Anti-epidermal Growth Factor Receptor Treatment Research Articles

Clinical impact of DNA methylation status on first-line antiepidermal growth factor receptor treatment in patients with metastatic colorectal cancer.

3528 Background: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer. However, there is a lack of consensus of CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. Previously, we reported that genome-wide DNAmethylation statuscould predict the effect of epidermal growth factor receptor (EGFR) inhibitors more accurately than previously reported methylation classifications (Ouchi et al. Cancer Sci 2015). Moreover, we had developed a DNA methylation assay based on MethyLight to reflect genome-wide DNA methylation status and reported its usefulness in predicting prognosis in patients with metastatic colorectal cancer (mCRC) treated with EGFR inhibitors as a third-line chemotherapy (Ouchi et al. Cancer Sci 2022). This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with mCRC treated with first-line EGFR inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment, and analyzed the associations between genome-wide DNA methylation status using a novel comprehensive methylation marker panel and clinical outcomes and evaluated the predictive power and value of the methylation status. Results: Total 169 patients were included in the final analyses. The frequency of highly methylated CRC (HMCC) was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAFV600E mutation (P < 0.001). Patients with HMCC showed worse clinical outcomes than those with low methylated CRC in terms of response rate (P = 0.017), progression-free survival (PFS; P = 0.004), and overall survival (P = 0.019). In the multivariate analysis, peritoneal metastasis (Hazard ratio (HR): 2.24, P = 0.017), methylation status (HR: 3.04, P = 0.037), and BRAFV600E mutations (HR: 5.83, P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status may be an independent predictor of first-line EGFR inhibitors in patients with mCRC.

High sensitivity and rapid detection of KRAS and BRAF gene mutations in colorectal cancer using YbTixOy electrolyte-insulator-semiconductor biosensors

The KRAS and BRAF genes are attractive for a predictive biomarker to determine whether the colorectal cancer (CRC) patient predicts response to anti-epidermal growth factor receptor treatment. The detection of KRAS and BRAF mutation statuses has to be considered as a diagnostic and prognostic factor for the treatment of metastatic CRC patients because the targeted therapy may be expensive as well as toxic. In this work, we develop an YbTixOy electrolyte-insulator-semiconductor (EIS) biosensor to detect the KRAS and BRAF gene mutations in CRC. X-ray diffraction, atomic force microscopy, X-ray photoelectron spectroscopy, and secondary ion mass spectrometry were used to explore the structural features of YbTixOy films prepared under three Ti plasma power conditions. We found that the YbTixOy-based EIS sensor fabricated at the 80 W condition exhibited a higher sensitivity of 69.54 mV/pH (in pH range 2–12), a lower hysteresis voltage of 1 mV (in pH loop of 7→4→7→10→7), and a smaller drift rate of 0.15 mV/h (in pH 7) than those of the other Ti plasma power conditions. Furthermore, we successfully demonstrated that the single strain DNA probe-immobilized YbTixOy EIS biosensors functionalized with 3-aminopropyl triethoxysilane followed by glutaraldehyde were screened for the KRAS and BRAF gene mutations in CRC. High sensitivity and rapid detection of the YbTixOy-based EIS biosensor are expected to serve as the diagnostic tool for clinical examination and screening with CRC.

Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer.

The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patientswith metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. Genome-wide DNA methylation status is an independent factor associated with PFS in patientswith mCRC treated with first-line EGFR inhibitors.

KRAS mutations in patients with colorectal cancer in Libya.

