Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer

Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of mutation status is unknown. We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.)

Cancers épithéliaux de l' ovaire et bevacizumab (étude rétrospective observationnelle de 5 centres français)

L utilisation du bevacizumab dans le cancer de l ovaire en rechute repose sur un rationnel solide basé sur la place de l angiogenèse dans l oncogenèse ovarienne. Nous rapportons la plus grande série de patientes traitées par le bevacizumab pour un cancer épithélial ovarien en rechute et décrivons la tolérance, les modalités d utilisation et l efficacité de ce traitement. Il s agit d une étude rétrospective multicentrique (5 centres). Les caractéristiques cliniques des patientes, leur tolérance au traitement, ses modalités d utilisation et les données d efficacité ont été recueillies. Parmi les 156 patientes incluses, 42% ont eu une HTA et 27% une protéinurie. La dose de bevacizumab augmente le risque d HTA et de protéinurie de faible grade uniquement (OR=1.17; IC95% [0.05;1.31];p=0.004). L existence d une HTA préexistant à l introduction du bevacizumab augmente la gravité de la toxicité vasculaire du bevacizumab sans en augmenter la fréquence (OR=3.96; IC95% [1.48;10.58]). L existence d une carcinose péritonéale est un facteur de risque de perforation ou de fistule digestive (OR=2.78; IC95% [1.02;7.56];p=0.045). Le taux de survie sans progression à 6 mois a été de 60% et les médianes de survie sans récidive et de survie globale ont été de 8.3 mois (IC95% [6.5; 10.1]) et de 23.4 mois (IC95% [17.7;29.7]), respectivement. La carcinose péritonéale et l HTA sont des facteurs de risques de toxicité liée au bevacizumab dans le cadre d un cancer épithélial ovarien en rechute. En tenir compte dans la sélection des patientes pouvant bénéficier de l efficacité encourageante du bevacizumab, peut leur assurer un profil de tolérance acceptable.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Hétérogénéité tumorale des cancers du sein

International audienceThe objective of this literature review is to describe the types of tumor heterogeneity in breast cancer and their clinical implication. Two kinds of tumor heterogeneity are described: intertumor heterogeneity and intra-tumor heterogeneity. In breast cancer, inter-tumor heterogeneity was best characterized in the 2000s thanks to high throughput analyses. These analyzes resulted in a molecular classification of breast cancers distinguishing four subtypes: Luminal A, Luminal B, HER 2+ and basal like. This variability may be observed between the primary tumor and metastases, namely the temporal intratumor heterogeneity. The average discrepancy for the progesterone receptor, estrogen, and between HER2 status appears to be 33%, 20% and 8%, respectively. It is then interesting to study the heterogeneity within the primary tumor: this spatial intra-tumor heterogeneity is poorly known. Physiopathology of intra-tumor heterogeneity light be deciphered by studies on cancer stem cells and clonal evolution model. In addition, the tumor microenvironment seems to actively contribute to this heterogeneity. The major interest to study this heterogeneity is the clinical implication that could result. While precision medicine is emerging, it is important to capture the heterogeneity of each specific tumor type. These new biological knowledge will allow us to anticipate such heterogeneity and individualize the management of breast cancer. Copyrigh

Efficacité des « seuils » dans la prise en charge des cancers de l'ovaire: revue de la littérature

International audienceObjective The "Institut national du cancer" has established since 2007 a minimum threshold of 20 patients per year per center to treat patients with gynecologic cancer. This review aims to assess whether the literature data validate this approach, and specifically for ovarian cancer. Methods A search of the MEDLINE database was conducted, to reference all relevant articles evaluating one hand the links between the survival of patients with ovarian cancer and the average volume of patients per center and by operator; and secondly the relationship between quality of oncological surgery and these volumes. Results Nineteen studies met our inclusion criteria; seventeen were retrospective and two were prospective; population samples ranged from 476 to 96,802 patients. The most important data, quantitatively and qualitatively, concern the evaluation of survival based on the average volume per center, with 8 out of 13 studies finding a statistically significant correlation between average volume per center and survival. Data on the quality of surgery are less abundant and more heterogeneous, depending on the definition of the "optimal" surgery by the authors. Conclusion The establishment of threshold centers appears to be an effective way to improve survival in ovarian cancer. However, these thresholds would have to be specific to ovarian cancer and not extended to "gynecological cancers.

