Triple negative breast cancer (TNBC) accounts for 10-20% of cases in breast cancer. Despite recent advances in the treatment of hormonal receptor+ and HER2+ breast cancers, there are no targeted therapies available for TNBC. Evidence supports that most patients with TNBC express the transmembrane Epidermal Growth Factor Receptor (EGFR). However, early phase clinical trials failed to demonstrate significant activity of EGFR-targeted monoclonal antibodies and/or tyrosine kinase inhibitors. Here, we review the recent discoveries related to the underlying biology of the EGFR pathway in TNBC, clinical progress to date and suggest rational future approaches for investigational therapies in TNBC.

BACKGROUND AND PURPOSE: Both stereotactic radiotherapy (SRT) and immune- or targeted therapy play an increasingly important role in personalized treatment of metastatic disease. Concurrent application of both therapies is rapidly expanding in daily clinical practice. In this systematic review we summarize severe toxicity observed after concurrent treatment.
MATERIAL AND METHODS: PubMed and EMBASE databases were searched for English literature published up to April 2016 using keywords "radiosurgery", "local ablative therapy", "gamma knife" and "stereotactic", combined with "bevacizumab", "cetuximab", "crizotinib", "erlotinib", "gefitinib", "ipilimumab", "lapatinib", "sorafenib", "sunitinib", "trastuzumab", "vemurafenib", "PLX4032", "panitumumab", "nivolumab", "pembrolizumab", "alectinib", "ceritinib", "dabrafenib", "trametinib", "BRAF", "TKI", "MEK", "PD1", "EGFR", "CTLA-4" or "ALK". Studies performing SRT during or within 30days of targeted/immunotherapy, reporting severe (⩾Grade 3) toxicity were included.
RESULTS: Concurrent treatment is mostly well tolerated in cranial SRT, but high rates of severe toxicity were observed for the combination with BRAF-inhibitors. The relatively scarce literature on extra-cranial SRT shows a potential risk of increased toxicity when SRT is combined with EGFR-targeting tyrosine kinase inhibitors and bevacizumab, which was not observed for cranial SRT.
CONCLUSIONS: This review gives a best-possible overview of current knowledge and its limitations and underlines the need for a timely generation of stronger evidence in this rapidly expanding field.

BACKGROUND: Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor, is used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the effects of panitumumab in combination with irrinotecan-based chemotherapy remain uncertain. Therefore, we conducted this meta-analysis to assess the efficacy and safety of combination treatment of panitumumab plus chemotherapy in the treatment of mCRC.
METHODS: By searching electronic databases (PubMed, Embase, and Web of Science), all clinical trials which assessed the effects of panitumumab plus irrinotecan-based chemotherapy in mCRC would be included. Main outcome measures included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and adverse events. Pooled estimates were calculated by a fixed-effects model or random-effects model, according to the heterogeneity among the included studies.
RESULTS: Eleven trials with a total number of 1338 patients met the inclusion criteria and were included in this meta-analysis. The combination treatment of panitumumab and irrinotecan-based chemotherapy was associated with a median PFS of 5.83 months, OS of 11.15 months, and ORR of 33%. Subgroup analysis showed that, in the first-line and second-line treatment, the combination therapy for PFS was 9.27 and 5.01 months, for OS was 8.87 and 11.68 months, and for ORR was 61% and 26%, respectively. In the wild-type and mutant KRAS populations, the combination therapy for PFS was 5.76 and 5.27 months, for OS was 11.15 and 10.64 months, and for ORR was 37% and 18%, respectively. Moreover, combination therapy also induced an incidence of 56% treatment-related adverse events.
CONCLUSION: Panitumumab plus irrinotecan-based chemotherapy is effective and well-tolerated in the treatment of patients with mCRC, especially in those with wild-type KRAS tumors.

In metastatic colorectal cancer (mCRC), fluorouracil-based combination therapy with oxaliplatin or irinotecan is the mainstay of first-line treatment. Patient survival has been significantly improved with the introduction of monoclonal antibodies against VEGF (bevacizumab), VEGFR2 (ramucirumab) or EGFR (cetuximab or panitumumab) in first- and second-line therapies. However, all patients treated with chemotherapy and targeted therapies will eventually relapse, and recently the emergence of alterations in EGFR, RAS, BRAF, ERB-B2, MET and possibly in other genes has been shown to jeopardize response to EGFR blockade. In chemorefractory patients, multikinase inhibition with regorafenib has proved to be effective and rechallenge with chemotherapy or anti-EGFR agents is empirically pursued. This review will critically discuss how the evolving knowledge of mechanisms of resistance driven by intratumoural dynamic molecular heterogeneity can impact on rational choice of treatments in this setting.

