Role of neo-adjuvant hormonal therapy in the treatment of breast cancer: a review of clinical trials

The clinical benefits of endocrine therapy for patients with hormonosensitive breast cancer are well established. For many years, 5 years of tamoxifen was the gold standard of adjuvant treatment. The recent development of new endocrine agents provides physicians with a more effective therapeutic approach. Nevertheless, the success of neoadjuvant endocrine therapy is much more recent and less reported in the literature. This article reviews the studies published about neoadjuvant endocrine treatment (tamoxifen and aromatase inhibitors). According to the literature, neoadjuvant endocrine therapy seems to be effective. In contrast to neoadjuvant chemotherapy, neoadjuvant endocrine therapy is well tolerated, with very few patients having to discontinue the treatment because of side effects. It does not constitute a standard treatment but could have potential for elderly women with operable, hormonosensitive, well differentiated and slowly progressing (SBR I) tumor or for patients with lobular MSBR 1 carcinoma (low chemosensitivity). The newer generation of aromatase inhibitors (letrozole, anastrozole, exemestane) appears to be more active (in terms of overall response rates and conservative surgery rate) than tamoxifen. Patients with an estrogen receptor Allred score of 6 and over are more likely to respond and gain a clinical benefit. The optimal duration of neoadjuvant therapy has not yet been investigated in detail. These preliminary results should be confirmed by further studies

Long-term disease-free survival in advanced melanomas treated with nitrosoureas: mechanisms and new perspectives

BACKGROUND: Median survival of metastatic malignant melanoma is 6.0 to 7.5 months, with a 5-year survival of ~6.0%. Although long-term complete remissions are rare, few reports describe cases after chemotherapy. Fifty-three patients with metastatic melanoma were treated with Cystemustine, a chloroethyl nitrosourea (CENU) (60 or 90 mg/m(2)). CASE PRESENTATION: We describe 5 cases, presenting with complete response with long-term disease-free survival of long-term remission of 14, 12, 9, 7 and 6 years after Cystemustine therapy alone. CONCLUSION: Long-term survival has already been described in literature, but in all cases they have been obtained after chemotherapy associated with or followed by surgery. But despite these noteworthy and encouraging but also rare results, it appears essential to increase cystemustine efficiency

Weight change during chemotherapy changes the prognosis in non metastatic breast cancer for the worse

<p>Abstract</p> <p>Background</p> <p>Weight change during chemotherapy is reported to be associated with a worse prognosis in breast cancer patients, both with weight gain and weight loss. However, most studies were conducted prior to the common use of anthracycline-base chemotherapy and on North American populations with a mean BMI classified as overweight. Our study was aimed to evaluate the prognostic value of weight change during anthracycline-based chemotherapy on non metastatic breast cancer (European population) with a long term follow-up.</p> <p>Methods</p> <p>Patients included 111 women diagnosed with early stage breast cancer and locally advanced breast cancer who have been treated by anthracycline-based chemotherapy regimen between 1976 and 1989. The relative percent weight variation (WV) between baseline and postchemotherapy treatment was calculated and categorized into either weight change (WV > 5%) or stable (WV < 5%). The median follow-up was 20.4 years [19.4 - 27.6]. Cox proportional hazard models were used to evaluate any potential association of weight change and known prognostic factors with the time to recurrence and overall survival.</p> <p>Results</p> <p>Baseline BMI was 24.4 kg/m2 [17.1 - 40.5]. During chemotherapy treatment, 31% of patients presented a notable weight variation which was greater than 5% of their initial weight.</p> <p>In multivariate analyses, weight change (> 5%) was positively associated with an increased risk of both recurrence (RR 2.28; 95% CI: 1.29-4.03) and death (RR 2.11; 95% CI: 1.21-3.66).</p> <p>Conclusions</p> <p>Our results suggest that weight change during breast-cancer chemotherapy treatment may be related to poorer prognosis with higher reccurence and higher mortality in comparison to women who maintained their weight.</p

Traitement des mélanomes et des gliomes par la cystémustine et optimisation par une carence alimentaire en méthionine

