Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.

BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33-83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole.

BACKGROUND: Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. METHODS: Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. RESULTS: Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0-67.2, n=150) when BMI was <25.0 kg m(-2); 65.6 (57.8-74.6, n=154) when 25.0-29.9 kg m(-2); 59.3 (47.1-74.6, n=50) when 30.0-34.9 kg m(-2); and 43.3 (23.0-81.7, n=16) when ≥35.0 kg m(-2). No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. CONCLUSIONS: Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: long term results of the Italian Tamoxifen Anastrozole trial.

The Italian Tamoxifen Anastrozole (ITA) trial investigated the efficacy of switching to anastrozole for women who were already on adjuvant tamoxifen since 2-3years. Relapse-free survival (RFS) was the primary end-point; event-free survival (EFS), overall survival (OS) and safety were secondary end-points. Herein, we report an update on the long term results of this trial. At a median follow-up time of 128 months (range 14-168 months), 94 events have been recorded in the tamoxifen group compared with 71 events in the anastrozole group (hazard ratio (HR)=0.71; 95% confidence interval (CI), 0.52-0.97; p=0.03). RFS was also significantly longer in the anastrozole group (HR=0.64; 95% CI, 0.44-0.94; p=0.023); no statistically significant difference between study arms concerning OS was shown, but the trial was not powered enough in respect to this end-point. The incidence of serious adverse events (SAE) like bone fractures was comparable (four in each arm), while gynaecological problems were still significantly more numerous among the women continued on tamoxifen (21 patients developed a SAE in this group, including eight endometrial cancers, compared to three patients who suffered from a SAE, including one endometrial cancer, in the anastrozole group: p<0.000). Present data confirm that switch is safe and can provide long-term gain in terms both of RFS and of EFS, which persists even several years since treatment discontinuation.

Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women with early breast cancer treated with letrozole.

Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85-274) at baseline, 35 pg/mL (12-64) at 6-weeks, 29 pg/mL (17-48) at 6 months and 25 pg/mL (8-46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial.

BACKGROUND: Tamoxifen, for many years the 'gold standard' in the adjuvant setting for the management of endocrine sensitive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy due to the development of resistance. This provided the rationale for a switching trial with anastrozole, the updated results of which are reported here. PATIENTS AND METHODS: This trial investigated the efficacy of switching to anastrozole for women already receiving tamoxifen. After 2-3 years of tamoxifen treatment, postmenopausal, node-positive, ER-positive patients were randomized to receive either anastrozole 1 mg/day or to continue tamoxifen, 20 mg/day, giving a total duration of 5-years treatment. The primary end point was disease-free survival and secondary endpoints were event-free survival, overall survival and safety. RESULTS: A total of 448 patients were enrolled. At a median follow-up time of 64 months (range 12-93), 63 events had been reported in the tamoxifen group compared with 39 in the anastrozole group [HR 0.57 (95% CI 0.38-0.85) P = 0.005]. Relapse-free and overall survival were also longer in the anastrozole group [HR 0.56 (95% CI 0.35-0.89) P = 0.01 and 0.56 (95% CI 0.28-1.15) P = 0.1]. However, the latter difference was not statistically significant. Overall more patients in the anastrozole group experienced at least one adverse event (209 versus 151: P = 0.000). However, numbers of patients experiencing serious adverse events were comparable (37 versus 40, respectively: P = 0.7). CONCLUSIONS: Switching to anastrozole after the first 2-3 years of treatment was confirmed to improve event-free and relapse-free survival of postmenopausal, node-positive, ER-positive early breast cancer patients already receiving adjuvant tamoxifen.

[Biologic therapy and epithelial ovarian cancer]. / La terapia biologica nel tumore epiteliale dell'ovaio.

The identification of new molecular prognostic and predictive factors for ovarian cancer may contribute in deciding individual therapeutic strategies; on the other hand, there has been growing interest in new biologic therapies to correct molecular or genic lesions of neoplastic cells (genic therapy), or to activate the specific immune response (immunological therapy). Chemotherapy collateral toxic effects, as myelotoxicity, should be reduced through transfection of genes that modulate drug resistance in stem cells. The data at present available suggest then the potential role of these new treatments, are more specific and less toxic than current therapies; however, other biological-molecular studies are required to obtain the clinical applications of the results: Aim of this study is to provide a review of the most interesting data in ovarian cancer biologic therapy.

Oral squamous carcinoma in a patient with cervix cancer: use of human papillomavirus analysis to differentiate synchronous versus metastatic tumor.

