MicroRNA-30c expression level is an independent predictor of clinical benefit of endocrine therapy in advanced estrogen receptor positive breast cancer

MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression and which have been implicated in cancer. We evaluated whether five candidate predictive miRNAs, derived from a pilot study in which 249 miRNAs were assayed, were associated with clinical benefit of tamoxifen therapy in advanced breast cancer. These five miRNAs were measured in an independent series of 246 estrogen receptor (ER)-positive primary breast tumors of patients who received tamoxifen for advanced disease by quantitative Real Time PCR. Univariate analysis showed that higher expression levels of hsa-miR-30a-3p, hsa-miR-30c, and hsa-miR-182 were significantly associated with benefit of tamoxifen treatment and with longer PFS (all P-values <0.01). In multivariate analysis, corrected for the traditional predictive factors, only hsa-miRNA-30c was an independent predictor (P-value <0.01). Finally, in an attempt to understand the biology connected to this miRNA, Global testing pathway analysis showed an association of hsa-miRNA-30c expression with HER and RAC1 signaling pathways. We identified hsa-miRNA-30c as an independent predictor for clinical benefit of tamoxifen therapy in patients with advanced breast cancer. Assessment of tumor levels and connected pathways could be helpful to improve treatment strategies.     

Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma

Purpose

Based on improvements of progression-free survival (PFS), new agents for metastatic renal cell carcinoma (mRCC) have been approved. It is assumed that one of the benefits is a delay in health-related quality of life (HRQoL) deterioration as a result of a delay in progression of disease. However, little data are available supporting this relationship. This study aims to provide insight into the most important determinants of HRQoL (including progression of disease) of patients with mRCC.

Methods

A patient registry (PERCEPTION) was created to evaluate treatment of patients with (m)RCC in the Netherlands. HRQoL was measured, using the EORTC QLQ-C30 and EQ-5D-5L, every 3 months in the first year of participation in the study, and every 6 months in the second year. Participation started as soon as possible following a diagnosis of (m)RCC. Random effects models were used to study associations between HRQoL and patient and disease characteristics, symptoms and treatment.

Results

Eighty-seven patients with mRCC completed 304 questionnaires. The average EORTC QLQ-C30 global health status was 69 (SD, 19) before progression and 61 (SD, 22) after progression of disease. Similarly, the average EQ-5D utility was 0.75 (SD, 0.19) before progression and 0.66 (SD, 0.30) after progression of disease. The presence of fatigue, pain, dyspnoea, and the application of radiotherapy were associated with significantly lower EQ-5D utilities.

Conclusions

Key drivers for reduced HRQoL in mRCC are disease symptoms. Since symptoms increase with progression of disease, targeted therapies that increase PFS are expected to postpone reductions in HRQoL in mRCC.

     

Cardiotoxicity from intensive chemotherapy combined with radiotherapy in breast cancer.

Cardiac function was evaluated in 86 breast cancer patients after standard chemotherapy, followed by ablative chemotherapy and chest irradiation. One patient died of subacute heart failure 3 months after ablative chemotherapy. At a minimum of 1 year''s follow-up (range 1-11 years) left vertricular ejection fraction (LVEF) was marginally abnormal in 4 of 27 disease-free survivors. One exceptional patient who received two transplantations is alive, with serious heart failure occurring after the second ablative chemotherapy. Including this patient, the percentage of patients free of clinical and subclinical cardiac dysfunction at 7 years is 78% (95% CI 61-95%). After ablative chemotherapy, cardiotoxicity was rarely life-threatening. The impact of subclinical cardiotoxicity in the long term is not clear and needs continued evaluation.     

Bleeding prophylaxis in autologous bone marrow transplantation for solid tumors. Comparison of cryopreserved autologous and fresh allogeneic single-donor platelets

Bleeding prophylaxis with cryopreserved autologous thrombocytes was evaluated in 43 patients treated with high-dose chemotherapy and autologous bone marrow transplantation. Platelet transfusions were given prophylactically. Nineteen patients received only autologous, 10 only fresh allogeneic single-donor, and 14 both types of transfusions. The effects of 104 autologous versus 93 allogeneic thrombocyte transfusions were compared. The increment at 1 h was for allogeneic platelets twice that for autologous platelets (30.6 versus 15.2 x 10(9)/l), but the interval between transfusions in days (2.3) was the same. Twelve patients received alternating autologous platelet transfusion after washing out the cryoprotectant dimethyl sulfoxide (18 transfusions) and non-washed autologous platelets (24 transfusions). Platelet increments, corrected increments, and predicted recovery were not influenced by omitting the washing procedure, and no side effects of dimethyl sulfoxide occurred.     

Dacarbazine (DTIC)-based chemotherapy or chemoimmunotherapy of patients with disseminated malignant melanoma.

Combinations of dacarbazine (DTIC) and other cytotoxic agents or alpha-interferon were given to 136 patients in five different regimens. The total response rate was 32% (95% confidence interval 24-40%); 13% had a complete remission. Female patients had a significantly higher chance of response than male patients: 46% vs 23%. There was also a difference in complete response rate: 25% vs 9%. The overall survival was 6 months; 8% of patients had a response of more than 6 months and 2% of more than 2 years. Although response rates vary among the various regimens described in the literature, the complete response rates are quite similar and the long-term disease-free survival of these combinations may be similar to that of dacarbazine alone.     

Incidence and effects of herpes simplex virus infection after autologous bone marrow transplantation for solid tumours

In a prospective study of 44 patients, who underwent autologous bone marrow transplantation (ABMT) for solid tumours, the results of serial viral cultures and determination of complement-fixing antibodies to herpes simplex virus (HSV) were analysed. No primary infections with HSV occurred. Of 31 initially HSV-seropositive ABMT patients, 61% developed positive HSV cultures. Half of these patients showed a significant antibody rise. Active HSV infection did not influence the recovery of the bone marrow after ABMT, but coincided with a significantly increased number of febrile days.     

Gonadal function after surgery and chemotherapy in men with stage II and III nonseminomatous testicular tumors

The gonadal functions were studied in 54 patients with disseminated nonseminomatous testicular tumors who had been subjected to combination chemotherapy (cisplatin, vinblastine, and bleomycin [PVB]) and surgery (hemiorchiectomy, retroperitoneal lymph node dissection or removal of retroperitoneal residual tumor after chemotherapy) and in 17 patients with a stage I tumor subjected to hemiorchiectomy exclusively. In the patients treated with chemotherapy, the plasma testosterone levels remained at the lower limit of normal and the luteinizing hormone (LH) levels remained elevated for 2 years after completion of treatment. The follicle-stimulating hormone (FSH) levels also remained significantly elevated, but showed a tendency to decrease after 2 years. Semen analysis was performed in 25 patients; of the other patients, 18 had no antegrade ejaculation, eight had undergone a vasectomy and three patients did not cooperate. Before treatment, 72% of the patients showed azoo- or oligozoospermia; 2 years after discontinuation of the chemotherapy, 48% had azoo- or oligozoospermia while 28% had more than 60 X 10(6) spermatozoa/mL. However, interestingly the proportion of patients with azoospermia had increased from 4% to 28%. In the course of this study, eight pregnancies occurred; one ended in an early spontaneous abortion; the other seven pregnancies ran an uncomplicated course. Seven healthy children were born. In 17 patients with a stage I tumor treated by hemiorchiectomy only, the testosterone, LH and FSH levels were also observed for 2 years; until 2 years after treatment, the testosterone levels remained lower and the FSH levels remained higher than normal. Insufficiency of the Leydig's cells in the unaffected gonad appeared to be responsible for the altered hormone concentrations in the blood.