IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages.

CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen

Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer

Background: Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance. Methods: We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples. Results: Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes. Conclusions: We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy. ClinicalTrials.gov: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m$^{2}$ iv, on day one of a 28 days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016

Molecular apocrine tumours in EORTC 10994/BIG 1-00 phase III study: pathological response after neoadjuvant chemotherapy and clinical outcomes

Background: We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. Methods: Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and “other”. The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. Results: IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4–43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2–68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. Conclusions: Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Evaluation de l'utilité du test génomique, 21 gènes, comme outil d'aide à la décision thérapeutique dans les cancers précoces du sein, exprimant les récepteurs aux oestrogènes: une expérience genevoise

Le risque de récidive du carcinome invasif du sein est influencé par un nombre de facteurs cliniques, histologiques et moléculaires. Les traitements adjuvants réduisent significativement ce risque, cependant leur bénéfice diffère selon les caractéristiques pathologiques et moléculaires de la tumeur. L'analyse de l'expression génique tumorale a démontré qu'elle permettait de prédire le comportement tumoral. Oncotype DX est un test qui analyse l'expression d'un panel de gènes tumoraux permettant d'identifier les patientes, souffrant d'un cancer du sein hormonosensible, à risque faible, intermédiaire et élevé de récidive et celles qui bénéficient ou non d'une chimiothérapie adjuvante. Nous avons évalué, par une étude prospective observationnelle, l'impacte de ce test sur les recommandations pour la chimothérapie adjuvante chez 60 patientes souffrant d'un cancer du sein précoce hormonosensible. Le résultat d'Oncotype DX a entrainé une modification de l'attitude thérapeutique, proposée initialement, chez 46.7% des patientes, principalement en leur évitant une chimiothérapie adjuvante (57.9%

« Docteur, je jeûne lors de la chimiothérapie » : illusion ou nouvelle réalité clinique ?

Fasting concomitantly with oncology treatments (chemotherapy mainly) induces a growing interest among patients following overmediatisation of recent discoveries. The goal of this article is to provide updated information about this approach. According to preclinical studies, fasting may be a way to increase the therapeutic index of major oncology treatments. However, clinical data is based on small exploratory studies only and the results of larger scale studies are not yet available. The approach of fasting during chemotherapy can and should neither be recommended nor implemented in standard care. However, further scientific and clinical investigation may contribute to a better understanding of the metabolic aspects of cancer

A genetic polymorphism repurposes the G-protein coupled and membrane-associated estrogen receptor GPER to a transcription factor-like molecule promoting paracrine signaling between stroma and breast carcinoma cells

GPER is a membrane-associated estrogen receptor of the family of G-protein coupled receptors. For breast cancer, the contribution of GPER to promoting the proliferation and migration of both carcinoma cells and cancer-associated fibroblasts (CAFs) in response to estrogen and other agonists has extensively been investigated. Intriguingly, GPER was previously found to be localized to the nucleus in one isolate of breast CAFs. Moreover, this nuclear GPER was shown to bind regulatory sequences of cancer-relevant target genes and to induce their expression. We decided to find out what induces the nuclear localization of GPER, how general this phenomenon is, and what its functional significance is. We discovered that interfering with N-linked glycosylation of GPER, either by mutation of the predicted glycosylation sites or pharmacologically with tunicamycin, drives GPER into the nucleus. Surveying a small set of CAFs from breast cancer biopsies, we found that a relatively common single nucleotide polymorphism, which results in the expression of a GPER variant with the amino acid substitution P16L, is associated with the nuclear localization of GPER. GPER with P16L fails to be glycosylated, presumably because of a conformational effect on the nearby glycosylation sites. GPER P16L is defective for membrane-associated signaling, but instead acts like an estrogen-stimulated transcription factor. In CAFs, it induces the secretion of paracrine factors that promote the migration of carcinoma cells. This raises the possibility that the GPER P16L polymorphism could be a risk factor for breast cancer

Anticorps et tumeurs solides

Grâce aux progrès biotechnologiques récents, les anticorps monoclonaux constituent une nouvelle classe de médicaments pour le traitement des tumeurs solides. Afin d’illustrer l’intérêt de cette classe thérapeutique et son évolution, nous présentons deux anticorps utilisés en pratique quotidienne (le trastuzumab et le cétuximab), ainsi que deux cibles prometteuses pour lesquelles des anticorps devraient être prochainement disponibles (IGF-1R et c-MET). Le trastuzumab et le cétuximab ont bouleversé les stratégies thérapeutiques dans les cancers du sein, les cancers du côlon et ceux de la sphère ORL, mais leur efficacité est cependant limitée à une fraction de patients et est le plus souvent transitoire. Les défis actuels sont donc nombreux : mieux comprendre le mode d’action de ces molécules, élucider les mécanismes de résistance, exploiter la synergie entre anticorps et chimiothérapie, sélectionner les patients pour lesquels un bénéfice peut être espéré. Résoudre ces questions devrait permettre de proposer dans le futur des traitements individualisés sur la base des caractéristiques des tumeurs et des patients