An exploratory study of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive metastatic breast cancer.

BACKGROUND: This exploratory study assessed the safety, pharmacokinetics, and antitumor activity of sunitinib combined with docetaxel and trastuzumab. METHODS: Patients with unresectable, locally recurrent or metastatic human epidermal growth factor receptor 2 (HER2)+ breast cancer received sunitinib plus docetaxel and trastuzumab. Sunitinib was administered at 37.5 mg/day for 2 weeks on treatment followed by 1 week off (Schedule 2/1). The primary endpoint was safety; secondary endpoints included pharmacokinetics and antitumor activity. RESULTS: Twenty-six patients enrolled; 24 received at least one dose of sunitinib plus docetaxel and trastuzumab, and one patient received one dose of docetaxel and trastuzumab only. These 25 treated patients were evaluable for safety. Twenty-three patients discontinued the study, primarily due to disease progression. The planned dose of sunitinib was maintained in 10 patients and reduced at least once to 25 mg/day in 14 patients. The most common grade 3/4 non-hematologic adverse events were fatigue/asthenia (28%), diarrhea (16%), stomatitis (12%), vomiting (8%) and dyspnea (8%). Neutropenia was reported in all 24 evaluable patients; most events were grade 4. Three grade 1-3 cardiac adverse events occurred. Sunitinib and docetaxel levels were consistent with known single-agent levels, suggesting that there were no clinically relevant drug-drug interactions. Of 22 evaluable patients, 16 (73%) experienced an objective response (all confirmed partial responses). CONCLUSIONS: Sunitinib combined with docetaxel and trastuzumab had an acceptable toxicity profile and showed preliminary antitumor activity as first-line treatment for metastatic HER2+ breast cancer.

Relapse risk after autologous transplantation in patients with newly diagnosed myeloma is not related with infused tumor cell load and the outcome is not improved by CD34+ cell selection: long term follow-up of an EBMT phase III randomized study.

BACKGROUND AND OBJECTIVES: This European Group for Blood and Marrow Transplantation (EBMT) multicentre randomized phase III study was designed to assess the safety and efficacy of CD34+ selection in newly diagnosed myeloma patients undergoing autologous transplantation. DESIGN AND METHODS: One hundred and eleven patients responsive to initial chemotherapy were randomized to receive CD34+ selected (arm A) or unselected PBPC (arm B) after conditioning with high-dose melphalan and TBI. ASO-PCR was used to assess purging efficacy and reinfused tumor load. Tumor load could be assessed in 59 patients. RESULTS: CD34+ selection gave a median tumor cell depletion of 2.2 logs (0.77-5.96). No tumor cells were detected in products infused in 17/26 (A) and 5/33 (B) patients. The five year overall survival (OS), event free survival (EFS) and relapse rate (RR) were 51%, 20% and 80% in arm A and 45%, 18% and 80% in arm B respectively with no significant difference between the two groups. Thirteen patients in arm A and 2 in arm B experienced episodes of serious early infection (p=0.02). There were 3 early transplant related deaths in A but none in B. INTERPRETATION AND CONCLUSIONS: Despite significant tumor cell reduction, CD34+ selection does not reduce RR and increases the risk of severe post-transplant infections. There was also no difference in RR between patients in either arm who received grafts with detectable tumor cells and those receiving grafts with no detectable tumor cells, suggesting that reinfused tumor cells may not be the main cause of relapse after autologous transplant in myeloma.

Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently described genetic cause of hyponatremia in male infants. Whether this X-linked condition could be detected in the adult or also could affect women is unknown. A large five-generation family was identified in which the recently described arginine-vasopressin receptor type 2 (AVPR2) mutation that is responsible for NSIAD was segregated. The proband was a 74-yr-old patient who had a syndrome of inappropriate antidiuresis and whose hyponatremia resisted administration of two AVPR2 antagonists. The phenotype of family members who carry the mutation was investigated. Patients with normal serum sodium were subjected to a water-load test. The previously reported activating missense R137C mutation in the AVPR2 gene in three hemizygous male and four heterozygous female individuals was identified. Except in one woman, spontaneous episodes of hyponatremia or abnormal water-load test were identified in all patients with the mutation, whether male or female. Skewed X inactivation was evidenced in the blood of the asymptomatic woman, which is compatible with preferential inactivation of her mutated allele. NSIAD is not limited to male infants. The diagnosis also should be considered in both male and female adults.

Post-transplantation tumour load in bone marrow, as assessed by quantitative ASO-PCR, is a prognostic parameter in multiple myeloma.

High-dose therapy (HDT) and autologous transplantation prolongs remission duration and survival in multiple myeloma (MM), but relapse still occurs at a median of 2 years post-HDT. In order to investigate whether the number of residual tumour cells in the bone marrow (BM) after transplantation can predict the duration of response, a quantitative allele-specific oligonucleotide polymerase chain reaction (qASO-PCR) assay was used to measure tumour load in BM at 3-6 months post-HDT in 67 patients. The method of maximally selected log-rank statistics was used to test for the existence of a cut-off value in the BM tumour load data set. A cut-off value with respect to progression-free survival (PFS) was identified (P = 0.001). The estimated threshold for placing patients into a "good" or "bad" prognostic group was 0.015% (n = 22 and 38 respectively) with a median PFS of 64 months vs. 16. Multivariate analysis showed grouping by PCR result to be an independent prognostic factor for PFS (estimated hazard ratio after shrinkage, 3.91). This study identifies for the first time a threshold of the post-HDT tumour load with prognostic significance for PFS in MM. Quantitative molecular assessment thus may help to identify those patients who are in need of further treatment early after autologous transplantation.