaisland H, Averbuch SD, Ochs J, LoRusso PM. Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, Kaye SB, Gianni L, Harris A, Bjork T, Averbuch SD, Feyereislova A, Swaisland H, Rojo F, Albanell J. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, et al. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Bell DW, Lynch TJ, Haseriat SM, Harris PL, Okimoto RA, Brannigan BW, Sgroi DC, Muir B, Riemenschneider MJ, Iacona RB, Krebs AD, Johnson DH, Giaccone G, Herbst RS, Manegold C, Fukuoka M, et al. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, et al. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K. Hirsch FR, Varella-Garcia M, Bunn PA Jr, Franklin WA, Dziadziuszko R, Thatcher N, Chang A, Parikh P, Pereira JR, Ciuleanu T, von Pawel J, Watkins C, Flannery A, Ellison G, Donald E, Knight L, et al. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, et al.
Douillard JY, Shepherd F, Hirsh V, Mok T, Socinski MA, Gervais R, Liao ML, Bischoff H, Reck M, Sellers MV, Watkins CL, Speake G, Armour AA, Kim ES.
Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, Eckhardt SG, Tolcher A, Britten CD, Denis L, Ferrante K, Von Hoff DD, Silberman S, Rowinsky EK. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabárbara P, Bonomi P. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, et al. Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, Ayoub J, Lago S, de Albuquerque Ribeiro R, Gerogianni A, Cyjon A, Noble J, Laberge F, Chan RT, Fenton D, von Pawel J, et al. Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, Dakhil S, Hermann RC, Lynch TJ, Weber MR.
Inoue A, Suzuki T, Fukuhara T, Maemondo M, Kimura Y, Morikawa N, Watanabe H, Saijo Y, Nukiwa T. Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, Ando M, Yamazaki K, Saijo Y, Gemma A, Miyazawa H, Tanaka T, Ikebuchi K, Nukiwa T, Morita S, Hagiwara K; North East Japan Gefitinib Study Group.
Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Jänne PA, Joshi VA, McCollum D, Evans TL, Muzikansky A, Kuhlmann GL, Han M, Goldberg JS, Settleman J, Iafrate AJ, Engelman JA, et al. Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, Yamamoto S, Nokihara H, Yamamoto N, Sekine I, Kunitoh H, Shibata T, Sakiyama T, Yoshida T, Tamura T.
Janne PA, Wang XF, Socinski MA, Crawford J, Capelletti M, Edelman MJ, Villalona-Calero MA, Kratzke RA, Vokes EE, Miller VA. Yang CH, Fukuoka M, Mok TS, Wu Y-L, Thongprasert S, Saijo N, Chu DT, Jiang H, Duffield EL, Ichinose Y. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. To clarify intratumoral heterogeneity of HER2 expression and its potential clinical impact on assessment of HER2 status, we analyzed 148 endoscopic biopsy specimens and 117 excisional tumor specimens collected from 148 patients with primary gastric cancer.
The product of the human c-erbB-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity.
Comparison of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assessment for HER2 status in breast cancer. HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing.
Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line. Status of c-erbB-2 in gastric adenocarcinoma: A comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Pathological features of advanced gastric cancer (gc): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trail.
Prospective trials comparing standard platinum-based chemotherapy with EGFR TKIs in patients with and without activating EGFR mutations validated the predictive value of molecular selection of patients for first-line treatment of advanced NSCLC. It has been demonstrated that a subgroup of NSCLC patients achieves impressive response rates (RR), symptomatic improvement and long-term progression-free survival (PFS) with these agents. At the present time, prospective clinical data confirming the predictive value of receptor mutations for response to EGFR TKIs is available [20, 21]. Molecular biomarker study showed that no significant differences in survival were detected between patients with FISH positive or negative tumors in either treatment arm [41]. Response rate was 55% in 31 patients who received gefitinib and the median PFS was 9.2 months.
In the overall patient population, addition of chemotherapy did not significantly increase response rate or PFS.
Another acquired mutation in EGFR, which leads to substitution of alanine for threonine at position 854 (T854A) and hinders the inhibition of tyrosine phosphorylation by erlotinib, has also been reported [58].