Large prospective clinical trials have demonstrated that colorectal cancers (CRCs) with wild-type KRAS respond favorably to anti-epidermal growth factor receptor treatment, thus making mutational analysis obligatory prior to treatment. In our study, frozen CRC tissues from Libyan patients were analyzed for KRAS and HRAS mutations in codons 12/13 by direct sequencing and the correlations with clinical and pathological parameters were investigated. A total of 34 CRC cases, comprising 19 men and 15 women (age range, 24-87 years), were subjected to systematic analysis for RAS mutations. Although HRAS mutations were not detected in any of the patients in the study group, KRAS codon 12/13 mutations were present in 38.2% (13/34) of the patients. The frequent types of codon 12 mutations were glycine to aspartate (G12D, 46.1%); glycine to valine (G12V, 30.8%) and glycine to cysteine (G12C, 15.4%), while the codon 13 mutations were glycine to aspartate (G13D, 7.7%). G→A mutations occurred in 53.8% (7/13) of the patients, while G→T mutations occurred in 46.2% (6/13) of the patients. Mutations occurred at the first base of codon 12 or 13 in 2/13 (15.4%) and at the second base in 11/13 (84.6%) patients. There was no significant association between clinicopathological characteristics and KRAS mutation status, except the site of the tumors harboring KRAS mutations, which was as follows: The frequency was higher among tumors located in the left colon (8/13, 61.5%) compared to other sites (P=0.027). KRAS mutations were correlated with advanced age, with 10/13 being aged >50 years and affected 8/15 female patients (53%) compared with 5/19 male patients (26%). The highest frequency of KRAS mutations was observed in highly differentiated CRCs (8/13).

Identification of a Clinical Cutoff Value for Multiplex KRASG12/G13 Mutation Detection in Colorectal Adenocarcinoma Patients Using Digital Droplet PCR, and Comparison with Sanger Sequencing and PNA Clamping Assay.

KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is a major predictive marker for anti-epidermal growth factor receptor treatment, and determination of KRAS mutational status is crucial for successful management of colorectal adenocarcinoma. More standardized and accurate methods for testing KRAS mutation, which is vital for therapeutic decision-making, are required. Digital droplet polymerase chain reaction (ddPCR) is an advanced digital PCR technology developed to provide absolute quantitation of target DNA. In this study, we validated the clinical performance of ddPCR in determination of KRAS mutational status, and compared ddPCR results with those obtained by Sanger sequencing and peptide nucleic acid-clamping. Of 81 colorectal adenocarcinoma tissue samples, three repeated sets of KRASG12/G13 mutation were measured by ddPCR, yielding high consistency (ICC = 0.956). Receiver operating characteristic (ROC) curves were constructed to determine KRASG12/G13 mutational status based on mutant allele frequency generated by ddPCR. Using the best threshold cutoff (mutant allele frequency of 7.9%), ddPCR had superior diagnostic sensitivity (100%) and specificity (100%) relative to the two other techniques. Thus, ddPCR is effective for detecting the KRASG12/G13 mutation in colorectal adenocarcinoma tissue samples. By allowing definition of the optimal cutoff, ddPCR represents a potentially useful diagnostic tool that could improve diagnostic sensitivity and specificity.

Use of Bevacizumab for Elderly Patients With Stage IV Colon Cancer: Analysis of SEER-Medicare Data

BackgroundBevacizumab is used for the treatment of metastatic colon cancer in conjunction with first-line chemotherapy. In this study, we examined receipt of first-line bevacizumab and predictors of its use among older patients with stage IV colon cancer. Materials and MethodsWe used data from the Surveillance, Epidemiology, and End Results-Medicare dataset to identify patients with stage IV colon cancer diagnosed from 2005 to 2013 who received FOLFOX (5-fluorouracil/leucovorin/oxaliplatin) or FOLFIRI (5-fluorouracil/leucovorin/irinotecan) as first-line therapy. We used multivariable regression analysis to determine demographic and clinical factors associated with use of concomitant bevacizumab. ResultsWe identified 3785 patients with stage IV colon cancer who met our eligibility criteria. Of these, 2352 (62.1%) received bevacizumab. Bevacizumab use has decreased over time from 68.2% in 2005 to 57.6% in 2013 (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.91-0.97). Patients were less likely to receive bevacizumab if they were older (compared with 65-69 years, ≥ 80 years: OR, 0.64; 95% CI, 0.52-0.80), or had multiple comorbidities (compared with comorbidity score of 0, score of 1: OR, 0.73; 95% CI, 0.60-0.89). ConclusionOver one-half of elderly patients received bevacizumab as part of their first-line therapy for stage IV colon cancer. Bevacizumab use has been slowly decreasing since 2005. Newer anti-epidermal growth factor receptor treatments have not been supplanting bevacizumab, as first-line biologic use in general has also decreased during this time period.

The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased Tcell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.