Recent studies have paid much attention on the safety of bevacizumab as adjuvant chemotherapy for metastatic colorectal cancer. The aim of this meta-analysis was to study the efficacy and safety of bevacizumab in combination with irinotecan, bolus followed by infusional 5-fluorouracil, and leucovorin (FOLFIRI) and, irinotecan, bolus fluorouracil, leucovorin (IFL) for patients with metastatic colorectal cancer (mCRC).An electronic search of related trials was conducted from PubMed, EMBASE, Cochrane Library databases. Risk ratio (RRs) and its 95% confidence intervals (95% CIs) were calculated by using either DerSimonian-Laird method or Mantel-Haenszel method according to the heterogeneity of included articles. The risk of mortality, therapeutic efficacy, and adverse effect were meta-analyzed.In total, 6 RCTs including 2165 participants (1109 in the treatment group, 1056 in the control group) were included in this meta-analysis. Compared with FOLFIRI-panitumumab/cetuximab, the bevacizumab addition significantly reduced the complete response (CR) rate (RR [95%CI] = 0.31[0.11, 0.89], P = 0.03) and the risk of grade 3/4 adverse event (RR [95%CI] = 0.89[0.80, 0.98], P = 0.01). Compared with FOLFIRI and IFL alone, the addition of bevacizumb significantly increased the partial response (PR) and objective response (OR) rates. Compared with IFL alone, the addition of bevacizumb significantly reduced the mortality risk of PFS (RR [95%CI] = 0.53[0.42, 0.66], P < 0.00001) and OS (RR[95%CI] = 0.70[0.60, 0.82], P < 0.00001), but increased the risk of adverse events (RR[95%CI] = 1.14[1.06, 1.21], P = 0.0002).Combination chemotherapy of bevacizumab plus FOLFIRI or IFL had a relative high efficacy and acceptable safety for treatment of mCRC.

Anti-epidermal growth factor receptor (EGFR) therapy has established efficacy in metastatic colorectal cancer, but a significant number of patients do not respond to such treatment. Recently, various biomarkers were reported to be useful in predicting resistance to anti-EGFR. All the potential biomarkers predicting resistance to anti-EGFR are reviewed herein from five aspects. First, upstream molecules, including epiregulin (EREG) and amphiregulin (AREG), might play different roles according to their abnormal levels in tumor tissue and serum. Second, the EGFR amplification and distinct polymorphisms may have roles in identifying patients for initial anti-EGFR mAbs therapy, while rare EGFR mutations have limited predictive values. Third, among the downstream molecularly related factors, rat sarcoma viral oncogene (Ras) has been identified as a successful predictor, while B-Raf proto-oncogene (BRAF) is considered as a prognostic factor rather than a predictor. Fourth, among the molecular bypass pathway components, phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) may be potential biomarkers in the future, while activation of hepatocyte growth factor (HGF)/c-Met signaling confers resistance to anti-EGFR therapy. Fifth, many microRNAs and additional molecular biomarkers are promising in predicting the efficacy of anti-EGFR therapy. Applications of multiple biomarkers are more effective than the use of a single biomarker in selecting patients who might benefit from cetuximab- or panitumumab-based treatments. Comprehensive molecular analyses of the EGFR signaling pathways should be considered in the future. Subsequent prospective trials will be required to further confirm the clinical utility of these biomarkers.

This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second-line chemotherapy for wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first-line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76-1.77], respectively. Progression-free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78-1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor-A (VEGF-A) levels and worse in those with low levels (P for interaction = 0.016). Second-line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.

When deciding how to treat patients with squamous cell carcinoma of the head and neck (SCCHN), several factors have to be taken into account: disease factors, patient factors, treatment factors, and the wish of the patient. This symposium article is summarizing the information on HPV (p16) in the context of decision making in SCCHN patients with locoregionally advanced disease and those with recurrent/metastatic disease. The literature data suggest that HPV(p16) has prognostic significance, both in locoregionally advanced disease (in particular, in oropharynx cancer) and in recurrent/metastatic disease, while there are only limited data on its predictive significance. Results of HPV (p16) testing should not change management outside clinical trials.

