Clin Genet 2014: 86: 37–43 Printed in Singapore. All rights reserved
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12408
Review
Innovative personalized medicine in gastric cancer: time to move forward Lee J., Kim K.-M., Kang W.K., Ou S.-H.I. Innovative personalized medicine in gastric cancer: time to move forward. Clin Genet 2014: 86: 37–43. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Globally, gastric cancer (GC) is the second leading cancer cause of death. To date, only one targeted therapy trial generated positive survival outcomes in a selected population among many targeted therapy trials. This trial showed the addition of trastuzumab to fluoropyrimidine/platinum chemotherapy as first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive GC that resulted in an overall survival (OS) benefit. The increasing use of next generation sequencing approach to genomically profile GC patients allows the identification of many more GC patients who could benefit from specific targeted agents. Here we provide a comprehensive review of targeted therapy trials in GC and discuss future potential actionable driver mutations in GC. Conflict of interest
None declared.
J. Leea , K.-M. Kimb , W.K. Kanga and S.-H.I. Ouc a Department of Medicine, Division of Hematology-Oncology, b Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and c Chao Family Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, 92868-3298, USA
Key words: actionable mutations – chemotherapy – gastric cancer – molecularly targeted agents – personalized medicine Corresponding authors: Sai-Hong Ignatius Ou, MD, PhD, Health Science Associate Professor of Medicine, Chao Family Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Bldg. 23, RT 81, Rm# 241, 101 The City Drive, Orange, CA 92868-3298, USA. Tel.: +714 456 5153; fax: +714 456 2240; e-mail: [email protected] and Jeeyun Lee, MD, PhD, SungKyunKwan University School of Medicine, Samsung Medical Center, Division of Hematology and Oncology, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, South Korea. Tel.: +82 23410 1779; fax: +82 23410 1754; e-mail: [email protected] Received 15 January 2014, revised and accepted for publication 16 April 2014
After lung cancer, gastric cancer (GC) is the leading cause of cancer-related death globally, accounting for 738,000 deaths in 2008 (1). Furthermore, GC is has the fourth highest incidence globally, with 989 600 cases in 2008 (1). To date, the only proven targeted therapy
for a subtype of GC is trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) targeting antibody, in combination with fluoropyrimidine/platinum for HER2-overexpressed GC (2). Many clinical trials have failed to show any survival benefit associated with
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Lee et al. the use of targeted agents in metastatic GC patients. Recently, the addition of ramucirumab, a monoclonal antibody against the vascular endothelial growth factor receptor 2 (VEGFR2), has showed significantly prolonged progression-free survival (PFS) (REGARD) (3) and overall survival (OS) (RAINBOW) (4) raising the hope of further success of targeted therapy in GC.
HER2 overexpression and HER2 amplification: the evidence to date
HER2 is one of the four members of the human epidermal growth factor receptor (HER) family, which comprises HER1 [epidermal growth factor receptor (EGFR)], HER2, HER3, and HER4. The HER family is itself one of the 20 human receptor tyrosine kinase families. Unlike other members of the HER family, HER2 does not contain a ligand binding site and signals through hetero-dimerization with other HER family members, most primarily EGFR (5). The frequency of HER2 amplification in cases of GC ranges from 6 to 23% (2, 6, 7). HER2 amplification was significantly associated with older age, an upper third location, male gender, intestinal type histology (according to the Lauren classification), and a high lymph node stage (8). The Trastuzumab for Gastric Cancer (ToGA) study investigated whether the addition of trastuzumab to conventional 5-fluorouracil (5-FU)/cisplatin-based chemotherapy would significantly improve OS (2). In the ToGA trial, HER2 overexpression was defined as a 3+ positive immunohistochemistry (IHC) or a 2+ positivity with HER2 fluorescence in situ hybridization (FISH), which was specifically defined as (HER2/CEP17 ≥ 2) (2). Of 3665 patients with advanced GC or gastroesophageal junction (GEJ) carcinoma who were screened for HER2 overexpression in the ToGA trial, 810 (22.1%) were positive for HER2 overexpression (2). The HER2-positivity rates were higher for GEJ carcinoma than for GC (33.2 vs 20.9%, respectively; p < 0.001) and higher for intestinal cancer than they were for diffuse and mixed cancers (32.2 vs 6.1% and 20.4%, respectively; p < 0.001). Most importantly, OS was significantly improved from 11.1 to 13.8 months [hazard ratio (HR) = 0.74; 95% CI: 0.60–0.91; p = 0.0045] (5, 7). In a post hoc analysis, significant improvements in OS with trastuzumab were associated with the presence of HER2 IHC 2+/FISH positive or HER2 IHC 3+ [n = 446; HR: 0.65, 95% confident interval (CI): 0.51–0.83] (2). Although the ToGA study was a success, the overall response rate (ORR) while significantly increased from 35% with chemotherapy alone to 47% with the addition of tratuzumab (p = 0.00175), the ORR with trastuzumab plus chemotherapy remained under 50%. Because of the success of the ToGA trial, other HER2 inhibitors have been investigated in similar or second-line settings. Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor (TKI), in combination with capecitabine is associated with significantly better PFS
