09.12.2015

Stage 1 her2 positive breast cancer treatment

SABCS 2015 Susan Mooberry Interview Susan Mooberry discusses her study 'Eribulin affects E-cadherin localization consistent with a reversal of the epithelial-to-mesenchymal transition'. Touch Oncology is for informational purposes and should not be considered medical advice, diagnosis or treatment recommendations. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In accordance of the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the intellectual property Yasar Albushra Abdul Rahiem Ahmed, Mohamed Ali.
All Copyright © 2014 are guarded by law and by SCIRP as a guardian. Recent advances in molecular signaling pathways that are dysregulated in gastric cancer lead to the development of new targeted therapies for the treatment of advanced and metastatic gastric cancer. Findings from recent major clinical trials provide important insight into the future of metastatic gastric cancer management, which may include the use of anti-angiogenesis, Mesenchymal epithelial transition factor (MET) and Hedgehog Pathways Inhibitortherapy across multiple treatment lines, in the salvage setting, and as part of novel regimens in combination with other targeted agents. INTRODUCTION Gastric cancer is a major health problem around the world [1]. In Asian countries where the disease is highly prevalent, screening facilitates early detection, but in Middle East and Western countries, the disease is typically diagnosed at an advanced, incurable stage [1,2].
Chemotherapy remains the treatment of choice for patients who have unresectable locally advanced, locally recurrent, or metastatic gastric cancer and an acceptable performance status [1]. In the United States, 2-drug regimens are generally preferred, although 3-drug regimens can be used to treat medically fit patients who have a good performance status and access to frequent evaluation for toxicity [1]. Despite the availability of a variety of different active regimens, the fatality-to-case ratio remains high [3].
Five-year survival is less than 10%, and median survival time is less than 1 year [4].
Targeted therapy is an attractive approach in this setting due to the limited efficacy of chemotherapy, its proven benefit in other cancers, and the lack of overlapping toxicity between targeted agents and chemotherapy [1].
Currently, one targeted therapy, trastuzumab, is approved for the treatment of advanced human epidermal growth factor receptor (HER)-positive gastric cancer, but others are in late-stage clinical development [5]. Molecular targets and inhibitory agents in advanced gastric cancer. Epidermal Growth Factor Receptor-Directed Therapy EGFR is overexpressed in a subset of gastric cancers, making it an attractive target for therapy. Trials to date, however, have failed to demonstrate clinical benefit associated with the addition of an anti-EGFR monoclonal antibody to first-line chemotherapy [8,9]. Conducted between June 2008 and December 2010, the phase 3 EXPAND trial randomized 904 patients with metastatic or unresectable, locally advanced gastric cancer to chemotherapy (cisplatin plus capecitabine) alone or chemotherapy plus cetuximab [8]. Patients were not selected for study based on tumor EGFR expression or KRAS mutation status, nor were patients with HER2-positive disease excluded. Progression-free survival (PFS), a reasonable primary endpoint at the time EXPAND was designed, was not ultimately prolonged in the cetuximab arm (Table 1).
Overall survival (OS) and overall response rates (ORR) were similar in the treatment arms, and—unlike in metastatic colorectal cancer—the development of an acne-like rash was not associated with prolonged PFS or OS in the cetuximab arm [8]. Based on these results, cetuximab cannot be recommended for use in combination with first-line chemotherapy for advanced or metastatic gastric cancer.
This open-label phase 3 trial randomized 553 patients with cancer of the esophagus, gastroesophageal junction (GEJ), or stomach to chemotherapy (epirubicin, oxaliplatin, capecitabine [EOC]) alone or chemotherapy plus panitumumab.
HER2-Directed Therapy HER2 is expressed in many tissues, including breast, gastrointestinal tract, kidney, and heart [10]. Up to 30% of breast cancers overexpress HER2, and these HER2- Table 1.
The success of trastuzumab, a monoclonal antibody directed against HER2, and other subsequently developed HER2-targeted therapies, has firmly established HER2-positive breast cancer as a distinct clinical entity and serves as a model for targeting HER2 in other cancers when overexpression or amplification is present [10].
There are notable differences in HER2 staining patterns in breast and gastric cancer, however, that necessitate the use of a modified HER2 scoring system for gastric cancer [1].
The modified scoring system has been validated and was used in the pivotal TOGA trial [11]. Pertuzumab is a monoclonal antibody that prevents the dimerization of HER2 with other HER receptors [10].


