BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy.

INTRODUCTION: Triple-negative breast cancer (TNBC) patients without pathological complete response (pCR) to neoadjuvant chemotherapy have an unfavourable prognosis. TNBC harbouring BRCA-1 germline mutations may be less responsive to taxanes, while sensitivity to DNA-damaging agents is retained. A similar effect was seen in tumours with epigenetic BRCA-1 silencing. Patients without pCR to neoadjuvant chemotherapy consisting of epirubicin plus docetaxel routinely received post-operative CMF at our centre. Here, we investigated the effect of adjuvant CMF in patients with or without BRCA-1 methylation or TP53 mutation. METHODS: DNA was extracted from formalin-fixed paraffin-embedded tissue. For determining BRCA-1 methylation status, quantitative methylation-specific PCR was performed. For the investigation of TP53 mutation status, DNA was PCR amplified and sequenced by Sanger sequencing. RESULTS: Twenty-four patients were included; BRCA-1 methylation was present in 41.7 %, while TP53 mutations were observed in 66.7 %. At a median follow-up of 27.5 months, 20 % of patients with BRCA-1 methylation had a disease-free survival (DFS) event, as compared to 64.3 % in the non-methylated group (p = 0.0472). Median DFS in the non-methylated group was 16 months and was not reached in the methylated group (n.s.). No association TP53 mutation status with clinical outcome was observed. CONCLUSIONS: Adjuvant CMF is of limited activity in TNBC refractory to taxane-based neoadjuvant chemotherapy. In this population, BRCA-1 methylation was associated with a significant decrease in DFS events suggesting a better prognosis and potentially retained activity of DNA-damaging agents.

Whole body hyperthermia by extracorporeal circulation in spontaneously breathing sarcoma patients: hemodynamics and oxygen metabolism.

PURPOSE: This phase I study was performed to evaluate the feasibility and toxicity of a new method of extracorporeal perfusion-induced whole body hyperthermia (WBHT) in patients with advanced sarcoma avoiding the need of intubation and general anesthesia. METHODS: One double-lumen femoral venous access was inserted by Seldinger's technique to obtain WBHT (41.8°C for 120 minutes) via an extracorporeal circuit. No concomitant chemotherapy was applied. Up to 4 treatments of WBHT were performed under moderate sedation in 6 spontaneously breathing patients. Invasive hemodynamic monitoring was performed by use of a pulmonary artery catheter. RESULTS: After their first WBHT session, 2 patients were excluded from further treatment due to transient liver toxicity or catheter-related complication, so a total of 12 cycles remained for analyses. In all patients, conscious sedation resulted in sufficient spontaneous respiration without the need for mandatory ventilation. Median time to reach the target temperature was 84 minutes (range 60-142). Hemodynamic changes revealed the expected hyperdynamic state: heart rate, cardiac index, and stroke volume index significantly increased (p<0.05), whereas blood pressure and systemic and pulmonary vascular resistance index significantly decreased (p<0.05). A net fluid balance of 5822±1766 mL as well as norepinephrine (mean; 0.062 µg·kg¹·min⁻¹) were necessary to maintain the mean arterial blood pressure >60 mmHg. CONCLUSION: Our data demonstrate the feasibility of this method of extracorporeal WBHT without mandatory ventilation. Hemodynamic side effects in spontaneously breathing patients during perfusion-induced WBHT seem less severe than those observed in radiant heat WBHT.

Hypothyroidism in patients with renal cell carcinoma: blessing or curse?

BACKGROUND: Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC. METHODS: Eighty-seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid-stimulating hormone (TSH), tri-iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 µM/mL) with normal T3 and T4 levels. RESULTS: Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14-0.85; P = .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P = .014). CONCLUSIONS: The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered.

Feasibility of two dose-dense FEC regimens with growth factor support for adjuvant therapy in patients with early breast cancer: results from a randomised study of the Central European Cooperative Oncology Group (CECOG).

Addition of epirubicin to adjuvant chemotherapy can provide important benefits for patients with early breast cancer, but the optimal dose remains unclear. Further improvements can be achieved with dose-dense regimens, but densification of fluorouracil/epirubicin/cyclophosphamide (FEC) has proved difficult, with FEC(60) providing little benefit over standard chemotherapy and FEC(100) associated with toxicity. We investigated the feasibility of two intermediate dose-dense FEC regimens. Patients were randomised to six cycles of FEC(75) or FEC(90), with all three drugs given on day 1 of each 14-day cycle. Patients also received pegfilgrastim 6 mg as a single subcutaneous injection on day 2 of each cycle. The primary efficacy endpoint was the proportion of subjects receiving > or =85% relative dose intensity and was achieved by 96% and 88% of patients in the FEC(75) and FEC(90) arms, respectively. Of 147 FEC(75) infusions, 4.1% were delayed, while 9.8% of 143 FEC(90) infusions were delayed. The most common reasons for delay were adverse events and personal/logistical reasons. One dose reduction occurred during the study (FEC(90)), related to diarrhoea. Grade 3-4 haematological toxicities were reported in two patients in the FEC(90) arm. There were no incidences of febrile neutropenia during the study. The most common adverse events were increases in liver enzymes and gastrointestinal events; no event resulted in discontinuation. Only one patient (FEC(90)) experienced serious adverse events (vomiting and throat oedema). In conclusion, dose-dense FEC(75 )and FEC(90) are feasible with pegfilgrastim support. These regimens are associated with a very low risk of Grade 3-4 toxicity.

Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group.

PURPOSE: The multidrug resistance protein 1 (MRP1) is expressed in human breast cancer cells and may contribute to the clinical drug resistance of breast cancer patients. Therefore, we determined the impact of MRP1 expression on the clinical outcome of adjuvant therapy in patients with early-stage breast cancer. PATIENTS AND METHODS: Immunostaining for MRP1 was performed on tissue sections from 516 premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease. Statistical analyses were performed to assess the effect of MRP1 expression on survival and to test for interaction between MRP1 expression and treatment. RESULTS: MRP1 expression independently predicted shorter relapse-free survival (RFS) and overall survival (OS) in patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF; RFS: hazard ratio [HR] = 1.48; 95% CI, 1.16 to 1.88; P = .002; OS: HR = 1.82; 95% CI, 1.10 to 3.01; P = .02), but it did not predict shorter RFS and OS in patients who received tamoxifen plus goserelin (RFS: HR = 0.99; 95% CI, 0.74 to 1.31; P = .9; OS: HR = 0.68; 95% CI, 0.40 to 1.15; P = .1). Tests for interaction between MRP1 expression and treatment were statistically significant for both RFS (P = .04) and OS (P = .006). CONCLUSION: Our data suggest that MRP1 expression plays an important role in the clinical resistance to adjuvant CMF chemotherapy but does not seem to affect response to adjuvant endocrine treatment with tamoxifen plus goserelin. Thus, MRP1 may be a useful marker for the selection of patients with early-stage breast cancer for the appropriate adjuvant therapy after prospective confirmatory evaluation.

Making treatment choices: a physician's discussion of patients' needs.

Medical treatment decisions in early as well as advanced breast cancer follow established guidelines clearly defined by consensus statements, meta-analyses, and evidence-based insights into the biology of the disease, and treatment efficacy. Nevertheless, to treat patients "holistically" while remaining mindful of individual characteristics, physicians must consider patients' concerns regarding the course of their disease, their distress, and, in advanced disease, their knowledge of a limited life expectancy when making treatment choices. Such considerations will contribute to a more satisfactory patient-physician relationship and superior quality of life.