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than capecitabine alone in the treatment of HER2 overexpressed breast cancer (9). In the TRIO-013/LOGIC (Lapatinib Optimization Study in ErbB2-[HER2]-Positive Gastric Cancer) trial, 545 patients with GC were randomized to receive capecitabine/oxaliplatin (CapeOx) and either daily lapatinib (CapeOx + L) or placebo (CapeOx + P). Unexpectedly, the LOGIC trial failed to show any survival benefit associated with the addition of lapatinib to CapeOX for patients with HER2-amplified GC. Specifically, the HR of CapeOx + L compared with CapeOx + P was 0.91 for OS (95% CI: 0.73–1.12, p = 0.35), and the median OS times were 12.2 and 10.5 months in these two groups, respectively (10). Similarly, the TYTAN (Tykerb with taxol in Asian ErbB2+ gastric cancer) trial also yielded disappointing results, in which lapatinib in combination with paclitaxel was compared with paclitaxel alone as second-line treatment of HER2-amplified (HER2/CEP17 ≥ 2) GC did not improve the median PFS (4.4 vs 5.4 months; HR = 0.85; p = 0.2441) nor the OS (8.9 vs 11.0 months; HR = 0.84; p = 0.2088) (11). TYTAN differed from ToGA in that ToGA included both patients who were positive according to HER2-FISH and patients with positive IHC, whereas TYTAN only enrolled patients with HER2-amplified GC, as determined by FISH alone. Indeed 35% of the enrolled patients who were positive for HER2-amplification by FISH had HER2 IHC results of 0 or 1+. Pre-planned subgroup analysis revealed that median OS among patients in the HER2 IHC 3+ subgroup as 14.0 months with lapatinib and paclitaxel compared with 7.6 months with paclitaxel alone (HR: 0.59; p = 0.0176) indicating HER IHC may be a better companion diagnostic test for HER inhibitors. A phase II trial with dacomitinib (a pan-HER inhibitor) monotherapy as a salvage regimen for patients with HER2-positive GC, the ORR was 7.4% (95% CI, 0–17.5%) and the median PFS was 2.1 months (95% CI, 2.3–3.4 months) (12). Other trials of HER2-targeted agents for GC are summarized in Table 1. In a study of gastric, colorectal, and breast carcinomas, a HER2 mutation was detected in 9 of 180 GCs. All of the mutations were missense mutations in exons 18, 19, or 20, which span the kinase domain of HER2 (13). The OncoMap survey of solid tumors showed HER2 mutations at sites L755S (1.5%) and L777L (0.5%) in GC (14). Whether these mutations represent driver or ‘activating’ mutations remains unclear because their associations with response to trastuzumab and other targeted agents are currently unknown. HER2 overexpression and HER2 amplification: combinatorial approaches and beyond
The failure of TYTAN and LOGIC trials to replicate the success of ToGA trial illustrates the importance of having robust and reliable companion diagnostics for patient selection, i.e. HER2 amplification by FISH or IHC. Furthermore, these trials that failed to show benefit underscore our incomplete understanding of the genetic heterogeneity of HER2-amplified GC, which potentially involves alternate pathway activations of other axes
Innovative personalized medicine Table 1. Clinical trials of HER2-targeted therapy in GC Trial
Type of study/line
Patient selection method
ToGa
Phase III/1st
HER2 IHC
LOGIC
Phase III/1st
HER2 amplification
TYTAN
Phase III/2nd
HER2 amplification
PF299804
Phase II/≥2nd
NCT01228045
Phase II/1st
NCT02015169
Phase II/neoadjuvant Phase II/2nd I/advanced III/1st
HER2 3+ IHC/2+ FISH+ HER2 3+ IHC/2+ FISH+ HER2 3+ IHC HER2 3+ IHC HER2 3+ IHC HER2 3 + IHC
II/2nd
HER2 2+ IHC
NTC01641939
GATSBY
HER2 3+
NCT01522768
II/trastuzumab refractory II/1st
HER2 3+ IHC
II/advanced solid tm II/advanced II/advanced
BYL719/AUY922 JACOB NCT01774786 NCT01774851
NCT01191697 NCT01953926 NCT01522768 NCT01152853
HER2+
Regimen
Response rate
Reference
5-FU/capecitabine + cisplatin ± trastuzumab Lapatinib + XELOX XELOX Paclitaxel + lapatinib Paclitaxel PF299804
47.3 vs 34.5 %
(2) (10)
27 vs 9%
(11)
7.4%
(12)
TS-1/cisplatin + trastuzumab
Ongoing
Lapatinib + XELOX
Ongoing
AUY922 BYL719/AUY922 Pertuzumab + trastuzumab + XP/FP Arm 1a: MM-111/paclitaxel/ trastuzumab Arm 1b: paclitaxel + trastuzumab Arm 2a: MM-111/paclitaxel Arm 2b: paclitaxel Trastuzumab emtansine (T-DM1) versus taxane BIBW2992
Ongoing Ongoing Ongoing
Ongoing Ongoing
HER2 mutations
XELOX/bevacizumab/ trastuzumab Neratinib
Ongoing Ongoing
Nonselected Nonselected
Afatinib Dacomitinib
Ongoing (12)
HER2, human epidermal growth factor receptor; GC, gastric cancer; IHC, immunohistochemistry.
and/or downstream pathway activations. Several investigations of breast cancer have found significant correlations between a poor response to trastuzumab and PTEN loss (15, 16). Moreover, it has been shown that PIK3CA mutations are associated with poorer PFS following trastuzumab therapy in breast cancer (17). In a study of 237 GC tissues using oncomap v4, a cancer panel that interrogates 474 mutations in 41 genes, PIK3CA mutations were the most frequently found mutations (5.1%) (18). A recent investigation found PIK3CA mutations and amplifications in 8 of 113 (7.1%) and 88 of 131 (67%) patients with GC, respectively. Of note, PIK3CA amplification was closely associated with increased phosphorylated Akt (p-AKT) levels and shorter survival in GC (19). The clinical impact of PIK3CA mutations and/or PIK3CA amplifications in GC should be elucidated in patients with GC who are treated with trastuzumab. Another signaling pathway that may be concurrently activated with the HER2 axis is the mesenchymal– epithelial transition (MET) pathway. It has been shown
that activated MET mediates resistance to lapatinib inhibition in HER2-amplified GC cell lines with MET coexpression and, further, that MET inhibition restores the lapatinib inhibition of HER2-amplified GC cells (20). Consistent with these findings, a proteomic analysis of 434 GC tissue specimens showed multiple receptor tyrosine kinases (RTKs) that were co-activated in GCs (21). MET amplification and MET overexpression
The MET receptor belongs to the hepatocyte growth factor receptor (HGFR) family, which also includes RON, and one of 20 human RTK families (22). In a survey of 489 esophagogastric adenocarcinomas, MET amplification was detected in 10 (2%) by FISH (23). In a phase II trial of foretinib (GSK1363089), a multi-targeted TKI (MET, RON, AXL, TIE-2, VEGFR2), in stage IV GC, only three patients (4.5%) of the 69 enrolled patients had MET amplification (MET/CEP7 ≥ 2.0) but none of the three patients responded to foretinib (24). Catenacci and
