Epidermal growth factor receptor and metastatic colorectal cancer: Insights into target therapies

Colorectal cancer(CRC)has high incidence and mortality worldwide.In 2012,CRC was the second most prevalent cancer among males(9%)and the third among females(8%).In recent decades,standard chemotherapies protocols combining 5-fluorouracil,leucovorin,irinotecan and oxaliplatin were important for improve survival in this set of patients.Further,biological drugs throughout epidermal growth factor receptor(EGFR)pathways showed interesting results in metastatic disease(mCRC)control when in association to standard chemotherapy regimens.Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phaseⅢtrials.This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard.     

Rationally designed treatment for metastatic colorectal cancer:Current drug development strategies

The therapeutic landscape of metastatic colorectal cancer(mCRC)has changed substantially with the emergence of new molecularly targeted agents(MTA)usedas single agents or alongside standard chemotherapy.The use of these MTAs extended the overall survival ofpatients with mCRC to a level that current chemotherapeutics alone could not achieve.In addition,improvement in surgical techniques and ablation modalities offer cure to a limited subset of patients with mCRC andMTAs have been found to have a significant role heretoo,as they aid resectability.However,for the majority of patients,mCRC remains an invariably incurabledisease necessitating continued courses of combinedtreatment modalities.During the course of these treatments,either cytotoxic or biological,cancer cells maintain their ability to acquire mitogenic mutations whichrender them resistant to treatment.Key challengesremain to identify appropriate subsets of patients whowill most likely benefit from these new MTAs and effectively select these based on validated biomarkers.Moreover,better knowledge of the biology of colorectal cancer and the mechanisms via which it bypasses blockade of known signalling pathways will help us design better and more rational sequencing of these treatments,so that we can maximise the survivorship of mCRC patients.This review outlines treatment strategies for known molecular alterations with new MTAs and highlights some promising strategies.     

Personalizing medicine for metastatic colorectal cancer:Current developments

Metastatic colorectal cancer(mCRC)is still one of the tumor types with the highest incidence and mortality.In 2012,colorectal cancer was the second most prevalence cancer among males(9%)and the third among females(8%).In this disease,early diagnosis is important to improve treatment outcomes.However,at the time of diagnosis,about one quarter of patients already have metastases,and overall survival of these patients at 5-years survival is very low.Because of these poor statistics,the development of new drugs against specific targets,including the pathway of angiogenesis,has witnessed a remarkable increase.So,targets therapies through epidermal growth factor and its receptor and also KRAS pathways modulation acquired a main role whether in association with standard chemotherapy and radiotherapy.With the current knowledge in the field of molecular biology,including genetic mutations and polymorphisms,we know better why patients respond so differently to the same treatments.So,in the future we can develop increasingly personalized treatments to the patient and not the disease.This review aims to summarize some molecular pathways and their relation to tumor growth,as well as novel targeted developing drugs and recently approved for mCRC.     

Chemotherapie des metastasierten kolorektalen Karzinoms

Increasing numbers of therapeutic options are becoming available for the systemic treatment of metastasized colorectal cancer (mCRC) which emphasizes the need for strategic decision making and planning across multiple lines of treatment. The choice of first-line therapy is influenced by clinical and molecular characteristics of patients and tumors, such as (K-)RAS gene mutations with respect to therapy guidance of epidermal growth factor receptor (EGFR) antibodies. First-line therapy is the major determinant of subsequent treatment regimens and can therefore be considered as the key decision in patients with mCRC. The German standard for first-line therapy in the majority of patients includes chemotherapy in combination with biological agents, with antibodies targeting EGFR possibly being the preferable option in patients with (K-)RAS wild-type tumors. The development of effective therapeutic strategies in patients with (K-)RAS mutant mCRC tumors must be promoted in the future and requires intensive research because the therapy options for this group of patients are very limited.     

Role of cetuximab in first-line treatment of metastatic colorectal cancer

The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)and vascular endothelial growth factor play an important role in the current treatment of these patients.However,only antibodies directed against EGFR have a predictive marker of response,which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS).Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC.The CRYSTAL study showed that adding cetuximab to FOLFIRI(regimen of irinotecan,infusional fluorouracil and leucovorin)significantly improved results in the first-line treatment of KRAS wildtype mCRC.However,results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory.On the other hand,recent advances in the management of colorectal liver metastases have improved survival in these patients.Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients.In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.     

Targeted therapy in advanced metastatic colorectal cancer: Current concepts and perspectives

The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.     