BACKGROUND: Cervical cancer usually spreads by direct infiltration and disseminates by lymphatic and hematogenous pathways. The common sites of distant metastases are the lungs, liver, and bones. Other rare metastatic sites have been previously described including only one case of oral cavity metastasis. CASE: We present here the second case of a patient with apparent oral cavity metastasis from cervical cancer. By cloning specific human papilloma virus (HPV) genomic regions, the two lesions showed HPV genomic sequences from different viruses (18 and 33, for the uterine cervix and the oral cavity, respectively), thus indicating the oral lesion as a synchronous second primary tumor. CONCLUSION: The use of molecular markers to distinguish between a secondary and a primary lesion is recommendable in cervical cancer, particularly when reporting rare site metastases.

[The role of aromatase inhibitors in the treatment of breast neoplasms. An evaluation of clinical efficacy and the tolerability profile]. / Il ruolo degli inibitori dell'aromatasi nel trattamento del tumore della mammella.

Constant acquisitions regarding endocrine pathogenesis and the biology of breast neoplasms have led to the evolution of hormone manipulation as a therapeutic option in patients suffering from this disease. There has been a shift from ablative surgical procedures to the use of drugs offering greater clinical efficacy and an improved tolerability profile. Since the late 1970s tamoxifen has been regarded as the gold standard for hormone treatment in hormone-responsive breast neoplasm, but promising new endocrine agents are now being compared in random trials. Of these, the latest generation of aromatase inhibitors appears to gather the widest consensus on the basis of the results published to date. This article aims to review this new category of drugs, illustrating their rationale of use, the results obtained in the treatment of breast neoplasm and the main studies in which they are currently being investigated.

[Sexuality in menopause. Importance of adequate replacement therapy]. / Sessualità in menopausa. L'importanza di un adeguato trattamento sostitutivo.

BACKGROUND AND AIMS: The harmful repercussions of estrogen deficiency in menopause on the female organism are also responsible for reduced libido and uncomfortable trophic disorders of the genitourinary tract leading to reduced vaginal lubrication and severe alterations affecting sexual function, as well as for the more commonplace vasomotor phenomena and psychoemotive changes. METHODS: The authors treated 102 menopausal patients who presented reduced libido and orgasmic difficulties, as well as other menopausal problems, with 17-beta estradiol+noretisterone acetate using a transdermal route. The main advantage offered by the transdermal route is that conjugated estrogens "bypass" the liver and reach the target organs in an unmodified manner. This treatment is well tolerated by almost all patients, even those suffering from slight gastroenteric and hepatic problems. RESULTS AND CONCLUSIONS: This study showed the good tolerability and almost complete innocuousness of the drug used. None of the patients receiving replacement therapy reported any collateral effects worthy of note or the onset of malignant lesions of the breast or pelvic organs. The results obtained show that the use of 17-beta estradiol+noretisterone acetate can effectively modify menopausal symptoms, improving both quality of life and sexual function.

[Abnormal uterine bleeding during climacteric. Correlation between transvaginal ultrasonography, hysteroscopy and histology]. / Sanguinamenti uterini anomali in climaterio. Correlazioni fra ecografia transvaginale, isteroscopia e istologia.

BACKGROUND AND AIMS: The authors evaluated the accuracy of ultrasonographic findings compared to hysteroscopic and histological results in the diagnosis of anomalous uterine bleeding in menopause. METHODS: Forty-eight women suffering from the above pathology and attending the Preventive Gynecology outpatient clinic of Department C of the Gynecology and Obstetrics faculty at Turin University during the period between September 1996 and July 1997, underwent first ultasonography using a transvaginal probe and then outpatient hysteroscopy with endometrial biopsy. RESULTS: A total overlap between the ultrasonographic image, hysteroscopic results and histological diagnosis was only obtained in the group of menopausal patients. CONCLUSIONS: In line with the data reported in the literature, the authors imposed a cut-off endometrial thickness of 4 mm above which further diagnostic tests were performed using hysteroscopy with targeted biopsy.

[Abnormal uterine hemorrhage in the climacteric. Diagnostic approach]. / Sanguinamenti uterini anomali in climaterio. Approccio diagnostico.

Having made a detailed list of the invasive and non-invasive diagnostic techniques used to evaluate anomalous uterine bleeding in menopause, the authors conclude by affirming that hysteroscopy undoubtedly represents the most reliable diagnostic technique and that echography should be the preferred first diagnostic step since it allows the adnexa to be examined and is less invasive and cheaper.