La cystémustine est une chloroethyl-nitrosourée (CENU) synthétisée et développée par l'unité INSERM U484 de Clermont-Ferrand. Cette molécule, en cours de développement, a fait l'objet de plusieurs essais cliniques de phase I et II qui ont montré une efficacité antitumorale principalement dans le gliome et le mélanome. Parmi les rares molécules qui ont montré une activité en monochimiothérapie vis à vis de ces deux localisations, les CENUs ont une place prépondérante. Cette famille d'agents antitumoraux a montré une efficacité certaine mais présente certains inconvénients dont le fait d'être peu spécifique des cellules tumorales et se heurte à la chimiorésistance tumorale. La réparation des adduits formés sur l'ADN par une enzyme, l'O(6)-methylguanine-DNA methyltransférase (MGMT), constitue l'un des mécanismes majeurs impliqués dans la chimiorésistance aux CENUs. L'exploration de nouvelles stratégies thérapeutiques semble donc nécessaire afin de sensibiliser les cellules tumorales. Comme le suggère des résultats expérimentaux, une carence en un acide aminé essentiel, la méthionine, permettrait d'améliorer l'efficacité des CENUs notamment grâce à une sensibilisation des cellules tumorales "méthionine-dépendantes" et à la diminution de l'activité MGMT. C'est avec l'objectif de compléter l'évaluation de l'index thérapeutique de la cystémustine dans le traitement des mélanomes et des gliomes à des stades avancés et de chercher à optimiser ce traitement que ce travail a été entrepris. Dans un 1er temps, nous avons montré que la cystémustine pouvait constituer une alternative thérapeutique en 2nde ligne des mélanomes métastatiques et des gliomes en rechute. Les résultats d'efficacité de la cystémustine dans le traitement des mélanomes métastatiques en 2nde ligne et des gliomes en rechute (avec respectivement, un taux de réponse de 14% et 19% et une survie de 4 et 8,3 mois) sont du même ordre que ceux publiés avec d'autres CENUs. La cystémustine offre aussi la possibilité de réponses complètes de longue durée dans le traitement des mélanomes métastatiques. Dans un 2ème temps, nous avons étudié l'association d'un régime carencé en méthionine à la cystémustine. Tout d'abord, nous avons montré la faisabilité et la bonne tolérance (statut nutritionnel) de cette association. Nous avons déterminé la durée optimale de régime carencé en méthionine à 1 jour de régime permettant d'obtenir une déplétion plasmatique maximale en méthionine de l'ordre de 50%. Nous avons aussi montré que cette association diminuait l'activité de la MGMT dans les cellules mononuclées sanguines ce qui constitue une preuve de concept de l'association. Concernant l'évaluation de l'index thérapeutique de cette association, les résultats préliminaires analysés sur les 20 patients actuellement inclus dans cet essai de phase I/II ont montré une toxicité comparable au traitement par cystémustine seule et une efficacité très limitée (2 stabilisations). Ces derniers résultats pourraient mettre en doute l'effet synergique d'une carence alimentaire en méthionine et de la cystémustine mais ne nous permettent pas de conclure. Ces résultats laissent entrevoir la nécessité de nouvelles investigations cliniques afin d'évaluer la stratégie de potentialisation d'une chimiothérapie par une carence en méthionine.Cystemustine is a chloroethylnitrosourea synthetized and developed in INSERM U484 of Clermont-Ferrand. During preclinical and clinical studies, this drug has already shown clinical activity against malignant glioma and melanoma. Among the few effective chemotherapy agents for treatment of these two localizations, nitrosoureas were wildely used. The chloroethylating agents have demonstrated efficacy but presented disadvantage as a low specificity for tumor cells. Moreover, some tumors were chemoresistants with the DNA-repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) as one of the main mechanisms involved in CENU resistance. Investigation of new therapeutic strategy would be necessary to sensitize tumor cells. As suggested by experimental results, a methionine deprivation could potentiate CENU efficacy by sensitizing tumor cells which were methionine-dependent and by down-regulation of MGMT activity. The aim of this study was to complete the investigation of cystemustine therapeutic index in treatment of advanced melanoma and glioma and to optimize this treatment. In first time, we showed that cystemustine could be a therapeutic option in second line treatment of metastatic melanoma and in recurrent glioma. The efficacy results of cystemustine in second line treatment of metastatic melanoma and in recurrent glioma (response rate of 14% and 19% and median survival of 4 and 8.3 months, respectively) seemed to be comparable to the results of the other CENU treatment. moreover, cystemustine provided the possibility of long duration complete responses in treatment of metastatic melanoma. In second time, we have studied the association of a methionine-free diet with cystemustine in a phase I/II clinical trial. First, we demonstrated the feasibility and the good tolerance (nutritional status) of the association. We have determined that the optimal methionine-free diet duration was of 1 day for a maximum depletion of plasma methionine of about 50%. We have also shown the down-regulation of the MGMT activity in peripheral blood mononuclear cells by the association of a methionine-free diet with cystemustine that could be considered as a proof of concept of this association. Concerning the therapeutic index assessement of the association, preliminary results analyzed among the 20 patients enrolled in this phase I/II clinical trial, have shown a comparable toxicity with previous trials with cystemustine alone, and a limited efficacy (2 stabilisation diseases). Thus, these results challenged the synergistic effect of a dietary methionine depletion with cystemustine, but did not allow us to conclude. These analysis suggest the need for further clinical investigations to evaluate the strategy of chemotherapy potentialization by methionine depletion.CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Melatonin supplementation to improve quality of life for elderly cancer patients