BACKGROUND: In metastatic colorectal cancer (mCRC), panitumumab is generally considered to be ineffective after the progression on cetuximab therapy. However, few studies have demonstrated that a small subset of mCRC patients may benefit from panitumumab in this setting.
PATIENTS AND METHODS: In our study, wild-type KRAS mCRC patients, enrolled into the nationwide Czech registry CORECT between January 2007 and December 2012, were screened for panitumumab therapy after progression on cetuximab.
RESULTS: We identified 26 mCRC in the registry with well documented progression on cetuximab in combination with irinotecan-based chemotherapy (FOLFIRI or irinotecan alone) who received panitumumab monotherapy. Partial response (PR) was achieved in 3 (11.5%) patients and stable disease (SD) in 7 (26.9%) patients after 8 weeks of therapy. Thirteen (50.0%) patients had evidence of progressive disease (PD) and in 3 (11.5%) cases response was not available. Furthermore, we confirmed that higher expression levels of newly described biomarker, miR-31-5p, in tumor are significantly associated with shorter progression-free survival (PFS) in patients treated with cetuximab (p=0.038); however, we did not observe association between miR-31-5p and response to panitumumab in mCRC patients after progression on cetuximab.
CONCLUSION: It remains possible that a subset of mCRC patients may benefit from panitumumab after progression on cetuximab.

Monoclonal antibodies binding the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, are widely used targeted therapeutics for the treatment of patients with colorectal cancer. The clinical significance of these drugs has so far been associated with combined chemotherapy or radiation. It has been shown that these treatment strategies have their clinical limitations and do not fully exploit the immunomodulatory effect of these drugs. In this review, we discuss the mechanisms of immunomodulation together with the anticancer immune response to the monoclonal antibodies targeted to the EGFR. The combination of anti-EGFR monoclonal antibodies with other immunotherapeutic treatment modalities certainly brings new opportunities for targeted therapy in patients with colorectal cancer.

BACKGROUND/AIM: Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer (mCRC). However, it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan.
PATIENTS AND METHODS: Data, from 139 patients who received panitumumab or cetuximab, in combination with irinotecan, for KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan were analyzed. The efficacy and safety of panitumumab plus irinotecan was compared to that of cetuximab plus irinotecan.
RESULTS: Baseline characteristics of the panitumumab plus irinotecan (n=42) and cetuximab plus irinotecan (n=97) groups were similar. Among patients with measurable lesions, the response rate was 34% in the panitumumab plus irinotecan group and 20% in the cetuximab plus irinotecan group. Median progression-free survival (PFS) was 4.3 and 5.7 months in the panitumumab and cetuximab groups, respectively. Median overall survival was 13.6 months with panitumumab and 11.2 months with cetuximab.
CONCLUSION: Panitumumab plus irinotecan was well-tolerated and displayed a similar level of efficacy to that of cetuximab plus irinotecan.

PURPOSE: Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy.
METHODS: Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study. All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events.
RESULTS: The incidence rates of hypomagnesemia and acneiform rash were 32.6 % (grade 1: 20.9 %, grade 2: 11.6 %) and 93.0 % (grade 1: 41.9 %, grade 2: 41.9 %, grade 3: 9.3 %), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5 %, P = 0.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash.
CONCLUSION: Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients.

BACKGROUND: The aim of our study was to analyze the possible relationships between treatment efficacy, and germinal gene polymorphisms linked to the irinotecan in combination with bevasizumab or panitumumab and capecitabine or 5-FU that has been routinely used in our practice, in the management of metastatic colorectal cancer (CRC).
MATERIALS AND METHODS: Ninety-four Greek with histologically proven metastatic CRC were included in the study. Treatment was administered until disease progression or unacceptable toxicity, for a maximum of eight cycles. Patients were stratified into stable disease. (SD) and progressive disease. (PD). Associations between clinical data, KRAS, UGT1A1. (UGT1A1*28) and DPD (IVS14+1 G. > A) polymorphisms, and toxicity were analyzed.
RESULTS: Fifty-eight (61.70%) patients were characterized with SD disease and 36 (38.30%) with PD. There were not statistical significant differences between carriers of KRAS mutated alleles between SD and PD groups. No significant difference was found between response rates and toxicity and DPD or UGT1A1 genotypes. Our results suggested that determination of DPD or UGT1A1 genotypes could not be useful for predicting severe toxicity of irinotecan in our population.
CONCLUSIONS: The clinical significance of the findings requires replication in larger populations. Furthermore, as 5.FU and irinotecan metabolism is complex, numerous genes in addition to DPD and UGT1A1 should be investigated.