In this situation, there appears to be dual input to signaling and combined inhibition of EGFR and the alternative pathway may be necessary to kill tumor cells. They are associated with significant tobacco exposure and worse prognosis, although contradictory data have been reported [73, 74]. A recent meta-analysis demonstrated 3% rate of objective tumor response to EGFR TKIs in patients with KRAS mutations, as compared to 26% in those with wild-type KRAS [80]. The comparison of the cetuximab treatment effects in patients with KRAS wild-type tumors and those with KRAS mutant tumors showed no marked differences with regard to PFS or OS [41]. EML4-ALK, EGFR, and KRAS mutations were all mutually exclusive, suggesting that ALK mutation may be an important oncogenic factor, and a potential therapeutic target in EGFR wild-type and KRAS wild-type lung cancer.
Among 82 patients treated in an expanded cohort of the dose-escalation study (250 mg twice daily), 57% had an objective RR and 72% were progression-free at 6 months [87]. EGFR amplification by FISH and protein expression measured by IHC are not informative for personalized therapy in advanced NSCLC but further analysis of studies that combine chemotherapy with monoclonal antibodies targeting EGFR is indicated. Clinical practice in the treatment of advanced NSCLC patients has shown that progression and symptomatic deterioration can occur very short after treatment discontinuation. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung.
Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Epidermal growth factor receptor immunohistochemistry: comparison of antibodies and cutoff points to predict benefit from gefitinib in a phase 3 placebo-controlled study in advanced non small-cell lung cancer.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. EGF receptor gene mutations are common in lung cancer from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib.

Mutations of epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Structures of lung-cancer-derived EGFR mutants and inhibitors complexes: mechanism of activation and insights into differential inhibitor sensitivity. A sensitive method for detecting EGFR mutations in non-small cell lung cancer samples with few tumor cells. Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non-small-cell lung cancer. Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib.
A multicenter phase II study to evaluate the efficacy and safety of gefitinib as first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results from a phase I trial.
Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD 1839 is generally well tolerated and has activity in non-small cell lung cancer and other solid tumors. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumors.
Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The Ideal I Trial).
Efficacy of gefitinib, an epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung cancer). Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with advanced solid malignancies. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Molecular and clinical biomarkers of outcome with cetuximab: Data from the phase III FLEX study in non-small cell lung cancer. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. First-line gefitinib for patients with advanced non–small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. First-line gefitinib in patients with advanced non-small cell lung cancer harboring somatic EGFR mutations. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer.
Final overall survival results from a phase III, randomised, open label, first-line study of gefitinib v. A randomized phase III study of gefitinib (Iressa) versus standard chemotherapy (gemcitabine plus cisplatin) as a first-line treatment for never-smokers with advanced or metastatic adenocarcinoma of the lung.
Efficacy results from the randomised phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin plus gemcitabine, in Chinese advanced non-small-cell lung cancer patients with EGFR activating mutations. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors and non-small-cell lung cancer: Current knowledge and future directions. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib.
Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Specifically, we assessed HER2 protein overexpression and gene amplification using, respectively, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).
2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
Detection of HER2 gene amplification by fluorescence in situ hybridization in breast cancer.
Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients.
HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic valuea€”conclusions from 924 cases of two independent series. Recently, preclinical and first-in-human studies have demonstrated impressive activity of ALK TKI in tumors harboring ALK rearrangement. Most patients have advanced disease at diagnosis and palliative therapy is the mainstay of management.
This review delineates the current role of EGFR inhibitors in the treatment of advanced NSCLC according to EGFR and KRAS status of the tumor, strategies to overcome resistance to agents targeting EGFR and also discusses other recently discovered molecular aberration in lung cancer, ALK rearrangement, which is being efficiently targeted with ALK inhibitors. DNA sequencing is the most accurate method for identification of EGFR mutations in tissue samples.
Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to gefitinib, treatment of NSCLC has changed dramatically [7, 8].
Apart from mutation analysis, EGFR protein expression determined by immunohistochemistry (IHC) and EGFR gene copy number determined by fluorescent in situ hybridization (FISH) have been evaluated as markers for clinical decision making regarding EGFR TKI therapy. Gefitinib was examined as monotherapy in two phase II studies called IDEAL trials [25, 26].
EGFR mutation was the only marker significantly predictive of differential erlotinib effect [39]. As anticipated by preclinical data, EGFR mutation status (positive in 17% of cases) was not predictive of benefit with cetuximab. EGFR expression, EGFR copy number and EGFR mutations were not associated with treatment outcomes [42].