International audienc

Combined methionine deprivation and chloroethylnitrosourea have time-dependent therapeutic synergy on melanoma tumors that NMR spectroscopy-based metabolomics explains by methionine and phospholipid metabolism reprogramming

International audienceMethionine (Met) deprivation stress (MDS) is proposed in association with chemotherapy in the treatment of some cancers. A synergistic effect of this combination is generally acknowledged. However, little is known on the mechanism of the response to this therapeutic strategy. A model of B16 melanoma tumor in vivo was treated by MDS alone and in combination with chloroethylnitrosourea (CENU). It was applied recent developments in proton-NMR spectroscopy-based metabolomics for providing information on the metabolic response of tumors to MDS and combination with chemotherapy. MDS inhibited tumor growth during the deprivation period and growth resumption thereafter. The combination of MDS with CENU induced an effective time-dependent synergy on growth inhibition. Metabolite profiling during MDS showed a decreased Met content (P < 0.01) despite the preservation of the protein content, disorders in sulfur-containing amino acids, glutamine/proline, and phospholipid metabolism [increase of glycerophosphorylcholine (P < 0.01), decrease in phosphocholine (P < 0.05)]. The metabolic profile of MDS combined with CENU and ANOVA analysis revealed the implication of Met and phospholipid metabolism in the observed synergy, which may be interpreted as a Met-sparing metabolic reprogramming of tumors. It follows that combination therapy of MDS with CENU seems to intensif

Weight change during breast cancer treatment: is it always of poor prognosis?

National audienceWeight change (gain or loss) is not uncommon in patients treated for breast cancer, especially when they receive chemotherapy. Weight changes observed during chemotherapy treatment performed before the 2000s, were associated with poor prognosis, but this relation is less found in more recent studies. Changes in body composition of women treated whith current chemotherapies remains to be determined. Post-treatment regular and moderate physical activity would reduce the risk of recurrence and mortality by 24-50%, both in obese and normal-weight women

Adapted Physical Activity for Breast Cancer Patients Treated with Neoadjuvant Chemotherapy and Trastuzumab Against HER2 (APACAN2): A Protocol for a Feasibility Study

