[Show abstract][Hide abstract] ABSTRACT: Bisphosphonate therapy has been readily accepted as standard of care for individuals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies.
A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone.
The proportion of patients who had an SRE was 30% (28 individuals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days).
This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates.
[Show abstract][Hide abstract] ABSTRACT: The tumour suppressor gene PTEN, located at chromosome sub-band 10q23.3, encodes a dual-specificity phosphatase that negatively regulates the phosphatidylinositol 3'-kinase (PI3 K)/Akt-dependent cellular survival pathway. PTEN is frequently inactivated in many tumour types including glioblastoma, prostate and endometrial cancers. While initial studies reported that PTEN gene mutations were rare in colorectal cancer, more recent reports have shown an approximate 18% incidence of somatic PTEN mutations in colorectal tumours exhibiting microsatellite instability (MSI+). To verify the role of this gene in colorectal tumorigenesis, we analysed paired normal and tumour DNA from 41 unselected primary sporadic colorectal cancers for PTEN inactivation by mutation and/or allelic loss. We now report PTEN gene mutations in 19.5% (8/41) of tumours and allele loss, including all or part of the PTEN gene, in a further 17% (7/41) of the cases. Both PTEN alleles were affected in over half (9/15) of these cases showing PTEN genetic abnormalities. Using immunohistochemistry, we have further shown that all tumours harbouring PTEN alterations have either reduced or absent PTEN expression and this correlated strongly with later clinical stage of tumour at presentation (P=0.02). In contrast to previous reports, all but one of the tumours with PTEN gene mutations were microsatellite stable (MSI-), suggesting that PTEN is involved in a distinct pathway of colorectal tumorigenesis that is separate from the pathway of mismatch repair deficiency. This work therefore establishes the importance of PTEN in primary sporadic colorectal cancer.