It was approved in 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive MBC who had not received prior anti-HER2 therapy or chemotherapy for metastatic disease based on the results of a randomized placebo-controlled trial that demonstrated significant prolongation of PFS and OS in the pertuzumab treatment arm [13]. In a HER2-overexpressing gastric cancer human xenograft model, the addition of pertuzumab to trastuzumab resulted in enhanced antitumor activity, and the combination is now in clinical development in advanced gastric cancer [7]. A randomized, double-blind, placebo-controlled trial is underway to determine whether the addition of pertuzumab to standard first-line therapy significantly extends OS for patients with HER2-positive metastatic gastric or GEJ cancer.
Upon binding to HER2, T-DM1 is internalized intact; lysosomal degradation leads to the release of the cytotoxic DM1 moiety inside the HER2-positive cell. T-DM1 was approved in 2013 as a single-agent treatment for patients with HER2- positive MBC who have previously received trastuzumab and a taxane [16]. Dual Targeted Therapy The oral agent lapatinib, which inhibits HER2 and EGFR, Table 3.
Clinical trials of pertuzumab-based and ado-TrastuzumabEmtansine therapy for the treatment of HER2-overexpressing advanced or metastatic gastric cancer.
The phase 3 LOGIC trial randomized 545 patients with HER2-positive advanced or metastatic gastric cancer to chemotherapy (capecitabine and oxaliplatin [CapeOx]) plus lapatinib or chemotherapy plus placebo [19]. Toxicity profiles in the study arms were similar, with the exception of increased diarrhea (overall and grade 3+) and overall skin toxicity in the lapatinibtreated patients [19].
Further analysis is needed to better understand the potential role of lapatinib in the first-line setting. Patients were required to have HER2 amplification by FISH to be eligible for study enrollment. In the overall analysis, combination therapy did not significantly prolong OS (11.0 months vs. ANGIOGENESIS INHIBITORS Angiogenesis, mediated by VEGF through the tyrosine kinase receptors VEGFR-1 and VEGFR-2, is another potential target for the treatment of advanced gastric cancer [21]. VEGF expression is associated with tumor aggressiveness and poor prognosis in gastric cancer, providing a rationale for evaluating angiogenesis inhibitors in this setting [22-24].
Bevacizumab The anti-VEGF monoclonal antibody bevacizumab has demonstrated efficacy in a variety of epithelial carcinomas and was therefore evaluated in the randomized, placebo-controlled, phase 3 AVAGAST trial as a first-line treatment for advanced gastric cancer [21].
It will be critical to validate these biomarkers in prospective clinical trials.
Of the two, plasma VEGF-A level may be the most viable candidate for clinical use once the improved, proprietary ELISA used in AVAGAST becomes widely available; however, additional research is needed to identify an appropriate, reproducible cut-off point to distinguish high and low VEGF levels [26].
The manufacturer of bevacizumab has discussed repeating the AVAGAST trial with biomarker-based stratification and is currently recruiting participants for such a trial [26]. Ramucirumab Ramucirumab, an investigational, fully human monoclonal antibody that targets VEGFR-2, is currently in latestage clinical development for the treatment of gastric cancer, non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, and breast cancer.
In April 2013, its manufacturer received “Fast Track” designation from the FDA to review ramucirumab as a second-line treatment for advanced gastric cancer [27]. Unlike bevacizumab, which targets VEGF directly, ramucirumab targets the extracellular domain of VEGFR-2 [27].
From October 2009 to January 2012, 355 patients were randomized 2:1 to ramucirumab or placebo, given every 2 weeks until disease progression, unacceptable toxicity, or death. Hypertension occurred more commonly in the ramucirumab group than in the placebo group (16.1% vs. Ramucirumab was not associated with higher rates of fatigue, decreased appetite, vomiting, anemia, or other notable toxicities when compared with placebo [28,29]. Both the clinical benefit and rates of grade 3 or higher adverse events associated with ramucirumab treatment appear to compare favorably to the rates associated with second-line chemotherapy reported in other phase 3 trials in this malignancy [22,30]. Historically, the role of second-line therapy in metastatic gastric cancer has been unclear, and the most recent guidelines from the National Comprehensive Cancer Network (NCCN), updated in April 2013, list three preferred second-line options—docetaxel, irinotecan, and paclitaxel—based on low-level evidence that these options are appropriate [1,4,31,32]. Docetaxel is not currently indicated for use in the second-line setting, but the results of COUGAR-2 provide high-level evidence of benefit. Together, REGARD and COUGAR-2 demonstrate that fit patients can benefit from additional therapy upon disease progression.
The comparative effectiveness of ramucirumab and docetaxel remains unknown, but the results of the ongoing, randomized, placebo-controlled RAINBOW trial, which is comparing second-line ramucirumab plus paclitaxel to paclitaxel plus placebo, will provide additional insight into the role of angiogenesis inhibitors in progressive disease [33]. MET PATHWAY INHIBITORS The MET receptor and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes associated with cell proliferation, invasion, and angiogenesis.