Colorectal cancer is the second leading cause of cancer death in the United States. At least 50% of patients develop metastases, and most of these patients have unresectable tumors. Treatment options for metastatic colorectal cancer (mCRC) include several lines of chemotherapy, salvage surgery, maintenance therapy, and local therapy. For decades, 5-fluorouracil (5-FU) was the only chemotherapy option for patients with mCRC. This changed markedly over the last decade with the approval of irinotecan, oxaliplatin, capecitabine, humanized monoclonal antibodies that target either vascular endothelial growth factor (bevacizumab, aflibercept, and ramucirumab) or the epidermal growth factor receptor (cetuximab and panitumumab), and, most recently, regorafenib and trifluridine/tipiracil. In this review, we focus on first-line treatments for mCRC. We discuss how results from multiple clinical trials over the last 10 to 20 years confirmed the benefit of adding oxaliplatin and irinotecan to the established 5-FU chemotherapy backbone, and then further defined benefit in certain patient subgroups with the addition of mAbs. Ongoing investigations attempt to illustrate the role of newer molecular and immune therapies in the fight against mCRC. We acknowledge the tremendous advances made in first-line mCRC treatment, admit that we still have a long way to go, and highlight exciting lines of research for patients with mCRC in the burgeoning fields of precision medicine and immunotherapy.

Colorectal cancer (CRC) remains a major public health problem in the United States and worldwide. The majority of patients who have CRC eventually present with metastatic disease. The overall therapeutic goals for most patients with metastatic CRC (mCRC) are to control the disease, prolong life span, and maximize quality of life. Therefore, the ratio of efficacy to toxicity is one of the most important factors in choosing among treatment options and sequencing regimens. In addition, the choice of first-line systemic therapy will affect the options for second-line treatment. Several newer cytotoxic agents for the treatment of mCRC have been approved during the past 2 decades by the US Food and Drug Administration (FDA), including irinotecan, oxaliplatin, and capecitabine. The combination of a fluoropyrimidine (5-fluorouracil or capecitabine) with either oxaliplatin or irinotecan has been widely accepted as standard cytotoxic chemotherapy for either the first- or second-line treatment of mCRC. The FDA has approved several pathway-targeting agents for the treatment of mCRC; these include agents that target the vascular endothelial growth factor receptor pathway (bevacizumab, ziv-aflibercept, and ramucirumab) and those that target the epidermal growth factor receptor pathway (cetuximab and panitumumab). Here, we review the current clinical options for the second-line treatment of mCRC and the rationales for their use.

INTRODUCTION: Monoclonal antibodies such as bevacizumab, ramucirumab, cetuximab and panitumumab play an important role in the treatment of metastatic colorectal cancer (mCRC). With the introduction of these drugs considerable improvements in both progression-free survival (PFS) and overall survival (OS) were achieved. However these antibodies are associated with a unique side effect profile.
AREAS COVERED: This review provides an overview about drug efficacy of bevacizumab, cetuximab, panitumumab and ramucirumab in the treatment algorithm of mCRC. Additionally, we discuss the most common toxicites of these monoclonal antibodies.
EXPERT OPINION: The most common toxicities associated with the VEGF-A directed antibody bevacizumab are hypertension, proteinuria, thromboembolism, bleeding, gastrointestinal perforation and prolonged wound healing. Similarly, the rate of hypertension and proteinuria is increased during treatment with the VEGFR2 antibody ramucirumab. On the other hand the most frequent side effects of EGFR targeted antibodies are skin rash, hypersensitivity reactions and hypomagnesemia. Due to the murine portions of cetuximab the incidence of infusion reactions is more frequent compared to panitumumab which is a pure human monoclonal antibody.