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Lee et al. colleagues reported one patient with MET 3+ IHC, MET gene polysomy, and high serum HGF level achieved durable complete response for 2 years with a monovalent anti-MET receptor monoclonal antibody, onartuzumab (MetMAb) (25). Currently, a randomized phase III trial is accruing patients to investigate whether the addition of onartuzumab to modified FOLFOX6 chemotherapy in patients with HER2-negative and MET-positive (2+/3+ IHC) GC can significantly improve OS when compared to mFOLFOX6 chemotherapy alone (METGastric, ClinicalTrials.gov identifier: NCT01662869). MET IHC is strongly correlated with mRNA and copy-number gain assessed by quantitative real-time polymerase chain reaction (PCR) and FISH (26, 27). Another ongoing phase III MET targeted ongoing trial comparing epirubicin/cisplatin/capecitabine (ECX) with rilotumumab (a monoclonal antibody against HGF the primary ligand for MET) vs placebo (RILOMET-1; ClinicalTrials.gov identifier : NCT01697072) (28) based on positive results from randomized phase II trial of rilotumumab/ECX in GC with high MET expression (29). Both trial results are eagerly awaited to perhaps once and for all define the clinical utility of inhibiting MET in GC. EGFR amplification and EGFR overexpression
EGFR is another family member of the HER family and is amplified in GC (2.3–7.9%) (23, 30–33). One of the largest screening studies of EGFR overexpression (511 GC samples) used IHC and FISH, EGFR IHC positivity remained a poor prognostic factor (HR = 1.413; 95% CI: 1.063–1.878; p = 0.017) while EGFR FISH positivity was not prognostic for survival (32). Monoclonal antibodies against the EGFR (cetuximab or panitumumab) in combination with chemotherapy have been investigated in two randomized clinical trials in unselected GC patients, the EXPAND trial and the REAL-3 trial (Table 2). In the EXPAND trial, the largest anti-EGFR antibody trial for GC, the addition of cetuximab to capecitabine/cisplatin did not result in any significant prolongation of PFS (HR = 1.09; 95% CI: 0.92–1.29; p = 0.32) or OS (HR = 1.00, 95% CI: 80.8 –1.17; p = 0.95) (34). Similarly, the REAL-3 trial, the median OS was lower in the epirubicin, oxaliplatin, capecitabine (EOC), panitumumab (EOC/P) group (8.8 months) than in the EOC group (11.3 months) (HR = 1.37; 95% C: 1.07–1.76; p = 0.013) (35). Biomarker analyses of the REAL-3 trial,
KRAS mutations, BRAF mutations, PIK3CA mutations, and PTEN expression were not correlated with response to panitumumab (36). Although data on EGFR IHC and EGFR amplification have not been reported, EGFR IHC and EGFR FISH should be evaluated in the REAL-3 and EXPAND trials because these markers were showed to be relevant in the FLEX trial of non-small cell lung cancer (37). Further, in a series of patients receiving cetuximab/5-FU/oxaliplatin/leucovorin chemotherapy, a strong correlation was found between increased EGFR gene copy number and OS following chemotherapy (38). Recently, an interesting pre-clinical study has showed response to cetuximab in all xenografts from patients who had GC with high EGFR mRNA expression levels, high EGFR IHC scores, and 50% of EGFR gene amplification (by FISH) (39). Furthermore, a subgroup analysis of a small phase II randomized trial of irinotecan with or without nimotuzumab (an EGFR monoclonal antibody) as second-line treatment of GC, patients with IHC 2+ or 3+ GC showed better PFS and OS with the addition of nimotuzumab to irinotecan (40). A randomized phase III trial investigating the addition of nimotuzumab to irinotecan as second-line treatment of EGFR IHC 2+/3+ GC is now ongoing (ENRICH trial, ClinicalTrials.gov identifier: NCT01813253). Hopefully, the selection of patients with IHC 2+/3+ GC will identify patients who will benefit from this EGFR monoclonal antibody. With regard to EGFR TKIs, single agent erlotinib showed no activity in unselected chemotherapy refractory GC patients (41). Three EGFR missense mutations (5.2%) have been identified in GC: Y801C, L858R and G863D (42). The clinical relevance of these mutations to drug responsiveness has not been identified, although the L858R mutation is well-established as an EGFR activation mutation in non-small cell lung cancer and is highly sensitive to EGFR TKIs. FGFR2 amplification
Fibroblast growth factor (FGF) receptor family members (FGFR 1–4) belong to the RTK superfamily. Binding of the FGF ligands to FGFR lead to activation of downstream signaling of the phosphoinositide 3-kinase (PI3K)-AKT and mitogen-activated protein kinase–extracellular signal–regulated kinase (MAPK-ERK) pathways (43). The frequency of FGFR2 amplification in GC ranges from 2 to 9%, according
Table 2. Clinical trials of EGFR-targeted therapy in GC Drug/Trial EXPAND/cetuximab REAL-III/panitumumab Nimotuzumab ENRICH (NCT01813253)
Type of study/line (n) III (904)/1st III (553)/1st II/2nd (82) III/2nd
Patient selection method Not selected Not selected Not selected EGFR IHC 2+ or 3+
Regimen
RR
Reference
Cetuximab/XP vs placebo/XP Panitumumab/EOC vs EOC alone Nimotuzumab/irinotecan vs irinotecan Nimotuzumab/irinotecan vs irinotecan
29 vs 30% 46 vs 42%
(34) (35) (40)
Ongoing
DOCOX, docetaxel/oxaliplatin; EGFR, epidermal growth factor receptor; EOC, epirubicin, oxaliplatin, capecitabine; FOLFIRI, 5-FU/irinotecan/leucovorin; FOLFOX, 5-FU/oxaliplatin/leucovorin; FUFIRI, 5-FU/irinotecan; FUFOX, 5-FU/oxaliplatin/leucovorin; GC, gastric cancer; IHC, immunohistochemistry; XP, capecitabine/cisplatin.
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Innovative personalized medicine Table 3. Clinical trials of FGFR-targeted therapy in GC Author/study/ref. NCT01457846 (The SHINE trial) NCT01719549 NCT01921673
Type of study
Year
Molecular agent
Randomized phase II Phase II Phase II
Completed accrual Ongoing Ongoing
AZD4547 Dovitinib Dovitinib plus docetaxel
GC, gastric cancer; FGFR, fibroblast growth factor.