Rilotumumab Rilotumumab is an investigational, human monoclonal antibody directed against HGF. An initial analysis presented in 2011 revealed that median PFS was extended in the combined rilotumumab arm relative to placebo (median PFS, 5.6 vs. Patients in the rilotumumab-containing arms experienced a higher incidence of peripheral edema, hematologic toxicities, and thromboembolic events than those in the placebo arm [36].
An updated biomarker analysis presented in 2012 demonstrated differential activity by MET protein expression [37]. A total of 450 patients will be enrolled, and the trial should be completed in 2016 [38].
Onartuzumab Onartuzumab (also known as MetMAb) is a humanized monovalent, or “one-armed”, antibody directed against MET.
The parent antibody from which onartuzumab was derived has agonist activity and, upon binding MET, induces receptor phosphorylation and downstream signaling; however, the monovalent Fab fragment that comprises onartuzumab is devoid of agonist activity and instead acts as an antagonist [39]. Evidence of activity in gastric cancer was seen in the phase 1 clinical trial, in which one patient with chemotherapy-refractory metastatic gastric cancer obtained a durable complete response to onartuzumab that lasted for 2 years [40].
A total of 800 patients with HER2-negative, MET-positive, inoperable metastatic gastric or GEJ adenocarcinoma will be randomized to first-line treatment with mFOLFOX6 and either onartuzumab or placebo.
Enrollment to MetGastric began in late 2012, and the trial should be complete in 2016 [41].
Hedgehog Pathway Inhibitors The hedgehog signaling pathway, which regulates early embryogenesis and the morphogenesis of specific organs and tissues, is increasingly recognized as having a role in carcinogenesis [42]. In mammals, Hh signaling begins when one of three ligands (Sonic hedgehog, Indian hedgehog, Desert hedgehog) binds to the receptor Patched (PTCH1) [43]. In the absence of ligand binding, PTCH1 works to inhibit the action of the protein Smoothened (SMO), but when binding occurs, PTCH1 releases SMO, which initiates a cascade of events that ultimately leads to the expression of Hh target genes [44]. It is under active investigation in other tumor types, including gastric cancer. Although Hh signaling has a variety of effects in the stomach, dysregulated ligand expression appears to have a role in gastric carcinogenesis, and overexpression occurs in gastroesophageal tumors [46,47]. Preliminary results presented at ASCO in 2013 of a randomized phase 2 trial examining the effects of vismodegib in 124 patients with untreated metastatic or locally advanced gastric or GEJ adenocarcinoma suggested no improvement in the primary endpoint of PFS [47]. However, researchers are conducting blood and tissue biomarker analyses to determine whether a subset of patients may benefit from this treatment approach [47].
CONCLUSION Molecular-targeted therapy is changing the treatment of gastric cancer.
The addition of trastuzumab to first-line chemotherapy is now a standard of care for the treatment of HER2-positive advanced or metastatic disease, and other HER2-targeted therapies are in late-stage clinical development. Most patients, however, do not have HER2-positive disease, and other options are needed. To date, EGFR-targeted therapies have not been proved effective in unselected patients, but ongoing biomarker analyses of phase 3 trials may ultimately identify a subgroup that can benefit from these agents. In contrast to first-line bevacizumab-based therapy, the investigational angiogenesis inhibitor ramucirumab has been shown to significantly extend survival in the second-line setting and is currently under FDA review. The MET pathway inhibitors, rilotumumab and onartuzumab, are currently being evaluated in randomized phase 3 trials, with results expected in several years. We disclose no financial and personal relationship with other people or organizations that could inappropriately influence their work. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. 2013 Gastrointestinal Cancers Symposium, San Francisco, 24-26 January 2013.
Annual Review of Cell and Developmental Biology, 27, 513-537.



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