Common KRAS and NRAS gene mutations in sporadic colorectal cancer in Northeastern Iranian patients

ObjectivesMutation analysis of the Epidermal Growth Factor Receptor downstream has been a main part of colorectal carcinoma evaluation. Large prospective clinical trials have shown only colorectal cancer (CRC) with wild-type KRAS and NRAS responds to anti-Epidermal Growth Factor Receptor treatment. Hence, mutation analysis is necessary prior to treatment. It is essential to conduct studies to learn about the mutation signature of such tumors. The aim of this study was to evaluate the frequency of hotspot mutations in KRAS and NRAS genes in Iranian CRC patients and to explore their correlations with clinicopathologic parameters. MethodsWe detected mutations in exon 2 (codons 12 and 13) of the KRAS and NRAS genes using high resolution melting analysis, Intplex design and Sanger sequencing in 87 Iranian CRC patients. Genomic DNA was isolated from fresh tissue samples of CRC patients. ResultsFrom 87 eligible cases, 51 were male and 36 were females. KRAS mutations in codons 12 and 13 were present in 28.7% of all analyzed CRCs. Our findings suggested that the tumors with KRAS mutations are not with well- and moderately differentiated tumors compared to poorly differentiated tumors (P value = 0.32). The most frequent types of mutations were glycine to aspartate on codon 12 (p.G12D), and glycine to aspartate on codon 13 (p.G13D). No mutation was found in the NRAS gene in our patients. ConclusionsBased on this study, the frequency of KRAS mutations seems to be in the spectrum of frequencies of other countries such as China, Japan, India, USA, France, and Germany and NRAS was similar to the West of Iran.

No Correlation between KRAS Status and Advanced Pancreatic Adenocarcinoma Survival

Erlotinib plus gemcitabine is one of the standard chemotherapies for unresectable pancreatic cancer. Pancreatic cancer has the highest frequency of KRAS gene mutations among human cancers, and some studies suggest that KRAS status might be a predictive biomarker for anti-epidermal growth factor receptor treatment. However, the reliability of this biomarker has not been confirmed. Here, we evaluated the impact of KRAS mutations in pancreatic cancer patients treated with first line gemcitabine-based chemotherapy. 23 patients treated with gemcitabine-based chemotherapy whose KRAS status could be examined from primary or metastatic lesions were enrolled. KRAS mutations were analyzed by sequencing codons 12 and 13. We retrospectively evaluated the correlation between KRAS status, and prognosis and treatment efficacy. Patient characteristics were as follows: median age 68 years, male/female=6/17, PS 0/1=9/14, TNM stage III/IV=1/22, and gemcitabine alone/erlotinib plus gemcitabine=13/10. Among the 23 patients, KRAS codon 12 was mutated in 15, one of whom also had mutation on codon 13. Median progression-free survival (PFS) and overall survival (OS) of all patients were 4.3 months (95% confidence interval (CI): 3.1 to 5.4) and 8.1 months (95% CI: 5.9 to 10.0; events in 96%), respectively. KRAS status showed no association with PFS (p=0.310), OS (p=0.934), or the efficacy of treatment with (p=0.833) or without erlotinib (p=0.478). Thus, in this study, there was no correlation between KRAS status and the efficacy of first line chemotherapy with gemcitabine with or without erlotinib. Identification of a rationale for personalized medicine in pancreatic cancer will require further exploratory prospective studies.

New Targets and New Drug Development in Colorectal Cancer

Despite improvements in clinical outcomes of patients with colorectal cancer (CRC) over the past decades, prognosis remains poor, with a 5-year survival rate of less than 10 %. Fluoropyrimidine-based regimens have defined the standard of care for metastatic disease. However, with the identification of different genetic alterations involved in tumor cell signaling pathways, understanding the molecular pathogenesis of CRC has become of increasing importance in order to select personalized targeted therapies from which patients may potentially benefit. RAS mutations have proven to predict response to anti-epidermal growth factor receptor treatments. Additional hypothetical biomarkers of response, such as BRAF, PI3KCA, and PTEN, are under evaluation in ongoing clinical trials. In this article, we seek to review the recent development of novel drugs aimed to target these molecular aberrations and their impact on metastatic CRC patients.