Companion Diagnostics company/Academia
Fig. 1. The optimal clinical research at the era of genomic medicine.
to different reports (30, 44–47). In a large screening study FGFR2 amplification was more common among the Caucasian (7.4%, 30/408) patients, as compared with the Korean (4.2%, 15/356) patients (47). FGFR2 amplification was associated with a diffuse histology among Korean patients. Further, in multivariate analyses, FGFR2 amplification was associated with significantly shorter OS in both the Caucasian (HR = 2.37; 95% CI 1.6–3.5; p = 0.0001) and Korean (HR = 2.33; 95% CI 1.28–4.25; p = 0.0129) cohorts (47). On the basis of encouraging results from pre-clinical in vitro studies and in vivo studies, several FGFR inhibitors are being tested in the context of clinical trials (Table 3). KRAS mutations and amplification
KRAS mutations are known to be negative predictors for response to cetuximab in colorectal cancer. The incidence of KRAS mutations in GC was 4.2% (30 of 712 GCs) in the largest international multicenter study on this topic, which included 278 GCs from the United Kingdom, 230 GCs from Japan, and 204 GCs from Singapore (48). In agreement with other studies, KRAS mutations were more frequently found in tumors of the intestinal type, according to the Lauren classification (49–51). One study has reported a potential relationship between KRAS amplification, the activation of KRAS signaling pathways, and cell growth in GC (52). The addition of MEK inhibitor to chemotherapy has shown to be beneficial in KRAS mutated lung cancer (53) hence this strategy could be potentially employed in GC patients also.
ARID1A mutation
In 2010, next-generation sequencing identified a high frequency of ARID1A mutations in ovarian cancer. Subsequently, whole exome sequencing revealed that 29% of GCs harbor ARID1A mutations (54, 55), which are frequently associated with PIK3CA mutations, Epstein-Barr virus infection, and microsatellite instability (56). ARID1A is a tumor suppressor gene that encodes for BAF250a protein. BAF250a is one of the accessory subunits of the SWI/SNF complex, which contributes to the regulation of gene expression. However there are currently no therapeutic agents that can effectively target ARID1A mutation given ARID1A serves as a tumor suppressor gene. Vascular endothelial growth factor (VEGF) pathway
The AVAGAST phase III trial with bevacizumab with capecitabine/cisplatin showed no clear benefit from the addition of bevacizumab in terms of OS, which was the primary endpoint for the trial (57). Recently, there were some recent successes in targeting VEGF pathway. Ramucirumab is a fully human IgG1 monoclonal antibody VEGFR-2 antagonist that inhibits ligand binding and receptor-mediated pathway activation in endothelial cells (58). The REGARD trial randomized unselected GC patients in a 2:1 ratio to receive ramucirumab (n = 238) or placebo (n = 117) and achieved significant OS benefit with ramucirumab (ramucirumab vs placebo, 5.2 vs 3.8 months, HR 0.776, 95% CI 0.603–0.998; p = 0.047) (3). REGARD trial is an important clinical trial in GC as it showed that VEGFR inhibitor is active in GC. The RAINBOW trial, which compared paclitaxel with or without ramucirumab in second-line chemotherapy, also showed significant prolonged OS in the combination arm with ramucirumab, (4). Future perspectives
Overall, the results from clinical trials of molecularly targeted agents for GC have been largely disappointing. Most of the large phase III trials with unselected GC patients failed to show any survival benefit from targeted agents. Even in trials using selective biomarkers, such as the LOGIC and TYTAN trials, the addition of the targeted agents failed to result in an observable benefit for patients with GC. An open and innovative ‘machinery’ is necessary to closely link pre-clinical models, molecular pathology, and multiplex cancer profiling with clinical trials and could provide rapid answers and allow drugs to be administered to the right patients without
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Lee et al. severe delays (Fig. 1). This research model would be particularly valuable to patients with GC because of the extensive molecular and pathologic heterogeneity that has been found in this disease. As illustrated in Fig. 1, considering that most biomarkers have a low incidence in GC, pharmaceutical companies, companion diagnostics initiatives, and academic research groups need to work in close harmony to achieve to screen for patients with rare genetic aberrations. References 1. Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011: 61: 69–90. 2. Bang YJ, Van Cutsem E, Feyereislova A et al. 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. Lancet 2010: 376: 687–697. 3. Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014: 383: 31–39. 4. Hansjochen WW, Van Cutsem E, Oh SC et al. RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE). J Clin Oncol 2014: 32(suppl 3; abstr LBA7). 5. Ou SH. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. Crit Rev Oncol Hematol 2012: 83: 407–421. 6. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 2008: 19: 1523–1529. 7. Sheng WQ, Huang D, Ying JM et al. HER2 status in gastric cancers: a retrospective analysis from four Chinese representative clinical centers and assessment of its prognostic significance. Ann Oncol 2013: 24: 2360–2364. 8. Cho J, Jeong J, Sung J et al. A large cohort of consecutive patients confirmed frequent HER2 positivity in gastric carcinomas with advanced stages. Ann Surg Oncol 2013: 20 (Suppl 3): S477–S484. 9. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006: 355: 2733–2743. 10. Hecht JR, Bang YJ, Qin S et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): the TRIO-013/LOGiC trial. J Clin Oncol 2013: 31(suppl 34; LBA4001). 11. Bang YJ, Xui R, Taroh S et al. A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer in Asian population: TyTAN study. J Clin Oncol 2012: 30(suppl 34; abstr 11). 12. Oh DY, Lee KW, Cho JY et al. A phase II open-label trial of dacomitinib monotherapy in patients with HER2-positive advanced gastric cancer after failure of at least one prior chemotherapy regimen. J Clin Oncol 2012: 30(suppl 4; abstr 54). 13. Lee JW, Soung YH, Seo SH et al. Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 2006: 12: 57–61. 14. MacConaill LE, Campbell CD, Kehoe SM et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 2009: 4: e7887. 15. Nagata Y, Lan KH, Zhou X et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004: 6: 117–127. 16. Fujita T, Doihara H, Kawasaki K et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 2006: 94: 247–252.