Treatment of advanced non small cell lung cancer

Lung cancer is the major cause of cancer death in the world. Non Small Cell Lung Cancer (NSCLC) accounts approximately 80-85% of all lung cancer diagnosis; the majority of patients will be diagnosed with non operable, advanced-stage disease. Palliative chemotherapy and/or radiotherapy represent the standard of care of this disease. Platinum based doublets with third generation agents are considered the standard of first line advanced NSCLC treatment. However, data arising from the availability of pemetrexed suggest that histology could play a key role in decision making. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) for therapeutic agents. Bevacizumab is the first recombinant humanized monoclonal antibody (mAb) binding VEGF to demonstrate clinical benefit and a rather survival prolongation in combination with chemotherapy in the treatment of non squamous chemo-naive advanced NSCLC patients. Two types of anti-EGFR targeting agents have reached advanced clinical development: mAbs and small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity (TKIs). Among TKIs gefitinib has been tested in several phase II-III studies showing an improvement in survival and responses in first, second and third line treatment in selected patients with specific clinical and molecular characteristics. Furthermore, erlotinib has showed to significantly improve survival in an unselected population of patients following the failure of one or two chemotherapy regimens. This review will discuss the different therapeutic options for first and second line treatment in the clinical practice.     

Predictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer

Colorectal cancer(CRC)is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide.The treatment of advanced CRC has improved significantly in recent years.With the emergence of two targeted antibodies,cetuximab(Erbitux),an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab(Avastin),a vascular endothelial growth factor monoclonal antibody,the treatment of metastatic CRC has entered the era of personalized therapy.Predictive and prognostic biomarkers have,and will continue to,facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC(mCRC).In this review,we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.     

Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer

Administration of monoclonal antibodies(mAbs)against epidermal growth factor receptor(EGFR)such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer(mCRC).However,the efficacy of these mAbs is limited due to genetic variation among patients,in particular K-ras mutations.The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC.Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF,MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors.Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation,our understanding of their mode of action is limited.Rational drug development based on stringent preclinical data,biomarker validation,and proper selection of patients is of paramount importance in the treatment of mCRC.In this review,we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFRRas-ERK and PI3K signalings.     

Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond

Colorectal cancer(CRC) is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide.Despite advances in therapeutic regimens,the number of patients presenting with metastatic CRC(mCRC) is increasing due to resistance to therapy,conferred by a small population of cancer cells,known as cancer stem cells.Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC.Agents are being developed to target key molecules inv...     

Mechanisms f resistance o anti-EEGFR monoclonal antibody treatment in metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) continues to be counted as a major health problem. The introduction of newer cytotoxics, irinotecan and oxaliplatin, has achieved a significant improvement in survival rates.Novel targeted therapies (bevacizumab, and cetuximab) in combination with most efficient chemotherapy regimens have pushed the median survival beyond the 2-year mark and increased the proportion of patients which could benefit from resection of metastatic lesions.In addition, everal studies have proved that the CRC mutation profiles should influence patient selection or stratification in prospective trials. KRAS mutational status represents a paradigm for biomarker development in the era of molecular targeted herapies. The present article is an overview of the most important studies in the development of biomarkers for the optimization of antiepidermal growth factor receptor (anti-EGFR) treatment in mCRC, beyond KRAS mutations, which is a work in progress. The aim will be to identify molecular markers that might be used to select patients with a higher probability of response to anti-EGFR monoclonal antibodies.Overall the accumulating vidence of the molecular biology of CRC has substantially changed the approach to mCRC treatment and has given clinicians more ational options for treating this illness.     

Treatment options in patients with metastatic gastric cancer:Current status and future perspectives

Despite advances in the treatment of gastric cancer,it remains the world’s second highest cause of cancer death.As gastric cancer is often diagnosed at an advanced stage,systemic chemotherapy is the mainstay of treatment for these patients.However,no standard palliative chemotherapy regimen has been accepted for patients with metastatic gastric cancer.Palliative chemotherapy including fluoropyrimidine,platin compounds,docetaxel and epirubicin prolongs survival,and improves a high quality of life to a greater extent than best supportive care.The number of clinical investigations associated with targeted agents has recently increased.Agents targeting the epidermal growth factor receptor 1 and human epidermal growth factor receptor 2(HER2)have been widely tested.Trastuzumab was the first target drug developed,and pivotal phaseⅢtrials showed improved survival when trastuzumab was integrated into cisplatin/fluoropyrimidine-based chemotherapy in patients with metastatic gastric cancer.Trastuzumab in combination with chemotherapy was thus approved to be a new standard of care for patients with HER2-positive advanced esophagogastric adenocarcinoma.Thus,the evaluation of HER2 status in all patients with metastatic gastroesophageal adenocarcinoma should be considered.Other agents targeting vascular endothelial growth factor,mammalian target of rapamycin,and other biological pathways have also been investigated in clinical trials,but showed little impact on the survival of patients.In this review,systemic chemotherapy and targeted therapies for metastatic gastric cancer in the first-and second-line setting are summarized in the light of recent advances.     

Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial

Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies.This comparative phase II trial (NCT 03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018.     

