β-Blocker usage and colorectal cancer mortality:a nested case-control study in the UK Clinical Practice Research Datalink cohort

BACKGROUND: Epidemiological and laboratory studies suggest that β-blockers may reduce cancer progression in various cancer sites. The aim of this study was to conduct the first epidemiological investigation of the effect of post-diagnostic β-blocker usage on colorectal cancer-specific mortality in a large population-based colorectal cancer patient cohort.

PATIENTS AND METHODS: A nested case-control analysis was conducted within a cohort of 4794 colorectal cancer patients diagnosed between 1998 and 2007. Patients were identified from the UK Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with a colorectal cancer- specific death (data from the Office of National Statistics death registration system) were matched to five controls. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) according to β-blocker usage (data from GP-prescribing records).

RESULTS: Post-diagnostic β-blocker use was identified in 21.4% of 1559 colorectal cancer-specific deaths and 23.7% of their 7531 matched controls, with little evidence of an association (OR = 0.89 95% CI 0.78-1.02). Similar associations were found when analysing drug frequency, β-blocker type or specific drugs such as propranolol. There was some evidence of a weak reduction in all-cause mortality in β-blocker users (adjusted OR = 0.88; 95% CI 0.77-1.00; P = 0.04) which was in part due to the marked effect of atenolol on cardiovascular mortality (adjusted OR = 0.62; 95% CI 0.40-0.97; P = 0.04).

CONCLUSIONS: In this novel, large UK population-based cohort of colorectal cancer patients, there was no evidence of an association between post-diagnostic β-blocker use and colorectal cancer-specific mortality.

CLINICAL TRIALS NUMBER: NCT00888797.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.

PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.

RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).

CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

PURPOSE: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.

PATIENTS AND METHODS: the presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique.

RESULTS: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes.

CONCLUSIONS: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.

Guidance for laboratories performing molecular pathology for cancer patients

Molecular testing is becoming an important part of the diagnosis of any patient with cancer. The challenge to laboratories is to meet this need, using reliable methods and processes to ensure that patients receive a timely and accurate report on which their treatment will be based. The aim of this paper is to provide minimum requirements for the management of molecular pathology laboratories. This general guidance should be augmented by the specific guidance available for different tumour types and tests. Preanalytical considerations are important, and careful consideration of the way in which specimens are obtained and reach the laboratory is necessary. Sample receipt and handling follow standard operating procedures, but some alterations may be necessary if molecular testing is to be performed, for instance to control tissue fixation. DNA and RNA extraction can be standardised and should be checked for quality and quantity of output on a regular basis. The choice of analytical method(s) depends on clinical requirements, desired turnaround time, and expertise available. Internal quality control, regular internal audit of the whole testing process, laboratory accreditation, and continual participation in external quality assessment schemes are prerequisites for delivery of a reliable service. A molecular pathology report should accurately convey the information the clinician needs to treat the patient with sufficient information to allow for correct interpretation of the result. Molecular pathology is developing rapidly, and further detailed evidence-based recommendations are required for many of the topics covered here.

Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance.

The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution.

Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study

BACKGROUND: Radium-223 dichloride (radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P).

PATIENTS AND METHODS: Analyses were conducted to determine treatment effects of radium-223 plus standard of care (SOC) versus placebo plus SOC on QOL using FACT-P and EQ-5D. Outcomes assessed were percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores during the study.

RESULTS: Analyses were carried out on the intent-to-treat population of patients randomized to receive radium-223 (n = 614) or placebo (n = 307). The mean baseline EQ-5D utility and FACT-P total scores were similar between treatment groups. A significantly higher percentage of patients receiving radium-223 experienced meaningful improvement in EQ-5D utility score on treatment versus placebo {29.2% versus 18.5%, respectively; P = 0.004; odds ratio (OR) = 1.82 [95% confidence interval (CI) 1.21-2.74]}. Findings were similar for FACT-P total score [24.6% versus 16.1%, respectively; P = 0.020; OR = 1.70 (95% CI 1.08-2.65)]. A lower percentage of patients receiving radium-223 experienced meaningful worsening versus placebo measured by EQ-5D utility score and FACT-P total score. Prior docetaxel use and current bisphosphonate use did not affect these findings. Treatment was a significant predictor of EQ-5D utility score, with radium-223 associated with higher scores versus placebo (0.56 versus 0.50, respectively; P = 0.002). Findings were similar for FACT-P total score (99.08 versus 95.22, respectively; P = 0.004).

CONCLUSIONS: QOL data from ALSYMPCA demonstrated that improved survival with radium-223 is accompanied by significant QOL benefits, including a higher percentage of patients with meaningful QOL improvement and a slower decline in QOL over time in patients with CRPC.

The impact of specialized oncology nursing on patient supportive care outcomes

Meeting the supportive care needs of cancer patients remains a challenge to cancer care systems around the world. Despite significant improvements in the organization of medical care of patients with cancer, numerous surveys of cancer populations demonstrate that significant proportions of patients fail to have their supportive care needs met. One possible solution is the introduction of a care coordinator role using oncology nursing to help ensure that patients' physical, psychological, and social support needs are addressed. Although having face validity, there is little empirical evidence on the effects of nurse-led supportive care coordinator roles on patient reported supportive care outcomes. In this article the authors present the results of a prospective longitudinal cohort study of 113 patients referred to a community-based specialist oncology nursing program. Using validated instruments they found significant improvements in patient-reported outcomes in key supportive care domains: unmet needs, quality of life, and continuity of care, as well as a shift in patterns of health resource utilization from acute care settings to the community over the course of the intervention. The results of this study are important in supporting the design and development of controlled trials to examine provider roles in the coordination of supportive cancer care. Copyright © Taylor & Francis Group, LLC.