High early growth response 1 (EGR1) expression correlates with resistance to anti-EGFR treatment in vitro and with poorer outcome in metastatic colorectal cancer patients treated with cetuximab

Purpose. Biomarkers, such as mutant RAS, predict resistance to anti-EGFR therapy in only a proportion of patients, and hence, other predictive biomarkers are needed. The aims were to identify candidate genes upregulated in colorectal cancer cell lines resistant to anti-EGFR monoclonal antibody treatment, to knockdown (KD) these genes in the resistant cell lines to determine if sensitivity to anti-EGFR antibody was restored, and finally to perform a pilot correlative study of EGR1 expression and outcomes in a cohort of metastatic colorectal cancer (mCRC) patients given cetuximab therapy. Methods. Comparative expression array analysis of resistant cell lines (SW48, COLO-320DM, and SNU-C1) vs sensitive cell lines (LIM1215, CaCo2, and SW948) was performed. The highest up-regulated gene in each resistant cell line was knocked down (KD) using RNA interference, and effect on proliferation was assessed with and without anti-EGFR treatment. Expression of the candidate genes in patients’ tumours treated with cetuximab was assessed by immunohistochemistry; survival analyses were performed comparing high vs low expression. Results. Genes significantly upregulated in resistant cell lines were EGR1 (early growth response protein 1), HBEGF (heparin-binding epidermal growth factor-like growth factor), and AKT3 (AKT serine/threonine kinase 3). KD of each gene resulted in the respective cells being more sensitive to anti-EGFR treatment, suggesting that the resistant phenotype was reversed. In the pilot study of mCRC patients treated with cetuximab, both median PFS (1.38 months vs 6.79 months; HR 2.77 95% CI 1.2-19.4) and median OS (2.59 months vs 9.82 months; HR 3.0 95% CI 1.3-23.2) were significantly worse for those patients with high EGR1 expression. Conclusion. High EGR1 expression may be a candidate biomarker of resistance to anti-EGFR therapy (AU)

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Urinary circulating DNA detection for dynamic tracking of EGFR mutations for NSCLC patients treated with EGFR-TKIs

Purpose. Changes in EGFR profiles of non small cell lung cancer (NSCLC) patients correlates to clinical outcome. Extracting quality tumor tissue remains a challenge for molecular profiling. Our study aims to ascertain the clinical relevance of urinary cell free DNA as an alternative tumor material source. Methods. 150 patients with activating EGFR mutation and received EGFR-TKIs were recruited to participate in the serial monitoring study. Matched primary tumor samples were taken together with blood and urine specimens before the initiation of TKIs. The EGFR mutation testing was performed and quantified using ddPCR. For serial time point measurements, urine and blood samples were extracted at 1-month intervals for duration of 9 months. Results. Urinary ctDNA yielded a close agreement of 88 % on EGFR mutation status when compared to primary tissue at baseline. Almost all samples detected via urine specimens were uncovered in plasma samples. Analysis of urinary cell free DNA at different time points showed a strong correlation to treatment efficacy. Interestingly, a secondary EGFR mutation T790M was detected for 53 % of the patients during monitoring. The results were corroborated with the plasma ctDNA analysis. The T790M+ group had a reduced median survival when compared to the wildtype group. Conclusion. Urinary cell free DNA may be a potential alternative to conventional primary tissue based EGFR mutation testing. Our findings showed that the assay sensitivity was comparable to results from blood plasma. Urinary samples being noninvasive and readily available have clinical utility for monitoring of EGFR TKI treatment (AU)

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Recomendaciones para la determinación de mutaciones de K-RAS en cáncer de colon / Guideliness for kras gene mutations testing in colorrectal cancer

Las determinaciones de mutaciones en el gen KRAS en el cáncer colorrectal en España se han venido realizando de manera sistemática en relativamente pocos centros, o bien se han realizado en un contexto de ensayo clínico. No obstante, gracias a la implementación de nuevas herramientas terapéuticas basadas en anticuerpos monoclonales frente al EGFR, el conocimiento del estado mutacional de KRAS es hoy en día un factor clave para la toma de decisiones terapéuticas debido a su valor predictivo negativo de respuesta al uso de dichos tratamientos. Este hecho ha potenciado la necesidad de la implementación de dichas determinaciones en la mayoría de los servicios de Anatomía Patológica de una manera estandarizada dentro de la práctica asistencial. Esta revisión propone una serie de recomendaciones generales con el fin de estandarizar la determinación de las mutaciones de KRAS, exponiendo los diferentes métodos técnicos disponibles, sus características y los aspectos clínicos relacionados, que serán de interés a la hora de incorporar dichas determinaciones en la rutina asistencial(AU)

Various centres in Spain systematically perform mutational status analyses of KRAS in colorectal cancer, some of which are related to various clinical trials. However, in the light of the use of anti-EGFR monoclonal antibodies in the treatment of colorectal cancer, the predictive value of KRAS has become a key factor in therapeutic decision making. Thus there is a growing necessity for the implantation of a standardized method of KRAS mutation analysis in the majority of pathology laboratories. The characteristics and associated clinical aspects of the different techniques available are reviewed and general recommendations for the standardization of KRAS mutation analysis are proposed(AU)

Assessment of c-erbB 3 and c-erbB 4 expression in breast cancer patients and correlation with clinicopathological parameters

Objetive: ErbB Receptor Tyrosine Kinases possess an establishedrole in mammary gland development and breast tumorigenesis.We aimed to assess the expression of c-erbB3and c-erbB4 RTKs in early breast carcinomas and investigateits possible correlation with Estrogen or Progesterone Receptors,tumor stage and grade, disease recurrence and patient’soutcome.Patients and methods: Forty-nine specimens of earlybreast carcinomas deriving from patients that had sustainedpartial or total mastectomy with axillary lymph node resectionwere studied retrospectively. Expression of RTKs was detectedimplementing: a) an anti-HER-3 mouse polyclonal antibody;and b) an anti-HER-4 mouse polyclonal antibody. For both cerbB3and c-erbB4, either a cytoplasmic or a nuclear stainingpattern of tumor cells was considered positive.Results: Expression of c-erbB4 exhibited statistically significantassociation with tumor grade and unfavorable patient’soutcome. C-erbB3 expression did not correlate with tumorrecurrence or patient’s outcome.No association was established between the expression ofboth RTKs and that of Estrogen or Progesterone Receptors.C-erbB4 expression did not posess statistically significant associationwith patient’s death or disease recurrence. C-erbB3 expressiondid not correlate with tumor grade or recurrence andpatient’s death.Conclusions: In the context of compound molecularmechanisms, alterations in c-erbB3 and c-erbB4 expressionmerit appraisal as future interventions in breast cancer treatmen (AU)

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Cell signalling: growth factors and tyrosine kinase receptors

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Estudio de la concentración del receptor del factor de crecimiento epidérmico (EGFR) en adenocarcinomas de pulmón. Asociación con altos niveles de proteína oncogénica erbB2 / Study of epidermal growth factor receptor concentration (EGFR) in lung adenocarcinomas. Association with high erb-B2 oncogenic protein levels

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