The authors also evaluated EGFR gene copy number by FISH and concluded that it did not provide additional predictive information. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared to chemotherapy, with regards to PFS (HR for progression or death = 0.74). Resistance is typically caused by mutations in the EGFR gene that are not associated with sensitivity to EGFR TKIs, such as insertion mutations in exon 20 [52], or by other somatic mutations in genes that have an impact on the EGFR signaling pathway, such as KRAS [53]. A combination approach may prevent the emergence of resistance that eventually occurs following initial response to EGFR TKIs and may increase the proportion of EGFR wild-type patients that respond.
Prevalence of mutation is about 20% in the overall lung cancer patient population, 5% to 15% in never-smokers patients with adenocarcinoma and approximately 5% in the squamous cell carcinoma subtype [75-77]. Data from the TRIBUTE trial (chemotherapy with or without erlotinib for previously untreated patients with NSCLC) suggest that, in KRAS mutated patients, OS and RR may be worse with the addition of EGFR TKI [81].
ALK rearrangement can be identified by FISH analysis using break-apart probes to ALK, which detects disruption of the ALK locus but does not confirm EML4 as the partner fusion gene. All patients tested negative for EGFR mutation and amplification of MET, another target for crizotinib, which suggested that the therapeutic effect is through inhibition of ALK. In addition, the value of determining KRAS mutation status to select EGFR TKI therapy is not clear. Chemotherapy in advanced gastric cancer: A systematic review and meta-analysis based on aggregate data.
Survival after gastric adenocarcinoma resection: eighteen-year experience at a single institution.
In this article, we review current data on molecular biology of lung cancer and evidence-based patient selection for targeted therapy.
Conventional chemotherapy of NSCLC has apparently reached a plateau of effectiveness in improving survival of lung cancer patients, and treatment outcomes must still be considered disappointing [2].
Using polymerase-chain reaction (PCR) amplification, deletions in exon 19 and exon 21 point mutations in codon 858 can be detected by length analysis and specific probes for wild-type and mutant sequences [12]. It has been shown that exon 19 deletions are more sensitive to erlotinib inhibition than the L858R mutation, a finding demonstrated by kinetic analysis [15] and also confirmed in clinical studies [16-18]. Technical considerations are important in assessing IHC, which suffers from the lack of a standard methodology and inconsistencies among testing centers [6].
In the INTEREST trial, 1,466 pretreated patients with advanced NSCLC were randomly assigned to receive gefitinib or docetaxel in the second-line setting [31].
EGFR mutations were confirmed in 17% of tumors (34 patients had classical EGFR activating mutations).
However, the prognostic value of mutation was confirmed, with longer overall survival in patients with EGFR mutation tumors compared to wild-type tumors in both treatment arms [41].
As seen in Table 1, a confirmatory trial with gefitinib as first-line treatment of advanced EGFR mutant NSCLC reported RR of 53% in 45 patients [18]. This was because most patients who harbor EGFR mutations also had high gene copy numbers [46].
Acquired resistance may be caused by additional mutations in the EGFR gene obtained during the course of treatment that change the protein-coding sequence or by amplification of another oncogene signaling pathway [54].
These agents may prevent and overcome primary and acquired resistance to first-generation reversible EGFR TKIs.
Preliminary data of a phase II randomized trial of erlotinib and placebo or in combination with a non-ATP competitive receptor TKI of c-MET (ARQ 197) were recently presented [69]. KRAS mutant patients (20% of available tumor samples) showed a RR of 8% with paclitaxel-carboplatin plus erlotinib, compared with 23% for patients that received the chemotherapy doublet alone. Recently, a novel highly sensitive antibody allowed for the routine detection of ALK-rearranged lung carcinomas by standard IHC [84]. Further confirmatory studies are underway, along with a phase III trial comparing treatment of ALK rearrangement positive patients with crizotinib or standard chemotherapy in the second-line setting. On the other hand, it is now well established that specific genetic lesions that drive the proliferation of cancer cells render some tumors very sensitive to therapeutic inhibitors targeting the mutated pathway. Erlotinib may be considered a salvage treatment in unselected patient populations of chemotherapy-refractory NSCLC, as disease stabilization and symptomatic improvement was observed independent of molecular or clinical predictors of benefit. A data extraction sheet was developed to document the required information from each paper and all publications were reviewed independently by the authors. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial.
