Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer.

Purpose: Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy.Experimental Design: We evaluated FRα expression in breast cancers by genomic (n = 3,414) and IHC (n = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro, and in human TNBC xenograft models.Results: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth.Conclusions: FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. Clin Cancer Res; 24(20); 5098-111. ©2018 AACR.

[Metformin treatment with or without life style changes in patients with polycystic ovary syndrome]. / Metforminkezelés hatása életmódbeli változtatással vagy változtatás nélkül polycystás ovárium szindrómában.

UNLABELLED: Treatment with metformin three times 500 mg daily had been advised since 2002, to patients suffering from the polycystic ovary syndrome diagnosed by the Rotterdam criteria and who did not want to take contraceptive pills. More recently, life style changes have also been introduced to treatment recommendation: increased physical activity, low glycaemic index diet; also with calorie restriction for the obese patients. AIM: To assess the efficacy of the two treatment forms on clinical symptoms of the disease. METHOD: The metformin only historical control group (metformin monotherapy) consisted of 27 patients between the ages from 18 to 39 years (mean 29 years); to which was the age-matched metformin and life style changes group (triple basal therapy) of 29 patients compared. The following parameters were registered at the beginning and the end of a six-month treatment period: global acne score, Ferriman-Gallwey hirsutism score, body mass index, waist-to-hip circumference ratio, and menstrual cycles. RESULTS: By the end of the treatment period, both acne and hirsutism scores improved significantly in both treatment groups (P<0.001); the improvements did not differ between them: acne 8.6±5.7 vs. 9.2±5.9 (P = 0.70); hirsutism 2.5±2.0 vs. 2.6±1.6 (P = 0.83). Body mass index and waist-to-hip ratio remained practically unchanged in the metformin only group: 0.26±1.0 kg/m2 (P = 0.21) and 0.001±0.02 (P = 0.71). Body mass index decreased in the triple therapy group by 0.91±1.1 kg/m2 (P<0.001); and waist-to-hip ratio by 0.019±0.03 (P<0.001). The decrease of the body mass index was more remarkable in overweight patients: 1.10±1.26 kg/m2 (P = 0.002) vs. 0.64±0.88 kg/m2 (P = 0.03) in lean patients. Recommendation on life style changes with metformin did not show further improvement of hyperandrogenic symptoms in comparison to metformin alone but the combined therapy diminished body size indexes. CONCLUSION: Authors recommend the triple basal treatment consisting of metformin, physical exercise and low glycaemic index diet to their patients with polycystic ovary syndrome for assessment of its long-term efficacy.

[Treatment experience with metformin in polycystic ovary syndrome]. / Polycystás ovarium szindróma metforminkezelésével szerzett tapasztalatok.

Based on the favourable international experience with metformin in the most common female endocrine disease, the polycystic ovary syndrome, which has insulin resistance in the background, the author's treatment advice has been this in such cases since early 2002: for sexually active women who do not want to become pregnant for the time being, anti-androgenic contraceptive pill; for those who do not want to take contraceptives, contraceptives are contraindicated, or who do want to conceive, metformin. 44/71 non-diabetic patients opted for metformin treatment. A 3 to 30 month follow-up period of 25 patients could be evaluated. Seven patients had transient vertigo, diarrhoea or abdominal discomfort at the beginning of the treatment. The severity of acne of 21 patients diminished significantly by three months and the acne score fell close to the half value by six months. Body hair of 17 women with hypertrichosis diminished significantly by six months. Menstrual cycles of 8/13 patients became regular by three months; a further woman became pregnant and continued metformin throughout pregnancy. Her blood pressure remained normal despite suffering from pre-eclampsia during all of her previous pregnancies. The average body mass index and waist-to-hip ratio did not change significantly during the follow-up. Apart from few initial, transient side effects, disadvantages of the treatment were not found. Long-term metformin treatment resulted in significant improvement of the symptoms of patients with polycystic ovary syndrome.