MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.

Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment.

BACKGROUND: Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. METHODS AND RESULTS: A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10,001 ("Treating to New Targets") and 8888 ("Incremental Decrease in End Points through Aggressive Lipid Lowering") patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters. CONCLUSIONS: In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful.

High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies.

OBJECTIVES: This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary artery disease (CAD), with a focus on the effect of very high values of these parameters. BACKGROUND: High plasma levels of HDL-C and apoA-I are inversely related to the risk of CAD. However, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed. METHODS: We conducted a post-hoc analysis of 2 prospective studies: the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk case-control study, including apparently healthy individuals who did (cases, n = 858) or did not (control patients, n = 1,491) develop CAD during follow-up. In IDEAL, only HDL-C and apoA-I were available; in EPIC-Norfolk, nuclear magnetic resonance spectroscopy-determined HDL particle sizes were also available. RESULTS: In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies. CONCLUSIONS: When apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This does not hold true for very high levels of apoA-I at fixed levels of HDL-C and apoB. These findings may have important consequences for assessment and treatment of CAD risk.

The role of CETP inhibition in dyslipidemia.

Cholesteryl ester transfer protein (CETP) inhibitors are currently being investigated because of their ability to increase high-density lipoprotein cholesterol levels. In various metabolic settings, the relationship between CETP and lipoprotein metabolism is complex and may depend largely on the concentration of triglyceride-rich lipoproteins. Two CETP inhibitors, JTT-705 and torcetrapib, are in an advanced phase of development. Following hopeful intermediate results, a large endpoint study using torcetrapib has just been discontinued due to increased mortality in torcetrapib-treated subjects. In this review we summarize clinical data on the use of CETP inhibitors.

Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk.

BACKGROUND: An elevated apolipoprotein B-apolipoprotein A-I (apo B-apo A-I) ratio is a risk factor for future coronary artery disease (CAD). It is not known whether this ratio is better than traditional lipid values for risk assessment and prediction and whether it adds predictive value to the Framingham risk score. OBJECTIVE: To evaluate whether the apo B-apo A-I ratio is associated with future CAD events independent of traditional lipid measurements and the Framingham risk score and to evaluate the ability of this ratio to predict occurrence of future CAD. DESIGN: Prospective, nested case-control study. SETTING: Norfolk, United Kingdom. PARTICIPANTS: Apparently healthy men and women (45 to 79 years of age) in the European Prospective Investigation into Cancer and Nutrition-Norfolk. Cases (n = 869) were persons who developed fatal or nonfatal CAD. Controls (n = 1511) were persons without CAD who were matched for age, sex, and enrollment period. MEASUREMENTS: Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein, and C-reactive protein levels were measured directly. Low-density lipoprotein (LDL) cholesterol values were calculated by using the Friedewald formula. RESULTS: The apo B-apo A-I ratio was associated with future CAD events, independent of traditional lipid values (adjusted odds ratio, 1.85 [95% CI, 1.15 to 2.98]), including the total cholesterol-HDL cholesterol ratio, and independent of the Framingham risk score (adjusted odds ratio, 1.77 [CI, 1.31 to 2.39]). However, it did no better than lipid values at discriminating between CAD cases and controls (area under the receiver-operating characteristic curve, 0.670 for total cholesterol-HDL cholesterol ratio vs. 0.673 for apo B-apo A-I ratio [P = 0.38]) and added little to the predictive value of the Framingham risk score (area under the receiver-operating characteristic curve, 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus apo B-apo A-I ratio [P < 0.001]). In addition, it incorrectly classified 41.1% of cases and 50.4% of controls. LIMITATIONS: No participant was taking lipid-lowering medication, and diabetes was uncommon. CONCLUSIONS: The apo B-apo A-I ratio is independently associated with, but adds little to, existing measures for CAD risk assessment and discrimination in the general population. Other characteristics of the test, such as the ability to perform it on nonfasting samples, may still make it useful in some settings.

Dyslipidaemia as predictor of progressive renal failure and the impact of treatment with atorvastatin.

BACKGROUND: In patients with chronic renal disease, other lipid markers than total cholesterol or low density lipoprotein (LDL)-cholesterol are probably more appropriate to detect a potential lipid-related risk for progression to renal failure. Statin therapy might be protective. METHODS: From 1999 to 2001, 177 consecutive patients with renal disease from our out-patient clinic were included and 169 could be followed-up for a mean period of 4.1 years. Seventy-two progressive patients (end-stage chronic renal disease or >5 ml/min/year decrease of creatinine clearance) were compared in 97 patients with stable or slowly progressive disease (<5 ml/min/year decrease). Throughout the study all patients were treated according to nephrology guidelines. Atorvastatin was instituted in patients with elevated LDL-cholesterol (LDL-C) after the baseline determinations RESULTS: Proteinuria, mean arterial pressure and the type of underlying renal disease were independently associated with progressive renal disease. After adjustment for these factors and whether or not statin therapy was started, an increase in plasma apo B concentration was the most predictive lipid parameter for renal failure. An increase in apo B from 0.77 g/l (10th percentile) to 1.77 g/l (90th percentile) was associated with progressive loss of renal function, represented by an odds ratio of 2.63 (95% CI: 1.02-6.76; P = 0.045). Treatment with atorvastatin in the dyslipidaemic patients to lower LDL-C, was also accompanied by a reduction of proteinuria in this group (P < 0.001). The patients who reached the target level for LDL-C of <2.6 mmol/l in response to atorvastatin showed less often progression than patients with higher LDL-C (P = 0.010). CONCLUSIONS: A high apo B at baseline appeared to be the strongest risk factor among various lipid parameters for progression of renal failure during the following years. Atorvastatin, aimed at lowering LDL-C, reduced proteinuria. Renal outcome was better in patients with the lowest LDL-C on treatment.

Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study.

OBJECTIVES: We assessed relations of low-density lipoprotein (LDL) particle number (LDL-P) and LDL particle size as measured by nuclear magnetic resonance spectroscopy with LDL cholesterol (LDL-C) and the risk of future coronary artery disease (CAD). BACKGROUND: Whereas LDL-C is an established risk factor for CAD, its discriminative power is limited. Measuring LDL-P and size may have stronger associations with CAD than LDL-C. METHODS: A nested case-control study was performed in the prospective EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study, which comprises 25,663 subjects. Cases (n = 1,003) were individuals who developed CAD during 6 year follow-up. Control subjects (n = 1,885) were matched for age, gender, and enrollment time. Odds ratios (ORs) for future CAD were calculated, and we also evaluated whether LDL-P could improve the Framingham risk score (FRS) to predict CAD. RESULTS: In univariate analyses, LDL-P (OR 2.00, 95% confidence interval [CI] 1.58 to 2.59) and non-high-density lipoprotein cholesterol (non-HDL-C) (OR 2.14, 95% CI 1.69 to 2.69) were more closely associated with CAD than LDL-C (OR 1.73, 95% CI 1.37 to 2.18). The additional value of LDL-P was lost after adjustment for HDL-C and triglyceride levels. Whereas LDL size was inversely related to CAD (OR 0.60, 95% CI 0.47 to 0.76), this relation was abolished upon adjustment for LDL-P. In a model adjusted for the FRS, LDL-P retained its association with CAD (p for trend 0.02). CONCLUSIONS: In this large study of individuals with moderately elevated LDL-C, LDL-P was related to CAD on top of FRS as well as after adjusting for LDL-C. The additional value of LDL-P was comparable to non-HDL-C, and it was abolished after adjusting for triglycerides and HDL-C.

Cholesteryl ester transfer protein and hyperalphalipoproteinemia in Caucasians.

It is unclear whether cholesteryl ester transfer protein (CETP) contributes to high density lipoprotein cholesterol (HDL-C) levels in hyperalphalipoproteinemia (HALP) in Caucasians. Moreover, even less is known about the effects of hereditary CETP deficiency in non-Japanese. We studied 95 unrelated Caucasian individuals with HALP. No correlations between CETP concentration or activity and HDL-C were identified. Screening for CETP gene defects led to the identification of heterozygosity for a novel splice site mutation in one individual. Twenty-five heterozygotes for this mutation showed reduced CETP concentration (-40%) and activity (-50%) and a 35% increase of HDL-C compared with family controls. The heterozygotes presented with an isolated high HDL-C, whereas the remaining subjects exhibited a typical high HDL-C/low-triglyceride phenotype. The increase of HDL-C in the CETP-deficient heterozygotes was primarily attributable to increased high density lipoprotein containing apolipoprotein A-I and A-II (LpAI:AII) levels, contrasting with an increase in both high density lipoprotein containing apolipoprotein A-I only and LpAI:AII in the other group. This study suggests the absence of a relationship between CETP and HDL-C levels in Caucasians with HALP. The data furthermore indicate that genetic CETP deficiency is rare among Caucasians and that this disorder presents with a phenotype that is different from that of subjects with HALP who have no mutation in the CETP gene.

Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels: pathways by which modulation of CETP activity may alter atherogenesis.

Raising high-density lipoprotein cholesterol (HDL-C) is a promising strategy in the struggle to prevent cardiovascular disease, and cholesteryl ester transfer protein (CETP) inhibitors have been developed to accomplish this. The first results are encouraging, and, in fact, in rabbits, inhibition of CETP reduces atherosclerosis. Because human data regarding the reduction of atheroma burden require more time, the biochemical mechanisms underlying the putative atheroprotection of CETP inhibitors are currently dissected, and several pathways have emerged. First, CETP inhibition increases HDL-C and reduces low-density lipoprotein cholesterol (LDL-C) levels consistent with CETP lipid transfer activity and its role in reverse cholesterol transport (RCT). This coincides with putative beneficial increases in both HDL and LDL size. However, many aspects regarding the impact of CETP inhibition on the RCT pathway remain elusive, in particular whether the first step concerning cholesterol efflux from peripheral tissues to HDL is influenced. Moreover, the relevance of scavenger receptor BI and consequently the central role of HDL in human RCT is still unclear. Second, CETP inhibition was shown recently to increase antioxidant enzymes associated with HDL, in turn associated with decreased oxidation of LDL. Atheroprotection in man is currently anticipated based on the improvement of these biochemical parameters known to influence atherosclerosis, but final confirmation regarding the impact of CETP inhibition on cardiovascular outcome will have to come from trials evaluating clinical end points.