Search

// Xiaojun Jiang 1 , Daniel Pissaloux 1 , Christelle De La Fouchardiere 2 , Francoise Desseigne 2 , Qing Wang 1 , Valery Attignon 1 , Marie-Eve Fondrevelle 5 , Arnaud De La Fouchardiere 5 , Maurice Perol 2 , Philippe Cassier 2 , Christelle Seigne 3 , David Perol 3 , Isabelle Ray-Coquard 2 , Pierre Meeus 4 , Jerome Fayette 2 , Aude Flechon 2 , Axel Le Cesne 7 , Nicolas Penel 6 , Olivier Tredan 2 , Jean-Yves Blay 1, 2 1 Department of Translational Research, Centre Leon Berard, 69008 Lyon France 2 Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France 3 Department of Clinical Research, Centre Leon Berard, 69008 Lyon France 4 Department of Surgery, Centre Leon Berard, 69008 Lyon France 5 Department of Pathobiology, Centre Leon Berard, 69008 Lyon France 6 Department of Medical Oncology, Centre Oscar Lambret, 59020 Lille France 7 Department of Medical Oncology, Gustave Roussy, 94805, Villejuif France Correspondence to: Xiaojun Jiang, e-mail: xiaojun.jiang@lyon.unicancer.fr Jean-Yves Blay, e-mail: jean-yves.blay@lyon.unicancer.fr Keywords: multi-kinase inhibitor, biomarker, regorafenib, chromosomal instability Received: May 06, 2015 Accepted: July 09, 2015 Published: July 21, 2015 ABSTRACT Validated predictive biomarkers for multi-tyrosine kinase inhibitors (MTKI) efficacy are lacking. We hypothesized that interindividual response variability is partially dependent on somatic DNA copy number alterations (SCNAs), particularly those of genes encoding the protein tyrosines targeted by MTKI (called target genes). Genomic alterations were investigated in MTKI responsive and non responsive patients with different histological subtypes included in the ProfiLER protocol (NCT 01774409). From March 2013 to August 2014, 58 patients with advanced cancer treated with one of 7 MTKIs were included in the ProfiLER trial and split into one discovery cohort ( n = 13), and 2 validation cohorts ( n = 12 and 33). An analysis of the copy number alterations of kinase-coding genes for each of 7 MTKIs was conducted. A prediction algorithm (SUMSCAN) based on the presence of specific gene gains (Tumor Target Charge, TTC) and losses (Tumor Target Losses, TTL) was conceived and validated in 2 independent validation cohorts. MTKI sensitive tumors present a characteristic SCNA profile including a global gain profile, and specific gains for target genes while MTKI resistant tumors present the opposite. SUMSCAN favorable patients achieved longer progression-free and overall survival. This work shows that the copy number sum of kinase-coding genes enables the prediction of response of cancer patients to MTKI, opening a novel paradigm for the treatment selection of these patients.

A 30-year-old HIV positive woman presented with a multifocal mass tumour associated with axillary and lateral-cervical lymphadenopathy in the right breast. Laboratory examination of the biopsy confirmed a case of mammary Burkitt’s lymphoma with a nodular infiltration of the breast. Antiretroviral treatment and chemotherapy were effective to control the tumour. Although Burkitt’s lymphoma rarely involves the breasts, it should be considered during routine breast examination of African woman.

International audience; De nouvelles recommandations internationales pour l’évaluation du statut HER2 dans les cancers du sein, basées sur plus de dix ans d’expérience et sur les résultats d’études cliniques et de concordance entre les différentes techniques de détection, viennent tout juste de voir le jour. Le présent article a pour objet de faire le point sur ces nouvelles recommandations, à la lumière de la publication récente du groupe de travail de l’American Society of Clinical Oncology (ASCO) et du Collège des pathologistes américains (CAP), adaptées à la pratique de la pathologie en France et revues par le groupe GEFPICS. À l’ère de la médecine personnalisée, la détermination du statut HER2 reste un élément phare dans le panel des biomarqueurs théranostiques des cancers du sein. Si l’interprétation du statut HER2 dans les cancers du sein est aisée dans la majorité des cas, un certain nombre de situations anatomocliniques est d’interprétation plus délicate, telles que la possibilité rare mais réelle de l’hétérogénéité intra-tumorale du statut de HER2, les formes à différenciation micropapillaire ou la ré-évaluation du statut des biomarqueurs lors de la rechute métastatique. Ces nouvelles recommandations abordent ces différentes questions, reprécisent les conditions pré-analytiques optimales et les critères d’interprétation (notamment des cas 2+), afin de réduire au maximum le risque de faux négatifs. Plus que jamais, la mobilisation de la spécialité d’anatomo-cytopathologie autour de la qualité des tests théranostiques témoigne de son implication dans la chaîne des soins en cancérologie., Summary International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation.]

Because of underestimation, surgical excision is recommended for atypical ductal hyperplasia diagnosed on directional vacuum-assisted biopsies. The following guidelines have been established according to our retrospective study published in 2008: excision for lesions ≥ 21 mm, follow-up for lesions6 mm with complete removal of microcalcifications, and follow-up or excision for 6 to 21-mm lesions with respectively less or2 atypical ductal hyperplasia foci.These guidelines were assessed in a prospective series of 124 patients with a median follow-up of 30 months. Conformity rate was 92%. Upgrading was 28% (15 of 53 patients) for conformed surgery and absent for surgery performed beyond the scope of guidelines. For the patients with benign result at surgery (n = 38) or just followed (n = 61), 3 cancers occurred in either breast at 1 to 3 years.These convenient guidelines can safely spare surgery for a subset of patients. However, annual mammographic follow-up is recommended since the risk of subsequent cancer remains high for both breasts.