A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). Patients with previously treated, codon 12/13 KRAS wt, mCRC were prospectively administered panitumumab 6 mg/kg IV q2weeks. Of 34 panitumumab-treated patients, 11 (32%) had progressive disease at 8 weeks and were classified as non-responders. A Nanostring nCounter-based assay identified a 5-gene expression signature (ERBB2, MLPH, IRX3, MYRF, and KLK6) associated with panitumumab resistance (P = 0.001). Immunohistochemistry and in situ hybridization determined that the HER2 (ERBB2) protein was overexpressed in 4/11 non-responding and 0/21 responding cases (P = 0.035). Two non-responding tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 KRAS mutation occurred in one panitumumab-resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities. This study identifies a 5-gene signature associated with non-response to single agent panitumumab, including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling. KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis, and the HER2 pathway plays an important role in resistance to therapy.

The drug MM-1151 may overcome resistance to cetuximab and panitumumab caused by some mutations in the extracellular domain of EGFR. The drug slowed disease progression in a colorectal cancer cell line that carried some of the mutations and curbed growth of cells derived from a cetuximab-resistant patient tumor. In a phase I trial, tumors shrank or stabilized in patients who carried the mutations and received the drug.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In the past 2 decades, advances in cancer therapeutics allowed for a remarkable improvement in terms of survival for patients with metastatic CRC. The advent of targeted therapy, coupled with more efficient chemotherapy regimens, was the pillar achievement that contributed to the success of CRC therapy. Cetuximab and panitumumab, monoclonal antibodies targeting the epidermal growth factor receptor pathway, are the focus of this review since their mechanism of action and efficiency are closely related to the mutational status of a predictive biomarker, the Kristen rat Sarcoma viral oncogene (KRAS). More recently, another biomarker, the neuroblastoma rat sarcoma viral oncogene (NRAS), was found to be as valuable for the refinement of this targeted therapy. The arguments for the use of extended analysis of the RAS gene are thoroughly reviewed because they directly affect the choice of targeted agents and potentially the choice of backbone chemotherapy.

BACKGROUND: It is well known that peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is associated with a poor prognosis. However, data on the prognostic significance of modern chemotherapy containing bevacizumab, cetuximab or panitumumab are not available.
MATERIALS AND METHODS: This retrospective review concerned 526 patients with metastatic CRC who were classified into two groups according to the presence or absence of PC, and were treated with systemic chemotherapy, with or without bevacizumab or anti-EGFR antibodies. The genetic background, in particular KRAS, BRAF, and PIK3CA gene mutations, and overall survival (OS) were compared between the two groups.
RESULTS: The median OS values were 23.3 and 29.1 months for PC and non-PC patients, respectively (hazard ratio [HR]=1.20; p=0.17). Among all patients, tumor location, number of metastatic sites and BRAF mutation status were significant prognostic factors, whereas the presence of PC was not. In the PC group, chemotherapy with bevacizumab resulted in a significantly longer OS than forchemotherapy without bevacizumab (HR=0.38, p<0.01), but this was not the case in the non-PC group (HR=0.80, p=0.10). Furthermore, the incidence of the BRAF V600E mutation was significantly higher in PC than in non-PC patients (27.7% versus 7.3%, p<0.01). BRAF mutations displayed a strong correlation with shorter OS in non-PC (HR=2.26), but not PC patients (HR=1.04).
CONCLUSIONS: Systemic chemotherapy, especially when combined with bevacizumab, improved survival in patients with PC from CRC as well as non-PC patients. While BRAF mutation demonstrated a high frequency in PC patients, but it was not associated with prognosis.

BACKGROUND: Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis.
METHODS: Patients received FOLFOXIRI (5-FU, 3,200 mg/m(2), 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m(2) i.v.; irinotecan, 125 mg/m(2); oxaliplatin, 85 mg/m(2) i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate.
RESULTS: Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1-33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all were complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found.
CONCLUSION: KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.

