Stéphane Vignot

Next-Generation Sequencing Reveals High Concordance of Recurrent Somatic Alterations Between Primary Tumor and Metastases From Patients With Non–Small-Cell Lung Cancer

PURPOSE Characterization of the genomic changes that drive an individual patients disease is critical in management of many cancers. In patients with non-small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases. PATIENTS AND METHODS Primary and matched metastatic tumor pairs from 15 patients were analyzed by using a targeted next-generation sequencing assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. RESULTS Among 30 tumors, 311 genomic alterations were identified of which 63 were known recurrent (32 in primary tumor, 31 in metastasis) and 248 were nonrecurrent (likely passenger). TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations. CONCLUSION This high concordance suggests that for the purposes of genomic profiling, use of archived primary tumor can identify the key recurrent somatic alterations present in matched NSCLC metastases and may provide much of the relevant genomic information required to guide treatment on recurrence.

Discrepancies between primary tumor and metastasis: A literature review on clinically established biomarkers

The identification of predictive factors of response is critical for the development and appropriate use of anti-cancer agents. The evaluation of biomarkers is usually performed by analyzing the primary tumor tissues but this approach does not take into account potential discrepancies between primary tumor and secondary lesions. This review proposes to describe currently available data regarding differential expression of established biomarkers between primary tumor and matched metastasis. In light of recent data, the need of iterative biopsies in metastatic setting has been suggested but technical and methodological limits in such analyses should not be ignored and this strategy cannot be definitively validated. Complementary studies are still needed since the question of spatial and temporal variability of biomarkers in solid tumors is clearly a key issue in an era where personalized therapy is strongly advocated by clinicians, researchers and patients.

Mitotic index and benefit of adjuvant anthracycline-based chemotherapy in patients with early breast cancer.

PURPOSE We have evaluated whether the mitotic index could predict the benefit of adjuvant anthracycline-based chemotherapy in patients with early breast cancer who are eligible for adjuvant chemotherapy according to Saint Gallen guidelines. PATIENTS AND METHODS A total of 937 patients from a single institution were included in two randomized trials that compared adjuvant anthracycline-based chemotherapy with no chemotherapy. These patients account for 83% of the overall population included in these trials. The first trial included premenopausal patients with node-negative disease, and the second one included postmenopausal patients, regardless of lymph node status. The treatment benefit was assessed according to the number of mitoses per field (x400). RESULTS The mitotic index was assessable in 888 patients (94%). All the patients presented as either node-positive or an average-risk breast cancer according to 2003 Saint Gallen consensus conference guidelines. The 5-year overall survival rates were 91% and 87% for patients treated or not with adjuvant chemotherapy (P = .09). In patients with low/medium mitotic index (< three mitoses/field; n = 450), the 5-year overall survival rate was 95% for patients treated or not with adjuvant chemotherapy (P = .56). In patients with high mitotic index (>/= three mitoses/field; n = 438), the 5-year overall survival rates were 86% and 79% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .02). CONCLUSION A high mitotic index is associated with the efficacy of adjuvant anthracycline-based chemotherapy in patients eligible for adjuvant chemotherapy in daily practice.

Renal cell carcinoma: Focus on safety and Efficacy of Temsirolimus

Metastatic renal cell carcinoma has harboured a poor prognosis for decades with immunotherapy being the only available therapy with high toxicity and modest effect. Dependance of renal cell carcinoma oncogenesis on the mTOR pathway has led to clinical development of temsirolimus in this setting. This sirolimus derivative has shown clinical efficacy in monotherapy for poor-risk renal cell carcinoma leading to an overall survival of 10.8 months in the pivotal phase III trial of this agent. Its specific adverse events consist of metabolic dysregulation (hyperlipemia, hyperglycemia), mucositis, rash and pneumonitis which can be severe and need careful monitoring and management. In this review, we will discuss of the clinical development of this molecule, its efficacy, its safety profile and future perspectives.

A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? On behalf of the REFCOR (French rare head and neck cancer network)

BACKGROUND Salivary gland carcinomas constitute a heterogeneous group of tumors, with over 20 histological subtypes of various prognoses. The mainstay of treatment is surgery, with radiotherapy advocated for unresectable disease or postoperatively in case of poor prognostic factors such as high grade, locally advanced and/or incompletely resected tumors. Concurrent chemotherapy is sometimes advocated in routine practice based on criteria extrapolated from squamous cell carcinomas of the head and neck, on radioresistance of salivary gland tumors and on results obtained in the metastatic setting. The aim of this review was to identify situations where chemotherapy is advocated. MATERIAL AND METHODS A search of literature was performed with the following key words: parotid, salivary gland, neoplasm, cancer, malignant tumor, chemoradiation, chemotherapy, radiotherapy and treatment. Case report and studies published before 2000 were not included. RESULTS Platinum-based regimens were the most frequent. Other regimens were reported and seemed dependent on histology. The level of evidence for the concurrent delivery of chemotherapy with radiation therapy is supported by a low level of evidence. Prescribing chemotherapy mostly relies on poor prognostic factors similar to those used to indicate high dose radiotherapy. Protocols vary with histology. CONCLUSION The rationale for adding chemotherapy to radiotherapy remains to be demonstrated prospectively. Although the type of systemic treatments used may be adapted on histology, the strongest rationale remains in favor of cisplatin.