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Innovative personalized medicine 38. Luber B, Deplazes J, Keller G et al. Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). BMC Cancer 2011: 11: 509. 39. Zhang L, Yang J, Cai J et al. A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Sci Rep 2013: 3: 2992. 40. Kim YH, Sasaki Y, Lee KH et al. Randomized phase II study of nimotuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-fluorouracil-based regimen-refractory advanced or recurrent gastric cancer in Korea and Japan: preliminary results. J Clin Oncol 2011: 29(suppl 4; Abstract 87). 41. Dragovich T, McCoy S, Fenoglio-Preiser CM et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol 2006: 24: 4922–4927. 42. Liu Z, Liu L, Li M et al. Epidermal growth factor receptor mutation in gastric cancer. Pathology 2011: 43: 234–238. 43. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract. Int J Oncol 2006: 29: 163–168. 44. Xie L, Su X, Zhang L et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin Cancer Res 2013: 19: 2572–2583. 45. Jung E-J, Jung E-J, Min SY et al. Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma. Hum Pathol 2012: 43: 1559–1566. 46. Matsumoto K, Arao T, Hamaguchi T et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer 2012: 106: 727–732. 47. Su X, Zhan P, Gavine PR et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer 2014: 110: 967–975. 48. van Grieken NCT, Aoyma T, Chambers PA et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency
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© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12408
Review
Innovative personalized medicine in gastric cancer: time to move forward Lee J., Kim K.-M., Kang W.K., Ou S.-H.I. Innovative personalized medicine in gastric cancer: time to move forward. Clin Genet 2014: 86: 37–43. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Globally, gastric cancer (GC) is the second leading cancer cause of death. To date, only one targeted therapy trial generated positive survival outcomes in a selected population among many targeted therapy trials. This trial showed the addition of trastuzumab to fluoropyrimidine/platinum chemotherapy as first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive GC that resulted in an overall survival (OS) benefit. The increasing use of next generation sequencing approach to genomically profile GC patients allows the identification of many more GC patients who could benefit from specific targeted agents. Here we provide a comprehensive review of targeted therapy trials in GC and discuss future potential actionable driver mutations in GC. Conflict of interest
None declared.
J. Leea , K.-M. Kimb , W.K. Kanga and S.-H.I. Ouc a Department of Medicine, Division of Hematology-Oncology, b Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and c Chao Family Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, 92868-3298, USA
Key words: actionable mutations – chemotherapy – gastric cancer – molecularly targeted agents – personalized medicine Corresponding authors: Sai-Hong Ignatius Ou, MD, PhD, Health Science Associate Professor of Medicine, Chao Family Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Bldg. 23, RT 81, Rm# 241, 101 The City Drive, Orange, CA 92868-3298, USA. Tel.: +714 456 5153; fax: +714 456 2240; e-mail: [email protected] and Jeeyun Lee, MD, PhD, SungKyunKwan University School of Medicine, Samsung Medical Center, Division of Hematology and Oncology, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, South Korea. Tel.: +82 23410 1779; fax: +82 23410 1754; e-mail: [email protected] Received 15 January 2014, revised and accepted for publication 16 April 2014
After lung cancer, gastric cancer (GC) is the leading cause of cancer-related death globally, accounting for 738,000 deaths in 2008 (1). Furthermore, GC is has the fourth highest incidence globally, with 989 600 cases in 2008 (1). To date, the only proven targeted therapy
for a subtype of GC is trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) targeting antibody, in combination with fluoropyrimidine/platinum for HER2-overexpressed GC (2). Many clinical trials have failed to show any survival benefit associated with
37
Lee et al. the use of targeted agents in metastatic GC patients. Recently, the addition of ramucirumab, a monoclonal antibody against the vascular endothelial growth factor receptor 2 (VEGFR2), has showed significantly prolonged progression-free survival (PFS) (REGARD) (3) and overall survival (OS) (RAINBOW) (4) raising the hope of further success of targeted therapy in GC.
HER2 overexpression and HER2 amplification: the evidence to date
HER2 is one of the four members of the human epidermal growth factor receptor (HER) family, which comprises HER1 [epidermal growth factor receptor (EGFR)], HER2, HER3, and HER4. The HER family is itself one of the 20 human receptor tyrosine kinase families. Unlike other members of the HER family, HER2 does not contain a ligand binding site and signals through hetero-dimerization with other HER family members, most primarily EGFR (5). The frequency of HER2 amplification in cases of GC ranges from 6 to 23% (2, 6, 7). HER2 amplification was significantly associated with older age, an upper third location, male gender, intestinal type histology (according to the Lauren classification), and a high lymph node stage (8). The Trastuzumab for Gastric Cancer (ToGA) study investigated whether the addition of trastuzumab to conventional 5-fluorouracil (5-FU)/cisplatin-based chemotherapy would significantly improve OS (2). In the ToGA trial, HER2 overexpression was defined as a 3+ positive immunohistochemistry (IHC) or a 2+ positivity with HER2 fluorescence in situ hybridization (FISH), which was specifically defined as (HER2/CEP17 ≥ 2) (2). Of 3665 patients with advanced GC or gastroesophageal junction (GEJ) carcinoma who were screened for HER2 overexpression in the ToGA trial, 810 (22.1%) were positive for HER2 overexpression (2). The HER2-positivity rates were higher for GEJ carcinoma than for GC (33.2 vs 20.9%, respectively; p < 0.001) and higher for intestinal cancer than they were for diffuse and mixed cancers (32.2 vs 6.1% and 20.4%, respectively; p < 0.001). Most importantly, OS was significantly improved from 11.1 to 13.8 months [hazard ratio (HR) = 0.74; 95% CI: 0.60–0.91; p = 0.0045] (5, 7). In a post hoc analysis, significant improvements in OS with trastuzumab were associated with the presence of HER2 IHC 2+/FISH positive or HER2 IHC 3+ [n = 446; HR: 0.65, 95% confident interval (CI): 0.51–0.83] (2). Although the ToGA study was a success, the overall response rate (ORR) while significantly increased from 35% with chemotherapy alone to 47% with the addition of tratuzumab (p = 0.00175), the ORR with trastuzumab plus chemotherapy remained under 50%. Because of the success of the ToGA trial, other HER2 inhibitors have been investigated in similar or second-line settings. Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor (TKI), in combination with capecitabine is associated with significantly better PFS
38
than capecitabine alone in the treatment of HER2 overexpressed breast cancer (9). In the TRIO-013/LOGIC (Lapatinib Optimization Study in ErbB2-[HER2]-Positive Gastric Cancer) trial, 545 patients with GC were randomized to receive capecitabine/oxaliplatin (CapeOx) and either daily lapatinib (CapeOx + L) or placebo (CapeOx + P). Unexpectedly, the LOGIC trial failed to show any survival benefit associated with the addition of lapatinib to CapeOX for patients with HER2-amplified GC. Specifically, the HR of CapeOx + L compared with CapeOx + P was 0.91 for OS (95% CI: 0.73–1.12, p = 0.35), and the median OS times were 12.2 and 10.5 months in these two groups, respectively (10). Similarly, the TYTAN (Tykerb with taxol in Asian ErbB2+ gastric cancer) trial also yielded disappointing results, in which lapatinib in combination with paclitaxel was compared with paclitaxel alone as second-line treatment of HER2-amplified (HER2/CEP17 ≥ 2) GC did not improve the median PFS (4.4 vs 5.4 months; HR = 0.85; p = 0.2441) nor the OS (8.9 vs 11.0 months; HR = 0.84; p = 0.2088) (11). TYTAN differed from ToGA in that ToGA included both patients who were positive according to HER2-FISH and patients with positive IHC, whereas TYTAN only enrolled patients with HER2-amplified GC, as determined by FISH alone. Indeed 35% of the enrolled patients who were positive for HER2-amplification by FISH had HER2 IHC results of 0 or 1+. Pre-planned subgroup analysis revealed that median OS among patients in the HER2 IHC 3+ subgroup as 14.0 months with lapatinib and paclitaxel compared with 7.6 months with paclitaxel alone (HR: 0.59; p = 0.0176) indicating HER IHC may be a better companion diagnostic test for HER inhibitors. A phase II trial with dacomitinib (a pan-HER inhibitor) monotherapy as a salvage regimen for patients with HER2-positive GC, the ORR was 7.4% (95% CI, 0–17.5%) and the median PFS was 2.1 months (95% CI, 2.3–3.4 months) (12). Other trials of HER2-targeted agents for GC are summarized in Table 1. In a study of gastric, colorectal, and breast carcinomas, a HER2 mutation was detected in 9 of 180 GCs. All of the mutations were missense mutations in exons 18, 19, or 20, which span the kinase domain of HER2 (13). The OncoMap survey of solid tumors showed HER2 mutations at sites L755S (1.5%) and L777L (0.5%) in GC (14). Whether these mutations represent driver or ‘activating’ mutations remains unclear because their associations with response to trastuzumab and other targeted agents are currently unknown. HER2 overexpression and HER2 amplification: combinatorial approaches and beyond
The failure of TYTAN and LOGIC trials to replicate the success of ToGA trial illustrates the importance of having robust and reliable companion diagnostics for patient selection, i.e. HER2 amplification by FISH or IHC. Furthermore, these trials that failed to show benefit underscore our incomplete understanding of the genetic heterogeneity of HER2-amplified GC, which potentially involves alternate pathway activations of other axes
Innovative personalized medicine Table 1. Clinical trials of HER2-targeted therapy in GC Trial
Type of study/line
Patient selection method
ToGa
Phase III/1st
HER2 IHC
LOGIC
Phase III/1st
HER2 amplification
TYTAN
Phase III/2nd
HER2 amplification
PF299804
Phase II/≥2nd
NCT01228045
Phase II/1st
NCT02015169
Phase II/neoadjuvant Phase II/2nd I/advanced III/1st
HER2 3+ IHC/2+ FISH+ HER2 3+ IHC/2+ FISH+ HER2 3+ IHC HER2 3+ IHC HER2 3+ IHC HER2 3 + IHC
II/2nd
HER2 2+ IHC
NTC01641939
GATSBY
HER2 3+
NCT01522768
II/trastuzumab refractory II/1st
HER2 3+ IHC
II/advanced solid tm II/advanced II/advanced
BYL719/AUY922 JACOB NCT01774786 NCT01774851
NCT01191697 NCT01953926 NCT01522768 NCT01152853
HER2+
Regimen
Response rate
Reference
5-FU/capecitabine + cisplatin ± trastuzumab Lapatinib + XELOX XELOX Paclitaxel + lapatinib Paclitaxel PF299804
47.3 vs 34.5 %
(2) (10)
27 vs 9%
(11)
7.4%
(12)
TS-1/cisplatin + trastuzumab
Ongoing
Lapatinib + XELOX
Ongoing
AUY922 BYL719/AUY922 Pertuzumab + trastuzumab + XP/FP Arm 1a: MM-111/paclitaxel/ trastuzumab Arm 1b: paclitaxel + trastuzumab Arm 2a: MM-111/paclitaxel Arm 2b: paclitaxel Trastuzumab emtansine (T-DM1) versus taxane BIBW2992
Ongoing Ongoing Ongoing
Ongoing Ongoing
HER2 mutations
XELOX/bevacizumab/ trastuzumab Neratinib
Ongoing Ongoing
Nonselected Nonselected
Afatinib Dacomitinib
Ongoing (12)
HER2, human epidermal growth factor receptor; GC, gastric cancer; IHC, immunohistochemistry.