Although the number of elderly patients is increasing each year, this population has been under-represented in clinical trials. At the same time, the survival of patients with metastatic colorectal cancer has been improving, not only because of improvements in chemotherapy, but especially because of the addition of monoclonal antibodies (bevacizumab, cetuximab and panitumumab). Therefore, it is necessary to define the role of these new drugs in the elderly population, a group that is heterogeneous and consists of those who are fit and able to tolerate all therapies equally as well as younger patients and unfit individuals who should only given best supportive care or therapies specifically modulated for them. Today, although data from phase II-III studies have helped to establish the role of bevacizumab in the elderly, few trials have studied anti-epidermal growth factor receptor (EGFR) antibodies in the same population. This review presents the results of studies carried out with anti-EGFR agents, with a hope that more trials will be carried out with these drugs in the elderly in the future.

BACKGROUND: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer.
METHODS: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy.
RESULTS: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively.
CONCLUSIONS: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

The number of molecular biomarkers to inform treatment decisions in patients with metastatic colorectal cancer (mCRC) continues to expand and with it the methodologies that can be employed to evaluate these biomarkers. Beyond standard diagnostic and prognostic biomarkers, such as those used for Lynch syndrome, mutations in KRAS exon 2 are well established as predictive for lack of response to the antiepidermal growth factor receptor therapies panitumumab and cetuximab. Recent studies have extended these findings by demonstrating that mutations in KRAS exons 3 and 4 and in NRAS exons 2, 3, and 4 (with all KRAS and NRAS mutations collectively referred to as RAS) are also predictive for treatment outcomes among patients with mCRC receiving panitumumab and cetuximab in combination with chemotherapy or as monotherapy. Consequently, evaluation of these additional loci has been incorporated into current clinical guidelines, and pathologists will need to develop testing procedures and algorithms to reliably and rapidly evaluate RAS status. With the increased number of mutations that must be examined to evaluate the status of RAS and other emerging biomarkers, next-generation sequencing technologies are likely to become increasingly important in mCRC testing. This review describes new considerations for pathologists that have arisen as a consequence of the incorporation of additional biomarker testing into clinical practice for mCRC.

The anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are used to treat RAS wild-type colorectal cancers (CRCs), but their efficacy is limited by the emergence of acquired drug resistance. After EGFR blockade, about 20% of CRCs develop mutations in the EGFR extracellular domain (ECD) that impair antibody binding and are associated with clinical relapse. We hypothesized that EGFR ECD-resistant variants could be targeted by the recently developed oligoclonal antibody MM-151 that binds multiple regions of the EGFR ECD. MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade. These data provide molecular rationale for the clinical use of MM-151 in patients who become resistant to cetuximab or panitumumab as a result of EGFR ECD mutations.

Anti-EGFR therapy and antiangiogenic therapies are used alone or in combination with chemotherapies to improve survival in metastatic colorectal cancer. However, it is unknown whether pretreatment with antiangiogenic therapy could impact on the efficacy of anti-EGFR therapy. We selected one hundred and twenty eight patients diagnosed with advanced colorectal cancer with a KRAS and NRAS unmutated tumor. These patients were treated with cetuximab or panitumumab alone or with chemotherapy as second or third-line. Univariate and multivariate Cox model analysis were performed to estimate the effect of a previous bevacizumab regimen on progression free survival and on overall survival during anti-EGFR therapy. In vitro studies using wild type KRAS and NRAS colon cancer cells were performed to evaluate the impact of VEGF-A on cetuximab-induced cell death. The median progression free survival (PFS) during anti-EGFR treatment was significantly different between the bevacizumab group and the non-bevacizumab group (2.8 and 4 months respectively; p = 0.003). The median overall survival from the beginning of the metastatic disease was similar in the two groups (41.3 and 42 months respectively; p = 0.7). In vitro, VEGF-A induced a resistance toward cetuximab cytotoxicity on three KRAS and NRAS wild type colon cancer cell lines in a VEGFR2 and Stat-3-dependent manner. All in all, our clinical data, supported by in vitro procedures, suggest that a previous anti-VEGF therapy decreases anti-EGFR efficacy. Although these results are observed in a limited cohort, they could be taken into consideration for a better strategy of care for patient suffering from metastatic colorectal cancer.