Bronchial endoscopic ultrasound elastography: preliminary feasibility data

To the Editor: Medical elastography consists of biomechanically characterising a zone of tissue on the basis of its response to the application of mechanical stress. This stress can be quasistatic (local compression) or vibratory (propagation of shear waves). In the various medical applications of elastography, the response to the stress is described by mapping the tensile modulus, or Young’s modulus. Young’s modulus corresponds to the slope of the stress–strain relationship measured during a series of tensile tests [1]. The elasticity of a tissue depends on its nature, its state (fat infiltration or fibrosis) and its homogeneity. A tumour situated in a zone of healthy tissue can, therefore, be detected by its decreased elasticity. The tumour can also be described in space, based on the principle that within anisotropic materials (typically represented by heterogeneous tissues), the value of Young’s modulus varies as a function of the direction of the force applied to the material tested. Simple colour coding of the tensile response provides mapping of the elasticity of the zone examined. Very hard tissues are generally coded as blue, while soft tissues are coded as red and intermediate tissues are coded as green. Elastography is now used in various fields of medicine, often in combination with ultrasound (ultrasound elastography, sometimes called computer-assisted palpation). It has been applied to the diagnosis of …

Mobile applications in oncology: is it possible for patients and healthcare professionals to easily identify relevant tools?

Abstract Aim: Mobile applications represent promising tools in management of chronic diseases, both for patients and healthcare professionals, and especially in oncology. Among the large number of mobile health (mhealth) applications available in mobile stores, it could be difficult for users to identify the most relevant ones. This study evaluated the business model and the scientific validation for mobile applications related to oncology. Methods: A systematic review was performed over the two major marketplaces. Purpose, scientific validation, and source of funding were evaluated according to the description of applications in stores. Results were stratified according to targeted audience (general population/patients/healthcare professionals). Results: Five hundred and thirty-nine applications related to oncology were identified: 46.8% dedicated to healthcare professionals, 31.5% to general population, and 21.7% to patients. A lack of information about healthcare professionals’ involvement in the development process was noted since only 36.5% of applications mentioned an obvious scientific validation. Most apps were free (72.2%) and without explicit support by industry (94.2%). Conclusions: There is a need to enforce independent review of mhealth applications in oncology. The economic model could be questioned and the source of funding should be clarified. Meanwhile, patients and healthcare professionals should remain cautious about applications’ contents. Key messages A systematic review was performed to describe the mobile applications related to oncology and it revealed a lack of information on scientific validation and funding. Independent scientific review and the reporting of conflicts of interest should be encouraged. Users, and all health professionals, should be aware that health applications, whatever the quality of their content, do not actually embrace such an approach.

Pulmonary toxicity related to systemic treatment of nonsmall cell lung cancer.

Physicians who are responsible for the delivery of systemic treatment in lung cancer should be aware of the potential risk of drug‐induced pulmonary toxicity (DIPT), because such toxicity may develop in the context of a multifactorial clinical condition. First, most patients with lung cancer may suffer from other non‐neoplastic, smoking‐related lung diseases, such as emphysema and chronic obstructive lung disease, which may generate pathologic changes in lung parenchyma. In addition, lung cancer itself may worsen the respiratory function, inducing atelectasis and lymphangitic carcinomatosis. The superimposed iatrogenic damage may lead to respiratory failure and, sometimes, death. The risk of DIPT from chemotherapeutic agents has been widely examined in the past; and, currently, the potential for lung toxicity has been extended by the introduction of molecular targeted therapies. Because there are no univocal criteria with which to recognize DIPT, the diagnosis often is made by exclusion; consequently, it is hard to establish an early diagnosis. The objective of this review was to describe the major DIPTs associated with antineoplastic agents against nonsmall cell lung cancer to help physicians with this difficult diagnostic challenge. Cancer 2011.

Discordances entre tumeur primitive et métastases : quel impact sur le développement de la médecine personnalisée ?

Molecular characterization of tumors is critical for the development and appropriate use of many anti-cancer agents. Potential discrepancies between primary tumor and secondary lesions lead to question on the optimal modalities for evaluation of biomarkers. In light of recent data, the need of iterative biopsies in metastatic setting has been suggested but technical and methodological limits in such analyses should not be ignored and this strategy can not be definitively validated. The evaluation of spatial and temporal variability of biomarkers in solid tumors should take into account tumoral context and therapeutic history of each patient for the development of personalized medicine in oncology.

SynthèseLa signalisation FGF/FGFR : implication dans l’oncogenèse et perspectives thérapeutiquesFGF/FGFR signalling: Implication in oncogenesis and perspectives

Deregulation of FGF (fibroblast growth factor)/FGFR (fibroblast growth factor receptor) signalling leads to the promotion of several oncogenic mechanisms: proliferation, epithelial-mesenchymal transition, cytoskeleton modifications, migration and angiogenesis. Deregulation of this pathway is reported in various cancers at early stages, and can therefore be responsible for the emergence of the hallmarks of cancer. It is necessary to precise downstream pathways of FGFR signalling to understand its oncogenic potential. We will then describe its implications in different cancer types. Oncogenic mechanisms will be studied through the example of melanoma, in which deregulation of FGF/FGFR pathway is considered as a driver event and occurs in nearly 90% of cases. The FGF/FGFR signalling pathway is a putative therapeutic target. Numerous agents are in active development, operating through a selective or multi-targeted approach. Recent studies have shown rather disappointing results in non-selected patients, but promising results in patients with FGF/FGFR pathway alterations. A careful screening of patients is the key to a valuable evaluation of these new targeted molecular therapies.