Guidelines for human epidermal growth factor receptor 2 testing: Biologic and methodologic considerations. Based on a better understanding of the biology of lung cancer, targeted therapies are also available to treat patients with NSCLC. In addition, the Scorpion Amplified Refractory Mutation System (SARMS) technology can be used to detect EGFR mutations in serum genomic DNA or circulating lung-cancer cells [13, 14]. On the other hand, cetuximab is not as potent as EGFR TKIs in tumors with exon 19 deletion or L858R EGFR mutations [19]. In addition, gene copy number evaluation by FISH may be affected by tumor heterogeneity within analyzed specimens.
Notably, responses were more likely in patients with specific characteristics: Asians, females, non-smoking and those with adenocarcinoma tumors.
Response rate was significantly higher in patients with these mutations (27% versus 7%) compared to patients with wild-type or other indeterminate mutations [36]. Interesting data came from another prospective trial in Japan that enrolled 30 patients with EGFR mutations and poor Performance Status (PS) without indication for palliative chemotherapy [44]. The Spanish Lung Cancer Group trial observed a prevalence of EGFR mutations in patients with lung cancer in Spain around 16% (350 of 2,105 cases) [16]. However, the overall population result is clearly of less relevance than the outcome in subgroups of patients.
In the LUX-Lung 2 study, 129 patients with activating EGFR mutations and no previous EGFR TKI therapy received BIBW2992 as single agent [59].
Of note, the RR for patients treated with chemotherapy alone did not differ significantly by KRAS mutation status (26% in those without mutation versus 23%) [81]. EML4-ALK positivity was related with resistance to EGFR TKIs but similar RR to platinum-based combination chemotherapy.
The most useful biomarker is EGFR mutation status and its determination is mandatory for proper therapeutic decisions. In addition, more clinical and translational data on irreversible EGFR inhibitors and dual targeted therapy in molecularly-selected subgroups of patients will help oncologists to personalize therapy of advanced NSCLC even further.
In 2011, he became Program Director at the Sanford-Burnham Medical Research Institute, La Jolla, California, USA, where he studies how protein misfolding in the endoplasmic reticulum (ER) causes degenerative disease.
Intratumoral heterogeneity was the main reason of discordant results between IHC and FISH or between endoscopic biopsy and excisional tumor specimens. Predictive markers of response to these agents are undergoing prospective validation and promising results have been reported.
Therefore, a detailed review of the clinical trials evaluating molecular markers of response to anti-EGFR agents is warranted. Posterior analysis demonstrated that patients with and EGFR mutation had an improved RR to gefitinib compared to wild-type patients (46% versus 10%), as shown in Table 1 [27].
This trial also confirmed symptomatic and survival benefit of erlotinib in patients without initial clinical predictors of response to EGFR TKIs [37].
In the INTEREST trial, KRAS mutation was not a predictive factor for a differential survival effect between gefitinib and docetaxel [32]. In addition, presence of EML4-ALK mutation was not associated differences in OS, as compared to those patients with wild type EML4-ALK and EGFR [86]. It is a good prognostic factor and has also predictive value for selecting treatment with EGFR TKIs. Overexpression of c-erb-B2 proteins in tumor and non-tumor parts of gastric adenocarcinomaa€“emphasis on its relation to H.
Patients with high EGFR copy number also had higher RR with gefitinib (13% versus 7.4%) [32].
One possible explanation to this finding is that erlotinib was administered at its maximum-tolerated dose, which could have different effects in the population of patients with wild-type EGFR, not hypersensitive to EGFR TKIs. Median PFS and OS for 217 patients who received erlotinib were 14 months and 27 months, respectively, and radiologic RR was around 70%. This drug has also shown activity in patients whose tumors harbored less common EGFR mutations [60].

Cervical cancer, specifically the prevention of this disease, was the most popular diagnostic focus and theme of investigation. Relationship of p53 and c-erbB-2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Evaluation of HER2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction.
This correlates with the higher prevalence of rash, a known marker of efficacy with these agents, in the erlotinib trial (76%, as compared to 37% in the gefitinib trial) [38]. Duration of response was similar for patients receiving first-line therapy (14 months) or second-line therapy (13 months) [16].