P-0198 - KRAS Mutations in Colorectal Cancer Patients in Serbia: 5 Years Experience of Central Testing

Introduction: The number of newly diagnosed patients with colorectal cancer (CRC) in Serbia is increasing: from year 1999 when 2893 new CRC cases were diagnosed up to 4180 in 2010. With the appearance of two anti epidermal growth factor receptor (EGFR) targeted antibodies, cetuximab and panitumumab, the era of personalized treatment of metastatic CRC has begun. Mutations of the KRAS gene occur in approximately 35%-45% of colorectal cancers, and about 90% of these mutations are located in codons 12 and 13. Clinical trials have shown that only CRC with wild type (wt) KRAS gene will respond to anti EGFR treatment, whereas no response is observed in CRC with KRAS mutation. Following the approval of cetuximab for wt KRAS CRC patients in 2007, KRAS mutation testing became a part of routine clinical practice in Serbia since 2008. In 2010, Laboratory passed external quality assessment, conducted by QuIP (Quality Initiative in Pathology). Methods: From April 2008 to December 2013, 1292 patients with CRC were tested for presence of KRAS mutations. Formalin-fixed and paraffin-embedded (FFPE) tumor samples from various centers were referred to Laboratory for molecular genetics as central one in Serbia. In 1198 tumor samples, DNA extraction was done by QIAamp®DNA FFPE Tissue kit, whereas in 94 samples DNA was isolated by cobas DNA Isolation kit. The presence of KRAS mutations was analyzed with TheraScreen° KRAS Mutation kit in 901 samples, KRAS StripAssayTM in 194 samples, Therascreen® KRAS RGQ PCR Kit in 103 samples and cobas® KRAS Mutation Test in 94 samples. Results: Of all samples investigated, 543 (42.0%) had KRAS mutations and 749 (58.0%) showed wt KRAS status. The group comprised of 841 (65.1%) men and 451 (34.9%) women. The overall mutation frequency was 42.7% in men and 41.3% in women. The seven most frequent mutations in 1198 patients tested for the presence of mutations in codons 12 and 13, were G12D (41.5%), G12V (20.0%), G12A (8.0%), G12C (7,9%), G12S (4.7%), G12R (2.4%) and G13D (15.5%). In the group of 94 patients, analyzed with cobas® KRAS Mutation Test, it was possible to distinguish only mutations in codons 12/13 from mutations in codon 61. 93.6% of patients had mutations in codons 12/13 and 6.4% showed mutations in codon 61. KRAS testing turnover time was approximately 7 days. Conclusion: KRAS mutation testing was successfully implemented in routine management of patients with colon cancer. Having one central laboratory was proven to be a good choice for a small country as Serbia. Our experience on large group of patients showed that use of commercial Real-Time based diagnostic kits has significantly improved reliability and sensitivity of analysis, and in the same time has shortened testing turnover time. It should be mandatory to include analysis of mutations in codons 61 and 146 in order to select the group of patients that would benefit most from specific treatment. External quality assessment for KRAS testing is needed.

Tissue-based biomarkers predicting outcomes in metastatic colorectal cancer: a review

Although there have been recent advances in the treatment of metastatic colorectal cancer, particularly with systemic chemotherapy, new biological agents and surgical metastasectomy, the disease remains difficult to treat. To personalise the management of mCRC and optimise patient outcomes, it is vital to acquire a deeper understanding of its natural history and mechanisms behind disease progression. This may be achieved by extensive study of tumour biomarkers: proteins or genetic alterations within neoplastic cells or their surrounding stroma that may be used to predict patient outcomes, disease trajectory and response to various therapies. The discovery of mutant Kirsten-RAS in determining patients who may be refractory to anti-epidermal growth factor receptor treatments has reinvigorated and reiterated the importance of our attempts to individualise cancer care. While many biomarkers have been studied and shown promise in the setting of mCRC, they are, with the exception of K-ras testing not used currently in a clinical setting due to conflicting results, small patient samples and methodological variations. Larger, multi-centric studies with uniform methods of tumour marker study are required to effectively tailor systemic therapies and select appropriate candidates for surgical metastasectomy.