and/or downstream pathway activations. Several investigations of breast cancer have found significant correlations between a poor response to trastuzumab and PTEN loss (15, 16). Moreover, it has been shown that PIK3CA mutations are associated with poorer PFS following trastuzumab therapy in breast cancer (17). In a study of 237 GC tissues using oncomap v4, a cancer panel that interrogates 474 mutations in 41 genes, PIK3CA mutations were the most frequently found mutations (5.1%) (18). A recent investigation found PIK3CA mutations and amplifications in 8 of 113 (7.1%) and 88 of 131 (67%) patients with GC, respectively. Of note, PIK3CA amplification was closely associated with increased phosphorylated Akt (p-AKT) levels and shorter survival in GC (19). The clinical impact of PIK3CA mutations and/or PIK3CA amplifications in GC should be elucidated in patients with GC who are treated with trastuzumab. Another signaling pathway that may be concurrently activated with the HER2 axis is the mesenchymal– epithelial transition (MET) pathway. It has been shown
that activated MET mediates resistance to lapatinib inhibition in HER2-amplified GC cell lines with MET coexpression and, further, that MET inhibition restores the lapatinib inhibition of HER2-amplified GC cells (20). Consistent with these findings, a proteomic analysis of 434 GC tissue specimens showed multiple receptor tyrosine kinases (RTKs) that were co-activated in GCs (21). MET amplification and MET overexpression
The MET receptor belongs to the hepatocyte growth factor receptor (HGFR) family, which also includes RON, and one of 20 human RTK families (22). In a survey of 489 esophagogastric adenocarcinomas, MET amplification was detected in 10 (2%) by FISH (23). In a phase II trial of foretinib (GSK1363089), a multi-targeted TKI (MET, RON, AXL, TIE-2, VEGFR2), in stage IV GC, only three patients (4.5%) of the 69 enrolled patients had MET amplification (MET/CEP7 ≥ 2.0) but none of the three patients responded to foretinib (24). Catenacci and
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Lee et al. colleagues reported one patient with MET 3+ IHC, MET gene polysomy, and high serum HGF level achieved durable complete response for 2 years with a monovalent anti-MET receptor monoclonal antibody, onartuzumab (MetMAb) (25). Currently, a randomized phase III trial is accruing patients to investigate whether the addition of onartuzumab to modified FOLFOX6 chemotherapy in patients with HER2-negative and MET-positive (2+/3+ IHC) GC can significantly improve OS when compared to mFOLFOX6 chemotherapy alone (METGastric, ClinicalTrials.gov identifier: NCT01662869). MET IHC is strongly correlated with mRNA and copy-number gain assessed by quantitative real-time polymerase chain reaction (PCR) and FISH (26, 27). Another ongoing phase III MET targeted ongoing trial comparing epirubicin/cisplatin/capecitabine (ECX) with rilotumumab (a monoclonal antibody against HGF the primary ligand for MET) vs placebo (RILOMET-1; ClinicalTrials.gov identifier : NCT01697072) (28) based on positive results from randomized phase II trial of rilotumumab/ECX in GC with high MET expression (29). Both trial results are eagerly awaited to perhaps once and for all define the clinical utility of inhibiting MET in GC. EGFR amplification and EGFR overexpression
EGFR is another family member of the HER family and is amplified in GC (2.3–7.9%) (23, 30–33). One of the largest screening studies of EGFR overexpression (511 GC samples) used IHC and FISH, EGFR IHC positivity remained a poor prognostic factor (HR = 1.413; 95% CI: 1.063–1.878; p = 0.017) while EGFR FISH positivity was not prognostic for survival (32). Monoclonal antibodies against the EGFR (cetuximab or panitumumab) in combination with chemotherapy have been investigated in two randomized clinical trials in unselected GC patients, the EXPAND trial and the REAL-3 trial (Table 2). In the EXPAND trial, the largest anti-EGFR antibody trial for GC, the addition of cetuximab to capecitabine/cisplatin did not result in any significant prolongation of PFS (HR = 1.09; 95% CI: 0.92–1.29; p = 0.32) or OS (HR = 1.00, 95% CI: 80.8 –1.17; p = 0.95) (34). Similarly, the REAL-3 trial, the median OS was lower in the epirubicin, oxaliplatin, capecitabine (EOC), panitumumab (EOC/P) group (8.8 months) than in the EOC group (11.3 months) (HR = 1.37; 95% C: 1.07–1.76; p = 0.013) (35). Biomarker analyses of the REAL-3 trial,
KRAS mutations, BRAF mutations, PIK3CA mutations, and PTEN expression were not correlated with response to panitumumab (36). Although data on EGFR IHC and EGFR amplification have not been reported, EGFR IHC and EGFR FISH should be evaluated in the REAL-3 and EXPAND trials because these markers were showed to be relevant in the FLEX trial of non-small cell lung cancer (37). Further, in a series of patients receiving cetuximab/5-FU/oxaliplatin/leucovorin chemotherapy, a strong correlation was found between increased EGFR gene copy number and OS following chemotherapy (38). Recently, an interesting pre-clinical study has showed response to cetuximab in all xenografts from patients who had GC with high EGFR mRNA expression levels, high EGFR IHC scores, and 50% of EGFR gene amplification (by FISH) (39). Furthermore, a subgroup analysis of a small phase II randomized trial of irinotecan with or without nimotuzumab (an EGFR monoclonal antibody) as second-line treatment of GC, patients with IHC 2+ or 3+ GC showed better PFS and OS with the addition of nimotuzumab to irinotecan (40). A randomized phase III trial investigating the addition of nimotuzumab to irinotecan as second-line treatment of EGFR IHC 2+/3+ GC is now ongoing (ENRICH trial, ClinicalTrials.gov identifier: NCT01813253). Hopefully, the selection of patients with IHC 2+/3+ GC will identify patients who will benefit from this EGFR monoclonal antibody. With regard to EGFR TKIs, single agent erlotinib showed no activity in unselected chemotherapy refractory GC patients (41). Three EGFR missense mutations (5.2%) have been identified in GC: Y801C, L858R and G863D (42). The clinical relevance of these mutations to drug responsiveness has not been identified, although the L858R mutation is well-established as an EGFR activation mutation in non-small cell lung cancer and is highly sensitive to EGFR TKIs. FGFR2 amplification
Fibroblast growth factor (FGF) receptor family members (FGFR 1–4) belong to the RTK superfamily. Binding of the FGF ligands to FGFR lead to activation of downstream signaling of the phosphoinositide 3-kinase (PI3K)-AKT and mitogen-activated protein kinase–extracellular signal–regulated kinase (MAPK-ERK) pathways (43). The frequency of FGFR2 amplification in GC ranges from 2 to 9%, according
Table 2. Clinical trials of EGFR-targeted therapy in GC Drug/Trial EXPAND/cetuximab REAL-III/panitumumab Nimotuzumab ENRICH (NCT01813253)
Type of study/line (n) III (904)/1st III (553)/1st II/2nd (82) III/2nd
Patient selection method Not selected Not selected Not selected EGFR IHC 2+ or 3+
Regimen
RR
Reference
Cetuximab/XP vs placebo/XP Panitumumab/EOC vs EOC alone Nimotuzumab/irinotecan vs irinotecan Nimotuzumab/irinotecan vs irinotecan
29 vs 30% 46 vs 42%
(34) (35) (40)
Ongoing
DOCOX, docetaxel/oxaliplatin; EGFR, epidermal growth factor receptor; EOC, epirubicin, oxaliplatin, capecitabine; FOLFIRI, 5-FU/irinotecan/leucovorin; FOLFOX, 5-FU/oxaliplatin/leucovorin; FUFIRI, 5-FU/irinotecan; FUFOX, 5-FU/oxaliplatin/leucovorin; GC, gastric cancer; IHC, immunohistochemistry; XP, capecitabine/cisplatin.