High EGFR copy number by FISH was predictive for efficacy only when accompanied by the presence of concomitant EGFR mutation. Its efficacy was also evaluated as a rescue treatment after failure to erlotinib or gefitinib in a randomized phase III trial [61]. Additionally, ALK rearrangement is a promising biomarker of benefit with ALK inhibitors and its detection resulted in prompt translation of preclinical data to patient care. Most of the studies were descriptive and none of the studies met the criteria of the highest quality.
Patients with a high EGFR copy number and wild-type EGFR did not benefit from gefitinib, but did benefit from chemotherapy [17]. Only 3 years after the initiation of the phase I trial, a phase III registration study of crizotinib in ALK-positive patients started enrollment. No difference in OS was seen in patients with EGFR mutation regardless of the treatment assigned [48]. The major reason for the lack of survival benefit is the cross-over effect, as half of the patients in the chemotherapy arm received EGFR TKIs at disease progression [48]. Importantly, although EGFR and ALK mutations are found mostly in patients with history of no smoking or light smoking who have adenocarcinoma, genotyping should be offered to all patients with advanced NSCLC if treatment with specific TKIs is available. There is a need for work on both men and women diagnosed with the most common cancers, as well as the family and care giver. The second trial assigned 309 chemotherapy-naïve patients with adenocarcinomas who had never smoked to receive 250 mg gefitinib daily or gemcitabine plus cisplatin at standard doses [49]. As first-line treatment of patients with known EGFR mutation or clinically selected (Asians with adenocarcinoma and non-or light smoking history), PF00029804 showed encouraging efficacy, with 6 month-PFS rate of 67% (85% in those with EGFR mutation) [63]. There is also a need for multidisciplinary work using complex interventions focusing on symptom management to improve patient outcomes. Both studies emphasize the importance of molecular selection of patients for first-line treatment with an EGFR TKI.
South Africa, as a developing country, is an anomaly as it is both developed with a good infrastructure and developing, as it faces huge social and economic challenges, with a large gap between the poor dependent on developing aid and skilled professionals (Layne 1998:183).
South Africa therefore faces the health challenges applicable to both the developed and developing world.
It is not clear how many people are diagnosed with cancer annually as the histological-based National Cancer Registry only reflects data up to 2005 (National Health Laboratory Service 2012). However, it is estimated that one in six South African men and one in seven South African women will develop cancer during their lifetime (health24 2013).
According to the Cancer Association of South Africa (CANSA) (CANSA 2012), the most prevalent cancers in women are breast, cervical, unknown primary site, colorectal and uterine cancer.
In men, the most prevalent are prostate, unknown primary site, lung, colorectal and oesophagus cancer. During this symposium, Falkson (1979), a medical oncologist, introduced medical oncology as an established, recognised and rapidly-growing speciality and highlighted the dire shortage of oncology nurses. Nurses were asked to join the ranks of their European and American colleagues by completing the diploma in oncology nursing. Intelligence, dedication and a wish to serve humanity were required from such a nurse as it would be expected that she would become a full member of the multiprofessional healthcare team and, in many instances, act as team leader.
In addition, the National Department of Health has, as of 1999, developed and adopted the National Cancer Control Policy which includes a cervical screening programme (CANSA 2008).
Cervical screening is executed at district health level in primary health clinics (Mojaki et al. The Scope of Practice (South African Nursing Council 1984) refers specifically to the prevention of disease and promotion of health through teaching and counselling individuals and groups and thus includes all cancers.
Despite cancer nursing being an established main nursing speciality, when looking to research to provide the evidence base for its practice, cancer nursing research is still a relatively young discipline (Molassiotis et al. Nursing research, however, originated in 1996 when a group of six nurses successfully completed a master's programme in nursing. It is not known whether oncology nursing was addressed in these studies as no mention is made of this speciality (Brink 1992).
In a systematic review of worldwide cancer nursing research between 1994 and 2003, Molassiotis et al. In addition, infrastructure plays a major role in the progress of cancer nursing research.
Quality research can only be conducted when funding is available to support research programmes (Molassiotis et al.