International audienceBackground: The standard care for HER2-positive breast cancer is chemotherapy plus a HER2-directed therapy. This can lead to treatment-induced cardiotoxicity. On the other hand, the practice of physical activity is known to improve cardiac function; thus HER2-positive breast cancer patients could draw particular benefit from physical activity during treatment. However, at the time of diagnosis for breast cancer, the majority of patients are insufficiently active according to physical activity recommendations of World Health Organisation, and it is difficult to remain or become active during the treatment. There is a lack of data in the literature on the optimal program to propose to patients to encourage them to be active during treatment. The aim of our study is to assess the feasibility of a home-based physical activity program during neoadjuvant chemotherapy and trastuzumab for HER2-positive breast cancer. Methods: The APACAN2 study is a single-centre, non-randomized interventional trial. Patients with HER2-positive breast cancer treated with anthracycline-based neoadjuvant chemotherapy and trastuzumab are eligible for enrolment. The supervised home-based physical activity program takes place during neoadjuvant chemotherapy (NACT). It combines aerobic and strengthening exercises. The primary endpoint is the proportion of patients reaching the international physical activity recommendations, i.e. 150 minutes of moderate-intensity activity per week at the end of NACT. The study started in April 2018 and seventy patients are expected to be recruited. Discussion: In the literature, the majority of studies on practice of physical activity in breast cancer focus on adjuvant chemotherapy or on the period after the end of treatment. To the best of our knowledge, the APACAN2 study is the first to evaluate a home-based physical activity program during neoadjuvant chemotherapy for HER2-positive breast cancer

Nanoparticules AGuIX1 et radiothérapie : du développement préclinique aux premiers essais chez l’homme

International audienceFor several years, the use of nanotechnology has been at the heart of research. The use of nanoparticles in oncology opens a vast field of clinical applications. Indeed, nanoparticles have the ability to act as radiosensitizers. They enhance the effectiveness of irradiation in tumor cells, and may represent a promising approach for the local treatment of tumors by external radiotherapy. In this context, the biotechnology company, NH TherAguix (Grenoble, France), has developed AGuIX (Activation and Guidance of Irradiation by X-ray) nanoparticles. These ultra-small nanoparticles, around 5 nm, are composed of a polysiloxane matrix and gadolinium chelates. The nanoparticles have very high radiosensitizing properties as well as contrast agent properties due to the presence of gadolinium. According to the various studies carried out, no signs of toxicity were observed in two animal species (rodents and monkeys) after intravenous administration. The biodistribution in different animal models has shown that the nanoparticles accumulate passively and selectively in tumours due to the EPR effect (Enhanced Permeability and Retention effect) and are cleared via renal elimination. A radiosensitizing effect has also been observed with different types of irradiation in vitro and in vivo on several types of cancers, including radio-resistant models. These promising nanoparticles are therefore currently undergoing clinical trials combined with radiotherapy in several centres in France and in the USA. This review summarizes the main preclinical results that have led to the first administration of AGuIX nanoparticles in humans.Depuis quelques années, l’utilisation des nanotechnologies est au cœur des recherches thérapeutiques. L’utilisation en cancérologie de nanoparticules ouvre un vaste champ d’applications cliniques. En effet, les nanoparticules ont la capacité d’agir comme des radiosensibilisants. Elles permettent d’améliorer l’efficacité de l’irradiation au niveau des cellules tumorales. Leur utilisation pourrait donc être une approche prometteuse pour le traitement local des tumeurs par radiothérapie externe. Dans ce contexte, la société de biotechnologies NH TherAguix (Grenoble, France) développe les nanoparticules AGuIX (Activation and Guidance of Irradiation by X-ray). Ce sont des nanoparticules de très petite taille, de l’ordre de 5 nm, constituées d’une matrice de polysiloxane et de chélates de gadolinium. Elles possèdent des propriétés radiosensibilisantes très importantes ainsi que des propriétés d’agent de contraste, grâce à la présence de gadolinium. D’après les différentes études réalisées, aucun signe de toxicité n’a été observé sur deux espèces animales (rongeurs et singes) après une administration intraveineuse. La biodistribution sur différents modèles animaux a prouvé une accumulation passive et sélective dans les tumeurs grâce à l’effet EPR (Enhanced Permeability and Retention effect) et une élimination rénale des nanoparticules après administration. Un effet radiosensibilisant a également été observé avec différents types d’irradiations in vitro et in vivo, sur plusieurs types de cancers, y compris des modèles radiorésistants. Ces nanoparticules prometteuses sont actuellement en cours d’évaluation dans des essais cliniques, en association avec la radiothérapie dans plusieurs centres en France et aux États-Unis. Cette revue résume ainsi les principaux résultats précliniques qui ont conduit à la première administration chez l’homme des nanoparticules AGuIX