Analysis of PTEN, BRAF and PI3K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS

We investigated predictive values of BRAF, PI3K and PTEN in cetuximab responses in KRAS wild-type (+) chemotherapy refractory, metastatic colorectal cancer (CRC) patients. Primary tumour tissues of 41 KRAS wild-type mCRC patients receiving cetuximab-based chemotherapy were investigated for PI3K, PTEN, KRAS and BRAF mutations. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and the Cox proportional hazards model was used. PTEN and PI3K expressions were 63 and 42 %, respectively. BRAF mutation was observed as 9.8 % among patients. Tumours with BRAF mutation had statistically lower response rates (RR) for cetuximab-based treatment than tumours with BRAF wild type (0 vs. 58 %, p = 0.02). PTEN expressing tumours had statistically higher RR for cetuximab-based treatment than tumours with PTEN loss (42 vs. 12 %, p = 0.04). PI3K expression had worse significant effect on cetuximab RR than PI3K non-expressed tumours (15 vs. 44 %, p = 0.023). Median PFS was significantly longer in patients with PTEN expression (14 months) than in patients with PTEN loss (5 months) (HR, 0.4; p = 0.028). Median PFS was significantly longer in patients with PI3K non-expression (15.2 months) than in patients with PI3K expression (4.1 months) (HR, 0.31; p = 0.001). Significant difference in PFS and OS between patients with BRAF mutated and BRAF wild-type tumours was not detected. However, patients with PTEN expression had significantly longer OS (15.1 months) than patients with PTEN loss tumour (9.9 months) (HR, 0.34; p = 0.008). Patients without PI3K expression had significantly longer OS (18.2 months) than patients with PI3K expression (10.1 months) (HR, 0.27; p = 0.001). Multivariate analyses revealed that PTEN expression (HR, 0.48; p = 0.02) and absence of PI3K expression (HR, 0.2; p = 0.001) were independent prognostic factors for increased PFS. Similarly, PTEN overexpression (HR, 0.62; p = 0.03) and absence of PI3K expression (HR, 0.27; p = 0.005) were independent prognostic factors for increased OS. In PTEN loss, PI3K expression may be used as biomarkers to further select KRAS wild-type patients undergoing anti-epidermal growth factor receptor treatment.

Rechallenge With Oxaliplatin and Fluoropyrimidine for Metastatic Colorectal Carcinoma After Prior Therapy

Patients with advanced colorectal cancer (CRC) who have received oxaliplatin, 5-fluoropyrimidine, and irinotecan chemotherapy (with or without bevacizumab) and antiepidermal growth factor receptor therapy (if KRAS is wild type) have no further standard treatment options. Although repeating a prior chemotherapy [in particular, oxaliplatin and fluoropyrimidine (FOX)] is an option, there is very little evidence in the literature for this approach; thus, we reviewed our registry to assess the frequency and outcome of rechallenging with FOX. Patients who had been rechallenged with FOX were identified from the South Australian metastatic CRC database. Patient characteristics were analyzed, and tumor response was retrospectively assessed using Response Evaluation Criteria in Solid Tumors criteria. Twenty patients were eligible for inclusion in this analysis. The number of prior lines of therapy received for metastatic CRC was 4 lines for 2 patients, 3 lines for 6 patients, 2 lines for 7 patients, and 1 line for 3 patients, with 3 patients having received oxaliplatin as adjuvant therapy. Four patients had received bevacizumab previously, 7 patients had undergone antiepidermal growth factor receptor treatment, and 4 patients had undergone liver resection earlier. Response rate was 18%, and 47% had stable disease. The median progression-free survival was 3.7 months, median overall survival was 7.8 months, and 1-year survival was 37%. In this selected population, there is evidence of modest activity of rechallenge with FOX chemotherapy, although radiologic response is uncommon.

Optimal strategies for the treatment of metastatic triple-negative breast cancer with currently approved agents

Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Resistance to current standard therapies such as anthracyclines or taxanes limits the available options for previously treated patients with metastatic TNBC to a small number of non-cross-resistant regimens, and there is currently no preferred standard chemotherapy. Duration of response is usually short, with rapid relapse very common and median survival of just 13 months. The newly approved agent eribulin has shown a survival benefit in patients who had previously been treated with anthracycline- or taxane-containing regimens, including in patients with TNBC. Platinum-based regimens are an emerging option for patients with BRCA1 mutation, and newer targeted agents such as anti-angiogenic treatment with bevacizumab or anti-epidermal growth factor receptor treatment with cetuximab, have shown some benefit in combination therapy. However, there remains an urgent unmet need for improved targeted agents for this patient population. Improved treatment may be facilitated by biomarker-led understanding of subgroup molecular targets, which may predict benefit from currently approved agents, as well as newer targeted drugs.

