HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C).

PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)

PURPOSE: Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.

PATIENTS AND METHODS: C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables.

RESULTS: Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk.

CONCLUSION: ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

Systematic Review Protocol to Evaluate the Effectiveness and Cost Effectiveness of Personalised Surveillance after Colorectal Adenomatous Polypectomy

Lifetime risk of developing colorectal cancer (CRC) is 5% and five-year survival at early-stage is 92%. CRC risk following index colonoscopy should establish post-screening surveillance benefit, which may be greater in high-risk patients. This review evaluated published cost-effectiveness estimates of post-polypectomy surveillance to assess the potential for personalised recommendations by risk sub-group. Current data suggested colonoscopy identifies those at low-risk of CRC, who may not benefit from intensive surveillance, which risks unnecessary harms and inefficient use of colonoscopy resources. Meta-analyses of incidence of advanced-neoplasia post-polypectomy for low-risk was comparable to those without adenoma; both rates were under the lifetime risk of 5%. Therefore, greater personalisation through de-intensified strategies for low-risk individuals could be beneficial and could employ non-invasive testing such as faecal immunochemical tests (FIT) combined with primary prevention or chemoprevention, thereby reserving colonoscopy for targeted use in personalised risk-stratified surveillance.
This systematic review aims to:
1. Assess if there is evidence supporting a program of personalised surveillance in patients with colorectal adenoma according to risk sub-group.
2. Compare the effectiveness of surveillance colonoscopy with alternative prevention strategies.
3. Assess trade-off between costs, benefits and adverse effects which must be considered in a decision to adopt or reject personalised surveillance.

Importance of risk factor management in diabetic patients and reduction in Stage B heart failure

BACKGROUND: A number of studies have demonstrated the presence of a diabetic cardiomyopathy, increasing the risk of heart failure development in this population. Improvements in present-day risk factor control may have modified the risk of diabetes-associated cardiomyopathy.

AIM: We sought to determine the contemporary impact of diabetes mellitus (DM) on the prevalence of cardiomyopathy in at-risk patients with and without adjustment for risk factor control.

DESIGN: A cross-sectional study in a population at risk for heart failure.

METHODS: Those with diabetes were compared to those with other cardiovascular risk factors, unmatched, matched for age and gender and then matched for age, gender, body mass index, systolic blood pressure and low density lipoprotein cholesterol.

RESULTS: In total, 1399 patients enrolled in the St Vincent's Screening to Prevent Heart Failure (STOP-HF) cohort were included. About 543 participants had an established history of DM. In the whole sample, Stage B heart failure (asymptomatic cardiomyopathy) was not found more frequently among the diabetic cohort compared to those without diabetes [113 (20.8%) vs. 154 (18.0%), P = 0.22], even when matched for age and gender. When controlling for these risk factors and risk factor control Stage B was found to be more prevalent in those with diabetes [88 (22.2%)] compared to those without diabetes [65 (16.4%), P = 0.048].

CONCLUSION: In this cohort of patients with established risk factors for Stage B heart failure superior risk factor management among the diabetic population appears to dilute the independent diabetic insult to left ventricular structure and function, underlining the importance and benefit of effective risk factor control in this population on cardiovascular outcomes.

Polypharmacy and inappropriate medication use in patients with dementia: an underresearched problem

Multimorbidity and polypharmacy are increasingly prevalent across healthcare systems and settings as global demographic trends shift towards increased proportions of older people in populations. Numerous studies have demonstrated an association between polypharmacy and potentially inappropriate prescribing (PIP), and have reported high prevalence of PIP across settings of care in Europe and North America and, as a consequence, increased risk of adverse drug reactions, healthcare utilisation, morbidity and mortality. These studies have not focused specifically on people with dementia, despite the high risk of adverse drug reactions and PIP in this patient cohort. This narrative review considers the evidence currently available in the area, including studies examining prevalence of PIP in older people with dementia, how appropriateness of prescribing is assessed, the medications most commonly implicated, the clinical consequences, and research priorities to optimise prescribing for this vulnerable patient group. Although there has been considerable research effort to develop criteria to assess medication appropriateness in older people in recent years, the majority of tools do not focus on people with dementia. Of the limited number of tools available, most focus on the advanced stages of dementia in which life-expectancy is limited. The development of tools to assess medication appropriateness in people with mild-to-moderate dementia or across the full spectrum of disease severity represents an important gap in the research literature and is beginning to attract research interest, with recent studies considering the medication regimen as a whole, or misprescribing, overprescribing or underprescribing of certain medications/medication classes including anticholinergics, psychotropics, antibiotics and analgesics. Further work is required in development and validation of criteria to assess prescribing appropriateness in this vulnerable patient population, to determine prevalence of PIP in large cohorts of people with the full spectrum of dementia variants and severities and to examine the impact of PIP on health outcomes.