How to select the optimal treatment for first line metastatic colorectal cancer

Choice of first line treatment for patients with metastatic colorectal cancer(mCRC)is based on tumour and patient related factors and molecular information for determination of individual treatment aim and thus treatment intensity.Recent advances(e.g.,extended RAS testing)enable tailored patient assignment to the most beneficial treatment approach.Besides fluoropyrimidines,irinotecan and oxaliplatin,a broad variety of molecular targeting agents are currently available,e.g.,anti-angiogenic agents(bevacizumab)and epidermal growth factor receptor(EGFR)antibodies(cetuximab,panitumumab)for first line treatment of mCRC.Although some combinations should be avoided(e.g.,oral or bolus fluoropyrimidines,oxaliplatin and EGFR antibodies),treatment options range from single agent to highly effective four-drug regimen.Preliminary data comparing EGFR antibodies and bevacizumab,both with chemotherapy,seem to favour EGFR antibodies in RAS wildtype disease.However,choosing the most appropriate treatment approach for mCRC patients remains a complex issue,with numerous open questions.     

First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer

Purpose  

Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.     

Current approach to relapsed acute lymphoblastic leukemia in children

Recurrent acute lymphoblastic leukaemia(ALL) is a common disease for pediatric oncologists and accounts for more deaths from cancer in children than any other malignancy. Although most patients achieve a second remission, about 50% of relapsed ALL patients do not respond to salvage therapy or suffer a second relapse and most children with relapse die. Treatment must be tailored after relapse of ALL, since outcome will be influenced by well-established prognostic features, including the timing and site of disease recurrence, the disease immunophenotype, and early response to retrieval therapy in terms of minimal residual disease(MRD). After reinduction chemotherapy, high risk(HR) patients are clear candidates for allogeneic stem cell transplantation(SCT) while standard risk patients do better with conventional chemotherapy and local therapy. Early MRD response assessment is currently applied to identify those patients within the more heterogeneous intermediate risk group who should undergo SCT as consolidation therapy. Recent evidence suggests distinct biological mechanisms for early vs late relapse and the recognition of the involvement of certain treatment resistance related genes as well cell cycle regulation and B-cell development genes at relapse, all providing the opportunity to search for novel target therapies.     

Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had...     

Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study

BackgroundMaintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens.MethodsBEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) – but remains unresectable – after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.     

Combined Analysis of EGFR and PTEN Status in Patients With KRAS Wild-Type Metastatic Colorectal Cancer

To determine the relationship between the expression of phosphatase and tensin homologue (PTEN) and epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and the clinical outcome of cetuximab-containing chemotherapy.A total of 158 consecutive mCRC patients with wild-type KRAS status who received chemotherapy with or without cetuximab, and for whom tumor tissue was available, were enrolled. The EGFR and PTEN expression was determined by immunohistochemistry (IHC).A total of 158 mCRC patients with wild-type KRAS status were enrolled in the study; 51 patients received chemotherapy combined with cetuximab, 107 patients received chemotherapy alone. Patients who received chemotherapy combined with cetuximab had longer overall survival (OS) compared with patients who received chemotherapy alone. High EGFR expression was detected in 60 patients (38.0%), while normal PTEN expression was detected in 60 patients (59.5%). The PTEN status was significantly related with the histological grade. For patients who received chemotherapy combined with cetuximab the median OS of patients with high-expression of EGFR was longer than the OS of patients with low EGRF expression; 25.0 versus 19.0 months, P = 0.002. For patient with normal PTEN the median OS were longer than the median OS for patients with loss of PTEN; 24.0 versus 19.0 months, P = 0.026. The overall response rate (ORR) had a borderline association with EGFR and PTEN expression (P = 0.055 and 0.048, respectively). In a multivariate analysis, ECOG PS, EGFR status, chemotherapy ± cetuximab, and the interaction of EGFR or PTEN and chemotherapy ± cetuximab were independent prognostic factors for OS.Our findings show that chemotherapy combined with cetuximab demonstrated encouraging antitumor activity for mCRC patients with wild-type KRAS status. Especially, those who have high EGFR expression or normal PTEN expression were more likely to benefit from such a treatment strategy. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.     

New molecular targeted therapies for advanced non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is a uniformly fatal disease and most patients will present with advanced stage. Treatment outcomes remain unsatisfactory, with low long-term survival rates. Standard treatment, such as palliative chemotherapy and radiotherapy, offers a median survival not exceeding 1 year. Hence, considerable efforts have started to be made in order to identify new biological agents which may safely and effectively be administered to advanced NSCLC patients. Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. However, novel targeted therapies that interfere with other dysregulated pathways in lung cancer are already in the clinic. This review outlines the most promising research approaches to the treatment of NSCLC, discussed according to the specific molecular pathway targeted.