Summary
Somatic mutations of ERBB2 (HER2) and
ERBB3 (HER3) are found in a wide range of cancers.
Preclinical modelling suggests that a subset lead to constitutive HER2
activation, but most remain biologically uncharacterized. We sought to
prospectively define the biologic and therapeutic significance of known
oncogenic HER2 and HER3 mutations and variants of unknown biological
significance by conducting a multi-histology, genomically selected,
‘basket’ study utilizing the pan-HER kinase inhibitor neratinib
(SUMMIT; Clinicaltrials.gov NCT01953926). Efficacy in HER2-mutant cancers varied
as a function of both tumour type and mutant allele to a degree not predicted by
preclinical models, with the greatest activity seen in breast, cervical and
biliary cancers and with tumours harbouring kinase domain missense mutations.
This study demonstrates how a molecularly driven clinical trial can be used to
further refine our biological understanding of both characterized and novel
genomic alterations with potential broad applicability for advancing the
paradigm of genome-driven oncology.
The pre-emptive skin treatment regimen was well tolerated. The incidence of specific >or= grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the pre-emptive group compared with the reactive group. Patients in the pre-emptive group reported less QOL impairment than patients in the reactive group.
Over the last 15 years, substantial progress has been made in understanding the potential and the limitations of the CA 125 assay. More than 2000 papers have been published concerning laboratory and clinical studies of CA 125. The original CA 125 assay utilized the OC 125 antibody that recognizes the CA 125 epitope on a high molecular weight glycoprotein. Despite repeated attempts, the gene encoding the peptide component has not yet been cloned. Monoclonal antibodies have been raised against other epitopes expressed by this molecule, leading to the development of the CA 125-II assay that exhibits less day-to-day variation. Using either assay, elevated levels of CA 125 are detected in a number of benign conditions, including endometriosis. CA 125 is most consistently elevated in epithelial ovarian cancer, but can be expressed in a number of gynecologic (endometrial, fallopian tube) and non-gynecologic (pancreatic, breast, colon and lung) cancers. The best established application of the CA 125 assay is in monitoring ovarian cancer. The rate of decline in CA 125 during primary chemotherapy has been an important independent prognostic factor in several multivariate analyses. Persistent elevation of CA 125 at the time of a second look surgical surveillance procedure predicts residual disease with > 95% specificity. Rising CA 125 values have preceded clinical detection of recurrent disease by at least 3 months in most, but not all studies. Given the modest activity of salvage chemotherapy, this information has not yet impacted on survival. Rising CA 125 during subsequent chemotherapy has been associated with progressive disease in more than 90% of cases. CA 125 may serve as an effective surrogate marker for clinical response in phase II trials of new drugs. CA 125 levels can aid in distinguishing malignant from benign pelvic masses, permitting effective triage of patients for primary surgery. Early detection of ovarian cancer remains the most promising application of CA 125. An algorithm has been developed that estimates the risk of ovarian cancer (ROC) based upon the level and trend of CA 125 values. A major trial has been initiated that uses the ROC algorithm to trigger transvaginal sonography and/or subsequent laparotomy. Such a trial could demonstrate improvement in survival through early detection. This strategy should provide adequate specificity, but sensitivity for early stage disease may not be optimal. In the future, improved sensitivity may be attained using multiple markers and neural network analysis. Most serum tumor markers have been proteins or carbohydrates, but lipid markers such as lysophosphatidic acid deserve evaluation. Genomic and proteonomic technologies should identify additional novel markers.
More than 95% of HoFH patients have a mutation in the LDL receptor, <4% in have a mutation in apolipoprotein B, and <0.5% have a mutation in proprotein convertase subtilisin/kexin 9 (PCSK9). 2,3 Although true genetic HoFH is not uncommon, the majority of patients are compound heterozygotes. 4 The residual LDL receptor activity, either negative (<2% function) or defective (2%-25% function), is associated with severity of LDL cholesterol elevation and the propensity for early cardiovascular disease.
1
Clinical Perspective on p 2120Conventional therapies such as statins 5,6 and ezetimibe 7 are the most commonly used drugs for HoFH and result in LDL cholesterol reductions of 15% to 25%. Patients usually also require LDL apheresis when available. 8 These improvements in LDL cholesterol, particularly with statins, appear to reduce cardiovascular disease morbidity and mortality.
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