Emerging treatments for HER2-positive early-stage breast cancer: Focus on neratinib

Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib

Anti-Müllerian hormone as a marker of ovarian reserve and premature ovarian insufficiency in children and women with cancer: A systematic review

Background: Female patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-M\ufcllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood. Objective and rationale: To conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review. Search methods: A systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up. Outcomes: Ninety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of 6590%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients. Wider implications: AMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research

Diagnostic and predictive accuracy of anti-Mullerian hormone for ovarian function after chemotherapy in premenopausal women with early breast cancer

Funding: This work was undertaken in part in the MRC Centre for Reproductive Health, (supported by MRC grant MR/N022556/1).Purpose Accurate diagnosis and prediction of loss of ovarian function after chemotherapy for premenopausal women with early breast cancer (eBC) is important for future fertility and clinical decisions regarding the need for subsequent adjuvant ovarian suppression. We have investigated the value of anti-mullerian hormone (AMH) as serum biomarker for this. Methods AMH was measured in serial blood samples from 206 premenopausal women aged 40–45 years with eBC, before and at intervals after chemotherapy. The diagnostic accuracy of AMH for loss of ovarian function at 30 months after chemotherapy and the predictive value for that of AMH measurement at 6 months were analysed. Results Undetectable AMH showed a high diagnostic accuracy for absent ovarian function at 30 months with AUROC 0.89 (96% CI 0.84–0.94, P < 0.0001). PPV of undetectable AMH at 6 months for a menopausal estradiol level at 30 months was 0.77. In multivariate analysis age, pre-treatment AMH and FSH, and taxane treatment were significant predictors, and combined with AMH at 6 months, gave AUROC of 0.90 (95% CI 0.86–0.94), with PPV 0.79 for loss of ovarian function at 30 months. Validation by random forest models with 30% data retained gave similar results. Conclusions AMH is a reliable diagnostic test for lack of ovarian function after chemotherapy in women aged 40–45 with eBC. Early analysis of AMH after chemotherapy allows identification of women who will not recover ovarian function with good accuracy. These analyses will help inform treatment decisions regarding adjuvant endocrine therapy in women who were premenopausal before starting chemotherapy.Publisher PDFPeer reviewe

Analyse rétrospective de 24 patientes traitées pour une méningite carcinomateuse compliquant un cancer du sein

Introduction La méningite carcinomateuse survient chez environ 1 à 2% des cancers du sein métastatiques. Cette atteinte est caractérisée par un pronostic particulièrement sombre de quelques semaines. Il n'existe à ce jour aucun traitement validé des méningites carcinomateuses compliquant un cancer du sein. Les prises en charge proposées comportent habituellement la réalisation d'une chimiothérapie et d'une radiothérapie, dans un contexte d'emblée palliatif. En raison de l'existence de la barrière hémato-encéphalique, qui limite l'accessibilité des molécules utilisées par voie veineuse, la chimiothérapie employée est fréquemment du méthotrexate intrathécal administré par ponction lombaire ou via un réservoir externe. Le but de ce travail a été d'analyser de façon rétrospective les résultats d'un protocole utilisant du méthotrexate à haute dose par voie intrathécale chez des patientes présentant une méningite carcinomateuse compliquant un cancer du sein. Patientes et méthodes Toutes les patientes traitées au Centre Henri Becquerel pour une méningite carcinomateuse d'origine mammaire entre Juin 1999 et Mai 2008 et ayant reçu au moins un cycle de méthotrexate intrathécal haute dose (15 mg par jour de Jl à J5 puis reprise à J14) ont été incluses rétrospectivement. L'analyse a porté sur l'évolution clinique, la survie globale, les données du LCR et la toxicité du traitement. Résultats : Les données concernant 24 patientes, dont l'âge moyen était de 49 ans, ont été analysées. Les patientes ont reçu un nombre médian de cures de chimiothérapie intrathécale de 4. Toutes les patientes sauf une ont présenté une stabilisation ou une amélioration des symptômes liés à la méningite carcinomateuse, et pour neuf patientes (38%) tous les symptômes liés à la méningite carcinomateuse ont complètement disparus. La régression complète des symptômes initiaux de la méningite et la négativation de la cytologie du LCR étaient les deux seuls facteurs pronostiques ou prédictifs pour la survie dans cette série. Onze patientes (46%) ont présenté une négativation de la cytologie du LCR en cours de traitement. Chez ces patientes, une réponse clinique était plus fréquemment observée (p=0,02) que chez les patientes conservant une cytologie du LCR positive pendant le traitement. Pour l'ensemble des patientes, la survie globale moyenne était de 175 jours, avec une médiane de 150 jours. Cette survie médiane était significativement plus longue dans le groupe des malades ayant une négativation de la cytologie du LCR (217 jours contre 102, p=0,005), et en cas de disparition de la totalité des symptômes liés à la méningite carcinomateuse (223 jours contre 140, p=0,04). Les courbes de survie confirment la valeur prédictive de la réponse cytologique (p=0,0016) et de la disparition des symptômes liés à la méningite carcinomateuse (p=0,047). Un état général altéré au moment du diagnostic de la méningite carcinomateuse ne constituait pas un facteur péjoratif de survie dans cette étude. La tolérance globale était bonne. Conclusion Cette étude rétrospective suggère un possible bénéfice du traitement par méthotrexate intrathécal à haute dose des méningites carcinomateuse d'origine mammaire. L'évolution clinique et cytologique en cours de traitement pourrait aider à décider de la poursuite ou de l'interruption du traitement intrathécal.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Controversies about fertility and pregnancy issues in young breast cancer patients: current state of the art.