Whether mutation status should be used to guide therapy is an important issue in many cancers. We correlated mutation profile in radioiodine-refractory (RAIR) metastatic thyroid cancers (TCs) with patient outcome and response to tyrosine kinase inhibitors (TKIs), and discussed the results with other published data. Outcome in 82 consecutive patients with metastatic RAIR thyroid carcinoma prospectively tested for BRAF, RAS and PI3KCA mutations was retrospectively analyzed, including 55 patients treated with multikinase inhibitors. Papillary thyroid carcinomas (PTCs) were the most frequent histological subtype (54.9 %), followed by poorly differentiated thyroid carcinoma [PDTC] (30.5 %) and follicular thyroid carcinoma [FTC] (14.6 %). A genetic mutation was identified in 23 patients (28 %) and BRAF was the most frequently mutated gene (23 %). Median progression-free survival (PFS) on first-line TKI treatment was 14.6 months (95% CI 9.9–18.4). BRAF mutation positively influenced median PFS, both in the entire TKI-treated cohort (median PFS 34.7 months versus 11.6 months; hazard ratio [HR] 0.29; 95% CI 0.09–0.98; p = 0.03) and in the TKI-treated PTC cohort (n = 22) [log-rank p = 0.086; HR 2.95; 95 % CI 0.81–10.70). However, in TKI-treated patients, PDTC histologic subtype was the only independent prognostic factor for PFS identified in the multivariate analysis (HR 2.36; 95% CI 1.01–5.54; p = 0.048). Patients with BRAF-mutant PTC had a significantly longer PFS than BRAF wild-type when treated with TKIs. However, due to the small number of BRAF-mutant patients, further investigations are required, especially to understand the potential positive effect of BRAF mutations in RAIR TC patients while having a negative prognostic impact in RAI-sensitive PTC patients.

International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation.

Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS' update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers.

International audience; Les tumeurs fixées et incluses en paraffine sont quotidiennement utilisées pour l’évaluation des biomarqueurs nécessaires au traitement des patientes atteintes d’un cancer du sein invasif. Les nouvelles recommandations internationales sur la phase pré-analytique ont été récemment revues, confirmant l’importance de la prise en charge optimale des prélèvements pour garantir des tests d’immunohistochimie ou d’hybridation in situ de qualité, quel que soit le biomarqueur envisagé. Incluant les procédés de fixation et de préparation des tissus, toutes les procédures pré-analytiques doivent être validées, standardisées et tracées. Elles nécessitent la collaboration et la formation de toutes les personnes impliquées dans le circuit du prélèvement, du préleveur jusqu’au technicien de pathologie et au pathologiste en passant par l’infirmière, ou le coursier. La prise en charge initiale optimale des pièces et une fixation de qualité sont des étapes majeures à maîtriser dans la phase pré-analytique. Cette mise à jour des recommandations du groupe d’étude des facteurs pronostiques immunohistochimiques dans le cancer du sein (GEFPICS) détaille et commente les différentes étapes pré-analytiques. L’observation de ces règles de bonne pratique, l’utilisation rigoureuse de témoins internes et externes et la participation régulière à des programmes d’assurance qualité sont autant de garanties pour une évaluation correcte et pérenne des biomarqueurs oncothéranostiques., Summary Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS’ update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers.

586 Background: No evidence exists concerning the superiority of oxaliplatin versus irinotecan-based chemotherapy for metastatic colorectal cancer. The choice is currently made by the clinicians according to awaited toxicity and association with targeted therapy. The correlation between response to chemotherapy (oxaliplatin and irinotecan containing regimens) and genomic alterations was investigated in metastatic colorectal cancer patients included in the ProfiLER protocol (NCT 02029001). Methods: From 03/2013 to 03/2014, 62 patients with metastatic colorectal cancer were included in the ProfiLER trial. Tumor samples were analyzed for mutations/insertions/deletions and copy number variations using target high-throughput sequencing (NGS) and comparative genomic hybridization array (CGH). Clinical data were collected retrospectively. We defined irinotecan and/or oxaliplatin responders as patients having CR, PR, SD as best response and non-responders as those having PD as best response. Results: 50/62 tumor samples fulfilled DNA quality requirements. CGH was feasible in 40 patients (64.5%). Among these 40 patients, 36 received oxaliplatin and irinotecan. None of the genomic alterations correlated to response to oxaliplatin. Conversely, analysis of the CGH and NGS data revealed different genomic alterations of tumors in patients receiving Irinotecan, allowing the separation between Irinotecan responders (IriR, n=27) and non-responders (IriNR, n=9) (Table). Conclusions: Specific genomic alterations of CRC cells seem to be associated with responses to systemic combination Irinotecan based-chemotherapy, including high GI, specific chromosomal gains, and tyrosine kinases mutations. A prospective validation of the CGH profile is planned and definitive results will be presented at the meeting. Clinical trial information: NCT 02029001. [Table: see text]

2621 Background: The ProfiLER study was designed to characterize tumor genomic alterations (GAs) in a panel of selected genes in patients (pts) with advanced malignancies. Whether the presence of G...