Chimiothérapie par PCV en première intention dans le traitement post opératoire des oligodendrogliomes anaplasiques.

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Chirurgie des métastases cérébrales multiples

Les métastases sont les tumeurs cérébrales les plus fréquentes. Souvent multiples lors du diagnostic, leur traitement reste un challenge thérapeutique. Dans cette série, nous avons cherché à déterminer les facteurs pronostiques en cas de chirurgie chez les patients ayant plusieurs métastases cérébrales (MC). Quarante patients atteints de MC multiples on été inclus rétrospectivement. Tous ont eu l exérèse d au moins une MC. Les caractéristiques du patient, des tumeurs, les indications opératoires, l indice de Karnofsky (KPS), le score recursive partitioning analysis (RPA) et le traitement par irradiation pan cérébrale (IPC) ont été étudiés. La médiane de survie globale était de 7 mois et de 12,5 mois en cas d exérèse de toutes les MC. Les facteurs augmentant la survie retrouvés en analyse univariée étaient: l âge =70 (p=0,049 et p=0,001), un score RPA I et une irradiation pan cérébrale (IPC) (p=0,003 et p= 70 (p=0.049 and p=0.001), a RPA class I (p=0.003) and WBRT (p<0.0001). Patients MST who underwent resection for functional reason was 3.6 months versus 10.5 months for the others indications (p=0.016).By multivariate analysis, significant variables included WBRT (p=0.003) and control of the primitive tumor (p=0.035). Surgical resection of BM in patients with multiples brain metastases is benefit in selected patients. The larges tumors who decreasing KPS or with a dangerous mass effect should be resected in order to gain time for WBRT. Resection of tumors in functional area should be discussed. Favorable factors for prolonged survival were a control of the systemic disease and a postoperative WBRT.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Emerging PARP inhibitors for treating breast cancer

International audienceSome breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting. Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance

Emerging PARP inhibitors for treating breast cancer

International audienceSome breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting. Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance

Vinflunine for the treatment of breast cancer

International audienceIntroduction: Breast cancer is the most frequently diagnosed cancer and the highest cause of cancer mortality in females worldwide. The development of drugs improving overall survival in late-stage metastatic breast cancer remains a challenge. Vinflunine is the most recently developed drug in the vinca alkaloid class. Its arrival has been eagerly awaited for treatment of solid tumors, and in particular, for metastatic breast cancer.Areas covered: The pharmacological features of vinflunine are described. Its clinical development as monotherapy or in combination in metastatic breast cancer is detailed. A literature search on the topic was conducted through PubMed, clinical trials and the proceedings of the main cancer congresses.Expert opinion: The overall results from phase III studies, and in particular those that combined vinflunine with capecitabine, have been less favorable. The combination's effectiveness was at best moderate compared with other drugs which also target metastatic breast cancer, and complicated by significant hematological and gastrointestinal adverse effects. Its use in advanced metastatic breast cancer cannot currently be recommended

A pharmacokinetic evaluation of alpelisib for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer

International audienceIntroduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. Expert opinion: Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought

Functional pre-therapeutic evaluation by genome editing of variants of uncertain significance of essential tumor suppressor genes

International audienceBackground: Targeted therapies in oncology are promising but variants of uncertain significance (VUS) limit their use for clinical management and necessitate functional testing in vitro. Using BRCA1 and BRCA2 variants, which have consequences on PARP inhibitor sensitivity, and POLE variants, potential biomarkers of immunotherapy response, we developed a rapid functional assay based on CRISPR-Cas9 genome editing to determine the functional consequences of these variants having potentially direct implications on patients' access to targeted therapies.Methods: We first evaluated the functional impact of 26 BRCA1 and 7 BRCA2 variants by editing and comparing NGS results between the variant of interest and a silent control variant. Ten of these variants had already been classified as benign or pathogenic and were used as controls. Finally, we extended this method to the characterization of POLE VUS.Results: For the 23 variants that were unclassified or for which conflicting interpretations had been reported, 15 were classified as functionally normal and 6 as functionally abnormal. Another two variants were found to have intermediate consequences, both with potential impacts on splicing. We then compared these scores to the patients' responses to PARP inhibitors when possible. Finally, to prove the application of our method to the classification of variants from other tumor suppressor genes, we exemplified with three POLE VUS. Among them, two were classified with an intermediate functional impact and one was functionally abnormal. Eventually, four POLE variants previously classified in databases were also evaluated. However, we found evidence of a discordance with the classification, variant p.Leu424Val being found here functionally normal.Conclusions: Our new rapid functional assay can be used to characterize the functional implication of BRCA1 and BRCA2 variants, giving patients whose variants were evaluated as functionally abnormal access to PARP inhibitor treatment. Retrospective analysis of patients' responses to PARP inhibitors, where accessible, was consistent with our functional score evaluation and confirmed the accuracy of our protocol. This method could potentially be extended to the classification of VUS from all essential tumor suppressor genes and can be performed within a timeframe compatible with clinical applications, thereby having a direct theranostic impact