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Innovative personalized medicine Table 3. Clinical trials of FGFR-targeted therapy in GC Author/study/ref. NCT01457846 (The SHINE trial) NCT01719549 NCT01921673
Type of study
Year
Molecular agent
Randomized phase II Phase II Phase II
Completed accrual Ongoing Ongoing
AZD4547 Dovitinib Dovitinib plus docetaxel
GC, gastric cancer; FGFR, fibroblast growth factor.
Companion Diagnostics company/Academia
Fig. 1. The optimal clinical research at the era of genomic medicine.
to different reports (30, 44–47). In a large screening study FGFR2 amplification was more common among the Caucasian (7.4%, 30/408) patients, as compared with the Korean (4.2%, 15/356) patients (47). FGFR2 amplification was associated with a diffuse histology among Korean patients. Further, in multivariate analyses, FGFR2 amplification was associated with significantly shorter OS in both the Caucasian (HR = 2.37; 95% CI 1.6–3.5; p = 0.0001) and Korean (HR = 2.33; 95% CI 1.28–4.25; p = 0.0129) cohorts (47). On the basis of encouraging results from pre-clinical in vitro studies and in vivo studies, several FGFR inhibitors are being tested in the context of clinical trials (Table 3). KRAS mutations and amplification
KRAS mutations are known to be negative predictors for response to cetuximab in colorectal cancer. The incidence of KRAS mutations in GC was 4.2% (30 of 712 GCs) in the largest international multicenter study on this topic, which included 278 GCs from the United Kingdom, 230 GCs from Japan, and 204 GCs from Singapore (48). In agreement with other studies, KRAS mutations were more frequently found in tumors of the intestinal type, according to the Lauren classification (49–51). One study has reported a potential relationship between KRAS amplification, the activation of KRAS signaling pathways, and cell growth in GC (52). The addition of MEK inhibitor to chemotherapy has shown to be beneficial in KRAS mutated lung cancer (53) hence this strategy could be potentially employed in GC patients also.
ARID1A mutation
In 2010, next-generation sequencing identified a high frequency of ARID1A mutations in ovarian cancer. Subsequently, whole exome sequencing revealed that 29% of GCs harbor ARID1A mutations (54, 55), which are frequently associated with PIK3CA mutations, Epstein-Barr virus infection, and microsatellite instability (56). ARID1A is a tumor suppressor gene that encodes for BAF250a protein. BAF250a is one of the accessory subunits of the SWI/SNF complex, which contributes to the regulation of gene expression. However there are currently no therapeutic agents that can effectively target ARID1A mutation given ARID1A serves as a tumor suppressor gene. Vascular endothelial growth factor (VEGF) pathway
The AVAGAST phase III trial with bevacizumab with capecitabine/cisplatin showed no clear benefit from the addition of bevacizumab in terms of OS, which was the primary endpoint for the trial (57). Recently, there were some recent successes in targeting VEGF pathway. Ramucirumab is a fully human IgG1 monoclonal antibody VEGFR-2 antagonist that inhibits ligand binding and receptor-mediated pathway activation in endothelial cells (58). The REGARD trial randomized unselected GC patients in a 2:1 ratio to receive ramucirumab (n = 238) or placebo (n = 117) and achieved significant OS benefit with ramucirumab (ramucirumab vs placebo, 5.2 vs 3.8 months, HR 0.776, 95% CI 0.603–0.998; p = 0.047) (3). REGARD trial is an important clinical trial in GC as it showed that VEGFR inhibitor is active in GC. The RAINBOW trial, which compared paclitaxel with or without ramucirumab in second-line chemotherapy, also showed significant prolonged OS in the combination arm with ramucirumab, (4). Future perspectives
Overall, the results from clinical trials of molecularly targeted agents for GC have been largely disappointing. Most of the large phase III trials with unselected GC patients failed to show any survival benefit from targeted agents. Even in trials using selective biomarkers, such as the LOGIC and TYTAN trials, the addition of the targeted agents failed to result in an observable benefit for patients with GC. An open and innovative ‘machinery’ is necessary to closely link pre-clinical models, molecular pathology, and multiplex cancer profiling with clinical trials and could provide rapid answers and allow drugs to be administered to the right patients without
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Lee et al. severe delays (Fig. 1). This research model would be particularly valuable to patients with GC because of the extensive molecular and pathologic heterogeneity that has been found in this disease. As illustrated in Fig. 1, considering that most biomarkers have a low incidence in GC, pharmaceutical companies, companion diagnostics initiatives, and academic research groups need to work in close harmony to achieve to screen for patients with rare genetic aberrations. References 1. Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011: 61: 69–90. 2. Bang YJ, Van Cutsem E, Feyereislova A et al. 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. Lancet 2010: 376: 687–697. 3. Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014: 383: 31–39. 4. Hansjochen WW, Van Cutsem E, Oh SC et al. RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE). J Clin Oncol 2014: 32(suppl 3; abstr LBA7). 5. Ou SH. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. Crit Rev Oncol Hematol 2012: 83: 407–421. 6. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 2008: 19: 1523–1529. 7. Sheng WQ, Huang D, Ying JM et al. HER2 status in gastric cancers: a retrospective analysis from four Chinese representative clinical centers and assessment of its prognostic significance. Ann Oncol 2013: 24: 2360–2364. 8. Cho J, Jeong J, Sung J et al. A large cohort of consecutive patients confirmed frequent HER2 positivity in gastric carcinomas with advanced stages. Ann Surg Oncol 2013: 20 (Suppl 3): S477–S484. 9. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006: 355: 2733–2743. 10. Hecht JR, Bang YJ, Qin S et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): the TRIO-013/LOGiC trial. J Clin Oncol 2013: 31(suppl 34; LBA4001). 11. Bang YJ, Xui R, Taroh S et al. A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer in Asian population: TyTAN study. J Clin Oncol 2012: 30(suppl 34; abstr 11). 12. Oh DY, Lee KW, Cho JY et al. A phase II open-label trial of dacomitinib monotherapy in patients with HER2-positive advanced gastric cancer after failure of at least one prior chemotherapy regimen. J Clin Oncol 2012: 30(suppl 4; abstr 54). 13. Lee JW, Soung YH, Seo SH et al. Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 2006: 12: 57–61. 14. MacConaill LE, Campbell CD, Kehoe SM et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 2009: 4: e7887. 15. Nagata Y, Lan KH, Zhou X et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004: 6: 117–127. 16. Fujita T, Doihara H, Kawasaki K et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 2006: 94: 247–252.
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