In addition, many cancer nurses use such findings as a guide for developing future research endeavours (Molassiotis et al. An integrative review allowed the researchers to examine the literature using a particular lens defined by the objectives of the study to examine critically and evaluate the previous research, provide a clear account of the body of work on the subject and to arrive at specific conclusions (Molassiotis et al. The aim of this integrative review was to quantify the publication output related to South African cancer nursing research conducted between 2002 and 2012 and to identify key trends relevant to cancer nurse researchers. Publications qualifying for inclusion had to be peer reviewed, conducted in a South African setting and co-authored by a South African nurse.
The key words South Africa in combination with cancer nursing and oncology nursing were used.
A data-extraction sheet was developed so as to document the required information from each paper including the year of publication, the journal of publication, the authors, affiliation of the authors, title of the study, participants and research methods used. Funding, a key word indicating the focus of the study and four sections dedicated to the judgement of the quality of the papers were also included. Quantitative research was assessed by means of the three-point grading system developed by Mann (Molassiotis et al. Grade I studies are divided into: Grade IA, referring to a randomised controlled trial where the sample size has been calculated and an accurate, standard definition of outcome variables is provided. Grade II studies are divided into: Grade IIA, where the sample size has been calculated and an accurate standard definition of outcome variables and adjustment for the effects of important variables are included. Five categories applied: descriptive vividness methodological congruence with subcategories (1) rigour in documentation, (2) procedure and (3) ethics and confirmability analytical preciseness theoretical connectedness heuristic relevance with subcategories intuitive recognition, relationship to the existing body of knowledge and applicability. The categories are the: success of the study mixed-methods design qualitative component quantitative component integration inferences made.
This instrument contains 20 criteria, including the readability of the report, conceptual structure, definition and description of the case, attention paid to the various contexts, presentation of the raw data and possible risks to the individual. The final quality of the studies was based on the total scores of each of the categories or criteria for the case study, with good-quality studies (QI) meeting at least 75% of the total criteria, fair-quality studies (QII) meeting between 50% and 74% of the total criteria and poor-quality studies (QIII) less than 50%. Both authors received formal training in the management, assessment and review of information and conducting reviews. A senior nurse researcher, not involved in the study, had the role of arbitrator in case of disagreement. Lists of publications obtained from the databases were first reviewed to exclude literature reviews, letters to the editor, editorials, clinical reports, dissertations, work published in non-accredited South African journals, discussion papers, comments on research published and grey literature.
Thereafter, full-text papers were used to review the study using the data-extraction sheet. Most (73) were found in Sabinet, 27 in Pubmed, 31 in Web of Science, 21 in CINAHL, 15 in PsycINFO, 14 in Medline and none in OVIDSP (list available on request). Of the 181 publications, 155 were excluded as they either did not meet the inclusion criteria or were duplicated. Most papers (65.4%) were published in journals focusing on research conducted in the South African and African context with two journals publishing 50% of the papers. However, 23.1% of the papers were published in international journals specifically dedicated to cancer. The year 2007 seems to be a defining moment as the first paper co-authored by South African nurses was published outside the borders of Africa, with a further eight published up to 2012 (Table 1). A comparison between the number of papers and prevalence of the specific cancers investigated is presented in Figure 2.
No evidence of work on symptom management could be found and no study investigated any aspect of the family or the care-giver. A total of 30 samples were selected as two studies selected two samples and one study three. Interviews were the most common method of collecting data and were used in 73.1% of the studies.
As indicated in Table 6, most studies (96.2%) did not meet the criteria to be regarded as good quality. Quantitative studies were either descriptive or surveys and no evidence could be found of any study using a calculated sample size, comparison group and control group. The quality of the qualitative work seemed to be better as 77.8% of the studies met at least 50% of the evaluation criteria to be regarded as fair quality. Theoretical connectedness and procedural rigour scored the lowest with relationship to the existing body of knowledge and intuitive recognition the highest. The study provided evidence that 26 papers focusing on cancer nursing were published over a period of 10 years.
When comparing the annual output reported in the current review with the output of other countries included in the worldwide review (Molassiotis et al. In terms of the number of publications per million of the population, South Africa is on a par with the UK, publishing 1.9 papers per million of the population. However, it should be remembered that eight years have passed since the world review and it would be interesting to see how South Africa performs in the next world review. It seems as if this review was the first assessing research output in any specialist field of nursing in South Africa. Country reviews of cancer nursing also seem to be unavailable and not having comparators complicates definite conclusions. When comparing the number of papers included in this review to the total of three included in the worldwide review (Molassiotis et al. 2006:434), it would be quite reasonable to say that oncology nursing research has progressed since the international review. In contrast, when considering the number of public and private cancer care providers, supportive and palliative care services rendered by CANSA, the Hospice and Palliative Association of South Africa and other non-governmental organisations where cancer nurses practise, the research output cannot be justified.