Impact of HER2 Status on Pathological Response after Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer

Purpose: Investigates the link between HER2 status and histological response after neoadjuvant chemotherapy in patients with early TNBC. Methods: We retrieved clinical and anatomopathological data retrospectively from 449 patients treated for the first time with standard neoadjuvant chemotherapy for early unilateral BC between 2005 and 2020. The primary endpoint was pathological complete response (pCR, i.e., ypT0 ypN0), according to HER2 status. Secondary endpoints included invasive disease-free survival (I-DFS) and overall survival (OS). Results: 437 patients were included, and 121 (27.7%) patients had HER2-low tumours. The pCR rate was not significantly different between the HER2-low group vs. the HER2-0 group (35.7% versus 41.8%, p = 0.284) in either univariate analysis or multivariate analysis adjusted for TNM classification and grade (odds ratio [OR] = 0.70, confidence interval [CI] 95% 0.45–1.08). With a median follow-up of 72.9 months, no significant survival differences were observed between patients with HER2-low tumours vs. patients with HER2-0 tumours in terms of I-DFS (p = 0.487) and OS (p = 0.329). Conclusions: In our cohort, HER2 status was not significantly associated with pCR in a manner consistent with data published recently on TNBC. However, the prognostic impact of HER2-low expression among TNBC patients warrants further evaluation

Management of Recurrent Glioblastomas: What Can We Learn from the French Glioblastoma Biobank?

Safe maximal resection followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ) is universally accepted as the first-line treatment for glioblastoma (GB), but no standard of care has yet been defined for managing recurrent GB (rGB). We used the French GB biobank (FGB) to evaluate the second-line options currently used, with a view to defining the optimal approach and future directions in GB research. We retrospectively analyzed data for 338 patients with de novo isocitrate dehydrogenase (IDH)-wildtype GB recurring after TMZ chemoradiotherapy. Cox proportional hazards models and Kaplan–Meier analyses were used to investigate survival outcomes. Median overall survival after first surgery (OS1) was 19.8 months (95% CI: 18.5–22.0) and median OS after first progression (OS2) was 9.9 months (95% CI: 8.8–10.8). Two second-line options were noted for rGB patients in the FGB: supportive care and treatments, with systemic treatment being the treatment most frequently used. The supportive care option was independently associated with a shorter OS2 (p < 0.001). None of the systemic treatment regimens was unequivocally better than the others for rGB patients. An analysis of survival outcomes based on time to first recurrence (TFR) after chemoradiotherapy indicated that survival was best for patients with a long TFR (≥18 months; median OS1: 44.3 months (95% CI: 41.7–56.4) and median OS2: 13.0 months (95% CI: 11.2–17.7), but that such patients constituted only a small proportion of the total patient population (13.0%). This better survival appeared to be more strongly associated with response to first-line treatment than with response to second-line treatment, indicating that the recurring tumors were more aggressive and/or resistant than the initial tumors in these patients. In the face of high rates of treatment failure for GB, the establishment of well-designed large cohorts of primary and rGB samples, with the help of biobanks, such as the FGB, taking into account the TFR and survival outcomes of GB patients, is urgently required for solid comparative biological analyses to drive the discovery of novel prognostic and/or therapeutic clinical markers for GB