Colon cancer is one of the leading causes of cancer death worldwide. Adjuvant chemotherapy following primary surgical treatment is suggested to be beneficial in eradicating invisible disseminated small tumors in colon cancer; however, an effective drug remains to be developed. Recently, we reported a novel drug screening system using a nanoimprinting 3-dimensional (3D) culture that creates multicellular spheroids, which simulate in vivo conditions and, thereby, predict effective drugs in vivo. This study aimed to perform drug selection using our recently developed 3D culture system in a human colon cancer HCT116 cell line stably expressing red fluorescent protein (HCT116-RFP), to determine the most effective agent in a selection of clinically used antitumor agents for colon cancer. In addition, we confirmed the efficacy of the selected drug regorafenib, in vivo using a mouse model of disseminated small tumors. HCT116-RFP cells were cultured using a nanoimprinting 3D culture and in vitro drug selection was performed with 8 clinically used drugs [bevacizumab, capecitabine, cetuximab, 5-fluorouracil (5-FU), irinotecan, oxaliplatin, panitumumab and regorafenib]. An in vivo study was performed in mice bearing HCT116-RFP intraperitoneally disseminated small tumors using 3'-[18F]-fluoro-3'-deoxythymidine-positron emission tomography and fluorescence microscopy imaging to evaluate the therapeutic effects. Regorafenib was determined to be the most effective drug in the 3D culture, and significantly inhibited tumor growth in vivo, compared to the untreated control and 5-FU-treated group. The drug 5-FU is commonly used in colon cancer treatment and was used as a reference. Our results demonstrate that regorafenib is a potentially efficacious adjuvant chemotherapeutic agent for the treatment of disseminated small colon cancer and, therefore, warrants further preclinical and clinical studies.

The curative surgical resection of metastatic disease in patients with stage IV colorectal cancer with a limited tumor burden is standard of care. However, the role for neoadjuvant medical therapy and the ideal composition of that therapy are not established. Several neoadjuvant medical therapies, including standard advanced colorectal cancer chemotherapy regimens-such as folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX); folinic acid, 5-FU, and irinotecan (FOLFIRI); and folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI)-have been evaluated, as has the addition of the biologic agents bevacizumab, panitumumab, and cetuximab. Those patients who are immediate surgical candidates do not seem to benefit from a neoadjuvant medical approach and should proceed directly to surgical resection. Those patients who are not surgical candidates at presentation can in some instances achieve a conversion of disease to a curable state with systemic therapy. Here, we review the studies that have explored different treatment regimens, therapeutic sequencing, and biologic inclusions for the treatment of these patients, with neoadjuvant intent. We also describe how we have established our own treatment paradigm for the management of potentially curable metastatic colorectal cancer.

Colorectal cancer has been a leading cause of cancer-related morbidity and mortality. For the research and individualization of therapy, primary cell lines of the colorectal cancer appear to be still an invaluable tool. We evaluated the differences in metastatic potential between four isolated primary colon cancer cells and cells derived from their lymph node metastasis. These results were compared with correspond immortalized cells-SW480 and SW620, respectively. The ability to migrate was tested using real-time measurement in xCELLigence system. Expressions of molecules involved in adhesion and invasion processes were examined using RT-PCR and western blot analysis. Furthermore, impact of cytotoxic effect of selected chemotherapeutics (irinotecan, oxaliplatin) and biological therapy (bevacizumab, cetuximab, panitumumab) was assessed by the WST assay. As expected, cell lines derived from lymph node migrated more aggressively and higher expression of adhesion molecules ICAM-1, EpCAM, and N-cadherin was detected. The expression of MMP-2 and -9 was elevated, on the other hand, in cell lines derived from primary tumor cancer cells as well as the expression of miR-21, miR-29a, and miR-200a. The most pronounced cytotoxic effect has been recorded with oxaliplatin and irinotecan (IC50 = 48.23 resp. 0.11 μg/ml), especially in cells originating from lymph node metastases. In total, comparison of isolated cell lines and immortalized cell lines has shown many similarities, as well as several differences. Adhesion/invasion molecules and several miRNAs, which play an important role in tumor development and the invasive and migratory behavior, could be a useful therapeutic target in malignant colorectal cancer.

Combination chemotherapy of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) plus panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), is one of the standard treatments for metastatic colorectal cancer (mCRC) without KRAS mutation. A few reports suggested no need of dose adjustment of cetuximab, a similar chimeric anti-EGFR antibody, in patients with renal impairment. However, panitumumab combined with cytotoxic drugs for hemodialysis patients has not been reported. We herein report a case of a hemodialysis mCRC patient successfully treated with mFOLFOX6 and panitumumab combination therapy.