Radiochemotherapy in Locally Advanced Squamous Cell Carcinomas of the Head and Neck

Squamous cell carcinoma of the head and neck (SCCHN) is a common disease that develops in the upper aerodigestive epithelium. The most important risk factors are tobacco and alcohol consumption. There is also increasing evidence that human papillomavirus plays an important role in the cause of SCCHN. The complex anatomy, the vital functions of the upper aerodigestive tract and the close proximity to vital structures, explain that the goal of treatment is not only to improve survival outcomes, but also to preserve organ function. Radiotherapy and surgery are the standard modalities of treatment, reflecting the locoregional predominance of SCCHN. Chemotherapy plays an important role in the treatment of patients with locoregionally advanced disease, in conjunction with radiotherapy and surgery. Indeed, standard therapy for resectable locoregionally advanced (stage III or IV) SCCHN cancers consists either of surgery and adjuvant chemoradiotherapy or definitive concomitant chemoradiotherapy, depending upon disease site, stage and resectability of the tumour, or institutional experience. Concomitant chemoradiotherapy has been shown in several randomised trials to improve disease-free and overall survival in the postoperative setting for resected disease with poor prognostic factors. Furthermore, multiple randomised studies and meta-analyses have shown that definitive chemoradiotherapy, as well anti-epidermal growth factor receptor treatment in one randomised study, improved disease-free and overall survival when compared with radiotherapy alone. This overview reviews the most relevant published studies on the multidisciplinary management of SCCHN and discusses future strategies to reduce locoregional failures.

The Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer Is Independent of K-ras Mutation Status: Analysis of a Phase III Study of Bevacizumab with Chemotherapy in Previously Untreated Metastatic Colorectal Cancer

Mutations of the K-ras gene were identified as a prognostic marker in metastatic colorectal cancer (mCRC). In addition, emerging data suggest that K-ras mutations are a negative predictor of clinical benefit from anti-epidermal growth factor receptor treatment in mCRC. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab treatment in mCRC is independent of alterations in the Ras/Raf/Mek/Erk pathway. We conducted additional analyses to better describe the clinical benefit of bevacizumab treatment in mCRC relative to K-ras mutation status. Additional statistical analyses were done with data from K-ras mutation analyses in 230 patients who were treated with irinotecan, fluorouracil, and leucovorin (IFL) in combination with either bevacizumab or placebo in a randomized phase III study. Following microdissection, tissue was subject to DNA sequencing to identify K-ras mutations in codons 12 and 13. Hazard ratios for the bevacizumab group relative to the control group were estimated from an unstratified Cox regression model. The median progression-free survival (PFS), OS times, and objective response rates were compared. K-ras status was assessed in 230 patients (28.3%). The median PFS was significantly longer in bevacizumab-treated patients with wild-type (wt)- (13.5 versus 7.4 months; hazard ratio 0.44, p < .0001) and mutant (m)-K-ras (9.3 versus 5.5 months; hazard ratio 0.41, p = .0008). A significantly higher response rate for IFL plus bevacizumab was observed only in wt-K-ras patients (60.0% versus 37.3%, p = .006) compared with 43.2% versus 41.2% in the m-K-ras group. Bevacizumab provides significant clinical benefit in patients with mCRC expressing either mutant or wild-type K-ras.

Cetuximab is an active treatment of metastatic and chemorefractory thymoma

Advanced chemorefractory thymic epithelial tumors still represent a challenge in clinical oncology. A rationale-based therapeutic approach targeting a key pathway should represent the ideal solution in a neoplasm that can over-express Epidermal Growth Factor Receptor (EGFR) in the epithelial component. On the basis of these considerations, two patients with metastatic heavily pretreated disease were evaluated for EGFR expression in the primitive tumor, being considered this data as a basis for an anti EGFR treatment with the monoclonal antibody cetuximab which targets EGFR. A strong EGFR expression was revealed by immunohistochemistry in the two cases considered, thus the patients received cetuximab and reported a partial response as assessed by Computed Tomography (CT), Positron Emission Tomography (PET) and fused PET-CT after three months of therapy. Therefore, both patients are still on therapy. This preliminary experience suggests that cetuximab may be a useful therapeutic choice in advanced pre-treated thymic tumors.