[Anomalous uterine hemorrhages in the climacteric. Their etiopathogenesis]. / Sanguinamenti uterini anomali in climaterio. Eziopatogenesi.

Anomalous uterine bleeding accounts for approximately two-thirds of the causes of outpatient gynecological check-ups for women in menopause. The high incidence of this pathology raises considerable problems from a clinical and social point of view. In this paper the authors outline the main causes of both organic and functional bleeding.

[Menopause. Hormone substitution therapy and prevention of cardiovascular risk]. / Menopausa. Terapia ormonale sostitutiva (HRT) e prevenzione del rischio cardiovascolare.

BACKGROUND AND AIMS: Cardiovascular disease is the major cause of death in over 60-year-old women. The mean age of onset is about 10 years later in women compared to men, a difference which can be explained by the end of physiological estrogen production in menopause. METHODS: The authors treated a group of 68 menopausal patients with HRT for a period of 5 years. RESULTS: A series of positive effects emerged from the study which were potentially capable of preventing ischemic cardiopathy. CONCLUSIONS: The authors reached the conclusion that--owing to its beneficial effects on lipid and glucose metabolism, as well as on coagulation factors and arterial pressure--HRT is able to prevent cardiovascular disease, reducing the risk of infarction by between 20 and 50%.

[Clinical efficacy of tamoxifen in the treatment of premenstrual mastodynia]. / Efficacia clinica del tamoxifene nel trattamento della mastodinia premestruale.

BACKGROUND: Premenstrual syndrome (PMS), which was first described by Frank in 1931, is a clinical condition that is not easy to classify in terms of either symptoms or from a diagnostic and therapeutic point of view. AIMS: The aim of this study was to evaluate the efficacy of tamoxifen, an antiestrogen drug, using a double-blind study with placebo in the treatment of mastodynia, one of the most frequent symptoms of PMS, given that an absolute or relative increase in estrogens is one of the most controversial etiopathogenetic hypotheses. METHODS: The study included a group of 88 outpatients aged between 22 and 40 with regular menstrual cycles and intense mastodynia. Before commencing therapy, a detailed medical history was compiled for each subject and all underwent a gynecological and breast examination, hematochemical and instrumental tests (scan and mammography) in order to rule out other PMS-related organic pathologies. The patients were randomly divided into two groups of 44: one group received tamoxifen at a dose of 10 mg by mouth from day 5 to day 24 of the menstrual cycle, whilst a placebo was administered to the other group using the same dosage scheme. All women underwent a thorough control examination at the end of treatment and two months after the end of treatment. RESULTS: At the end of treatment 90% of patients reported a complete resolution of symptoms, whilst 10% only showed a slight improvement. In the control group, 86% showed a transitory reduction in symptoms and 13% did not report any improvement. CONCLUSIONS: On the basis of the results obtained, the authors affirm the validity and efficacy of tamoxifen in the treatment of mastodynia in PMS owing to both its innocuity and its atoxity.

[Abnormal uterine hemorrhage in climacteric. Medical management]. / Sanguinamenti uterini anomali in climaterio. Terapia medica.

Following a review of the literature, the authors examine the drugs which are currently used to treat anomalous uterine bleeding during menopause, illustrating their aims and justifying the rationale underlying their use. They conclude by stating that a satisfactory treatment often does not exist, but it is the task of the specialist to gauge the level and sequence of treatments in order to achieve the hoped-for result.

[Use of a GnRH analogue (leuprorelin) in the therapy of endometriosis]. / Utilizzazione di un analogo del GnRH (leuprorelin) nella terapia dell'endometriosi.

BACKGROUND: Endometriosis is undoubtedly an extremely complex disease from both a diagnostic and therapeutic point of view. The finding that the continuous administration of GnRH analogs suppresses gonadotropin release by the hupophysis, thus blocking ovary function, has promoted researchers to use these drugs in the treatment of endometriosis. AIM: Having reviewed the data reported in the literature, the authors selected from the numerous drugs used to resolve implants (oestroprogestogens, danazol, progestogens, clomiphene citrata, GnRH analogs), a GnRH analog with a depot action known as leuprorelin (D-Leu6-Pro9-NH-Ethylamide). MATERIALS AND METHOD: This drug was administered to 98 patients suffering from endometriosis at a dose of one intramuscular phial every 30 days for six months. RESULTS AND CONCLUSIONS: The results obtained (complete resolution of disease in 610.2% of cases, partial remission in 30.6% of cases, transient improvement in 9.2% of cases owing to reduced patient compliance, percentage of pregnancies after treatment 12%), allow the authors to conclude that the use of a GnRH antagonist, like leuprorelin, owing to its efficacy and good tolerability, represents a valid alternative to oestroprogestogens and Danazol in the treatment of implants and the symptoms of endometriosis.