For trying to help physicians in counseling their young patients with breast cancer interested in fertility preservation and future reproductive plans, this manuscript aims to perform an overview of the main available data on 10 controversies in this field.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Intérêt clinique de la détection des mutations circulantes d’ ESR1 chez les patientes traitées pour un cancer du sein métastatique exprimant les récepteurs hormonaux

International audienc

ASO Visual Abstract: Contribution of Genomics to the Surgical Management and Study of Oral Cancer (May, 10.1245/S10434-021-10004-2, 2021)

International audienc

Impact of lymphopenia on efficacy of nivolumab in head and neck cancer patients

International audienceAbstractIntroductionLymphopenia has been correlated with poorer survival in patients with metastatic cancers treated with anti-PD-1 immunotherapy. Treatments such as chemotherapy, surgery or radiotherapy can induce lymphopenia. Radiation-induced lymphopenia is common and prolonged in head and neck cancer (HNSCC) patients. We evaluated the impact of lymphopenia, on efficacy of anti PD-1 nivolumab immunotherapy in HNSCC patients.MethodsA multicenter retrospective study included consecutive patients treated with nivolumab for recurrent/metastatic (R/M) HNSCC between January 2017 and June 2019. Lymphopenia was defined as lymphocyte counts below 1000 cells/mm3 upon initiation of nivolumab. Logistical regression was performed on factors associated with lymphopenia and ROC analyses assessed association between lymphopenia and survival.Resultsmedian age was 65. Of the 100 included patients, 60% had been treated by surgery, 67% had had first-line chemotherapy, and 89% loco-regional radiotherapy, 65% had concurrent chemotherapy with radiotherapy. Lymphopenia occurred in 56 (56%) patients upon initiation of nivolumab, with 29 (29%) patients having radiation-related lymphopenia. Prior locoregional radiotherapy was the only factor associated with lymphopenia upon initiation of nivolumab by logistical regression (OR 0.144 [0.029–0.706], p − 0.017). Lymphopenia upon initiation of nivolumab did not affect progression-free survival (PFS) (p − 0.815), overall survival (OS) (p − 0.783) or disease control rate (DCR) (p − 0.125). Locoregional symptomatology (HR − 2.37 [1.24–4.54], p − 0.009), metastatic symptomatology (HR − 4.74 [2.21–10.15], and persistent lymphopenia under nivolumab (HR 3.96 [1.19–13.17] p − 0.034) were associated with poorer OS in multivariate analysis.ConclusionsLymphopenia upon initiation of nivolumab was not associated with poorer survival in R/M HNSCC patients, but persistence of lymphopenia during immunotherapy might be a prognostic marker of patient survival

ASO Visual Abstract: Contribution of Genomics to the Surgical Management and Study of Oral Cancer

International audienc