Cancer and subsequently cancer research is not a national priority and the Medical Research Council and other stake holders awards 'extremely low funding' to cancer research (Albrecht 2006:36). Funding reported in this review compared negatively with world trends, where 48.8% of the total (n = 619) reported funding (Molassiotis et al. Cancer nursing research therefore seems to be a mere 'fact-finding' academic exercise not directed toward improving the health outcomes of communities and patients living with cancer, their caregivers and their families. Conducting small-scale research as part of a postgraduate degree in all probability adds to this situation.
In addition, no author was affiliated with a clinical setting and almost all the work derived from academic settings. This is also of great concern and questions the development of cancer nursing as specialist field in the past 10 years as research forms the basis of the development of nursing (Retsas 2000:599). Holyoake (2011) is of the opinion that the gap between the nursing 'elite' and everyday majority is wider than ever. Where the focus of international studies was generic issues of patients with mixed diagnosis (Molassiotis et al. Breast cancer as the most common cancer in females (National Health Laboratory Service 2012) received only limited exposure. Cervical cancer is, however, the most common cancer in Black women (National Health Laboratory Service 2012) and a preventable disease. In addition, the National Department of Health has been focusing on the prevention of cervical cancer with the screening programme introduced in 2000 (Department of Health 2000).
Preventing cervical cancer remains a challenge and it thus seems quite reasonable to focus on this disease. Although childhood cancer is a rare disease affecting approximately 800 to 1500 children annually (CANSA 2013), this field of specialist nursing warrants nursing research.
Work focusing on haematological cancers was also absent and, as non-Hodgkin's lymphoma is one of the most prevalent cancers in both men and women (CANSA 2012), this needs to be investigated. This trend does not concur with world trends where nurses and other health professionals were the participants in half of the studies and nursing issues and nursing roles the most common research focus (Molassiotis et al.
It seems as if South African nurses, in terms of the prevention and early detection of cancer, have no role concerns or confusion as suggested in the world review.
According to Richardson (2004:299), professional isolationism is not conducive to positive patient outcomes and mutual partnerships, valuing and shared working are the only way of improving cancer care.
Research should be conducted using a team approach, involving researchers from a range of disciplines who can investigate problems from diverse perspectives and using a range of methodological approaches. However, international quantitative work included approximately 10% good and 10% fair quality papers, but a higher percentage of poor quality qualitative work as compared with this review.
In addition, international collaborative work could also have been excluded if 'South Africa' was not included in the key words. Despite these limitations, it is still believed that the article provides a fair representation of cancer nursing research conducted in South Africa as the review covers the three South African-based journals publishing nursing research. It seems as if the research investigating this field of cancer care has reached maturity and there is thus an urgent need for more innovative and influential work to find effective solutions to the identified problems.
More studies are needed on the most prevalent cancers like prostate and breast cancer and cancer of an unknown primary site. To join the international drive toward evidence-based practice, symptom management using complex interventions should be the priority of nurses practising in cancer care settings.
This should preferably be done in a programmatic way in collaboration with other members of the multidisciplinary team to ensure that patient problems are addressed in a holistic culturally-sensitive manner. A need for work on symptoms like breathlessness, fatigue, cachexia and depression has been identified internationally (Molassiotis et al. Unique to developing countries is the high prevalence of cervical cancer and problems related to this disease and its treatment, such as sexual functioning and vaginal stenosis, should also be addressed. Lastly, it is essential to combine our efforts with international expertise to build on current evidence to find tailor-made solutions to the problems unique to people living with cancer in a developing country, their caregivers and families. An intervention study in a South African context' European Journal of Cancer Care, 21(1), 78-86. An enquiry into cancer related knowledge, understanding and health seeking behaviour of urban black women in Tshwane, South Africa', European Journal of Oncology Nursing, 14(3), 190-196.
A pilot study in a South African context', European Journal of Oncology Nursing, 15(2), 118-123.

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