[Dysspermia due to inflammation. The evaluation of sperm cultures]. / Dispermie su base flogistica. Valutazione delle spermioculture.

The study evaluates 160 cases of positive spermioculture taken from 522 sterile individuals examined by the authors at the Couple Sterility Outpatient unit in Department A of the Institute of Gynecology and Obstetrics at Turin University during the period between January 1984 and December 1993. The germs responsible for infection were assayed in order to evaluate the strains which showed the highest incidence every year. Whereas there was no significant change in the absolute number of cases of sterility over the period, the number of cases caused by infection increased significantly during the second five-year period. It was found that the germs predominantly implicated in the genesis of male sterility formed part of the so-called mixed flora group, responsible in women for syndromes of often asymptomatic bacterial vaginosis which are not identified and consequently not treated.

Asymptomatic bacteriuria in pregnancy: a diagnostic and therapeutic approach.

Pregnancy is a predisposing factor for urinary tract infection and pregnant women suffering from this pathology are exposed to dangerous risks which may condition maternal wellbeing and fetal prognosis. The apparently paradoxal finding of a higher incidence of perinatal problems in pregnant women with asymptomatic bacteriuria compared to those with manifest infections may be explained by the fact that the latter are adequately treated, whereas asymptomatic bacteriuria, which is difficult to diagnose, may continue in a subtle form for the entire duration of pregnancy. This emphasises the importance of the early diagnosis of infection using a protocol based on urine tests and urine culture and the adequate treatment of all cases of asymptomatic bacteriuria in order to reduce the incidence of maternal and fetal complications (acute pyelonephritis, increased fetal morbidity and mortality). The choice of the antibiotic to be used must be made on the basis of the urine culture test, the stage of gestation, maternal clinical data and the characteristics of the antibiotic itself (pharmacokinetics, maternal and fetal toxicity). With regard to the treatment protocol, the "single-dose" protocol is currently preferred. After negative urine culture tests, all patients must carry out a complete urine test each month with hormonal and echographic monitoring of the fetoplacental unit.

Asymptomatic bacteriuria in pregnancy: maternal and fetal complications.

From an analysis of the data reported in the literature it is clear that pregnancy is a predisposing factor for urinary tract infection and that pregnant women with this pathology are exposed to dangerous risks which may influence maternal wellbeing and fetal prognosis. Authors do not concur on the specific risks to the mother and fetus, one reason being that the statistics reported to date reveal discrepancies relating to the presence of disorders prior to pregnancy and the environmental, working and socio-hygienic conditions of the populations studied. The apparently paradoxical finding of a higher incidence of perinatal problems in pregnant women with asymptomatic bacteriuria compared to manifest forms can be attributed to the fact that the latter are treated with adequate therapies whereas asymptomatic bacteriuria, which is difficult to diagnose, may persist throughout pregnancy. This underlines the importance of early diagnosis using a protocol which entails the execution of serial urine tests and urine cultures and adequate treatment of all cases of asymptomatic bacteriuria in order to reduce the incidence of urinary tract infections and materno-fetal complications. Non-treated asymptomatic bacteriuria in fact represents a considerable risk factor since it may lead to the onset of acute pyelonephritis in approximately 5% of pregnant women and may increase the risk of fetal mortality.

[Intramuscular beta-interferon in the treatment of cervical intraepithelial neoplasia (CIN) associated with human papilloma virus (HPV) infection]. / Beta-interferone per via intramuscolare nel trattamento delle neoplasie cervicali intraepiteliali (CIN) associate ad infezione da human papilloma virus (HPV).

In an attempt to find less aggressive and more efficacious tools for the treatment of cervical neoplasia (CIN) associated with genital HPV infection, the authors have examined a therapeutic approach based on the strengthening of natural defences. For this purpose, a group of 10 patients diagnosed with CIN associated with HPV infection received beta-IFN therapy at a dose of 300,000 UI/die i.m. for 7 days, continuing the same dose on alternate days for 2 weeks. At the end of the follow-up results were satisfactory especially if compared with those from a control group of 9 patients. These results appear to indicate beta-IFN as the treatment of choice in HPV infections in young women wishing to have children in order to preserve the anatomic and functional integrity of the lower genetical tract.