Phase II study of intrathecal administration of trastuzumab in patients with HER2-positive breast cancer with leptomeningeal metastasis

BACKGROUND Patients with HER2-positive breast cancer (HER2+BC) develop central nervous system metastases twice as often as patients with luminal HER2-negative breast cancer. Leptomeningeal progression results in a drastically altered prognosis with limited therapeutic options. This phase II study was conducted in order to assess the efficacy of intrathecal (IT) trastuzumab in HER2+BC patients with leptomeningeal metastasis (LM), based on a phase I dose-escalation study that had determined the recommended weekly dose of 150 mg for phase II. METHODS Eligible patients received weekly administrations of 150 mg of IT trastuzumab. The primary endpoint was clinical neurologic progression-free survival (LM-related-PFS) after 8 weeks. Overall survival (OS), toxicities and quality of life (QoL) were secondary endpoints. RESULTS Among the 19 enrolled patients, 16 (84%) had concomitant brain metastases, 15 of them had received prior radiotherapy to the brain. All patients had received at least one line of systemic anti-HER2 therapy.After 8 weeks, 14 patients (74%) were free of neurological progression. The median LM-related-PFS was 5.9 months and the median OS was 7.9 months. According to the QLQ-C30 and BN20 scales, the global health-related QoL status seemed preserved and no toxicity above grade 3 was observed. CONCLUSIONS Conducting studies on patients with LM poses significant challenges and ethical dilemmas inherent to this population. Despite some limits, this phase II study's findings in terms of clinical neurologic response and quality of life's control confirms weekly administration of 150 mg of IT trastuzumab as a valuable option for HER+BC patients with LM and support the interest for further investigations

Bevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group

International audienceAbstract Most patients with advanced ovarian cancer (AOC) ultimately relapse after platinum-based chemotherapy. Combining bevacizumab, olaparib, and durvalumab likely drives synergistic activity. This open-label phase 2 study (NCT04015739) aimed to assess activity and safety of this triple combination in female patients with relapsed high-grade AOC following prior platinum-based therapy. Patients were treated with olaparib (300 mg orally, twice daily), the bevacizumab biosimilar FKB238 (15 mg/kg intravenously, once-every-3-weeks), and durvalumab (1.12 g intravenously, once-every-3-weeks) in nine French centers. The primary endpoint was the non-progression rate at 3 months for platinum-resistant relapse or 6 months for platinum-sensitive relapse per RECIST 1.1 and irRECIST. Secondary endpoints were CA-125 decline with CA-125 ELIMination rate constant K (KELIM-B) per CA-125 longitudinal kinetics over 100 days, progression free survival and overall survival, tumor response, and safety. Non-progression rates were 69.8% (90%CI 55.9%-80.0%) at 3 months for platinum-resistant relapse patients (N = 41), meeting the prespecified endpoint, and 43.8% (90%CI 29.0%-57.4%) at 6 months for platinum-sensitive relapse (N = 33), not meeting the prespecified endpoint. Median progression-free survival was 4.1 months (95%CI 3.5–5.9) and 4.9 months (95%CI 2.9–7.0) respectively. Favorable KELIM-B was associated with better survival. No toxic deaths or major safety signals were observed. Here we show that further investigation of this triple combination may be considered in AOC patients with platinum-resistant relapse

Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis

International audiencePurpose: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT).Methods: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics.Results: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease.Conclusions: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing.Registration identification: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1)

Prognostic value of intratumoral Fusobacterium nucleatum and association with immune-related gene expression in oral squamous cell carcinoma patients

International audienceChanges in the oral microbiome, particularly Fusobacterium nucleatum , are associated with oral squamous cell carcinoma (OSCC). F. nucleatum has been reported to modulate local immunity in cancers. We aimed to assess the association between intratumoral F. nucleatum and clinico-pathological features, relapse, and overall survival (OS) in two independent cohorts of patients with OSCC, and to explore the interplay with immune-related genes. We retrospectively analyzed tissue samples from a first cohort of 122 patients with head and neck squamous cell carcinoma, including 61 OSCC (cohort #1), and a second cohort of 90 additional OSCC (cohort #2). We then performed a sensitivity analysis on the merged cohort of OSCC patients (N = 151). F. nucleatum 16S rRNA gene sequences were quantified using real-time quantitative PCR. The presence of gram-negative bacteria and macrophages was confirmed by LPS and CD163 immunostainings, respectively. F. nucleatum positivity was associated with older age, less alcohol and combined alcohol plus tobacco consumption, and less frequent lymph node invasion. There was a trend for a lower recurrence rate in F. nucleatum -positive cases, with less metastatic relapses compared to F. nucleatum -negative tumors, and significantly longer OS, relapse-free and metastasis-free survival. F. nucleatum status was independently associated with OS in multivariate analysis. Immune-related gene and immunohistochemistry analyses showed that gram-negative bacteria load inversely correlated with M2 macrophages. F. nucleatum -associated OSCC has a specific immune microenvironment, is more frequent in older, non-drinking patients, and associated with a favorable prognosis