Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer.

BACKGROUND: The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS: This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS: The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS: PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.

Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC. RESULTS: Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07). INTERPRETATION: This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.

Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials.

BACKGROUND: Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance. METHODS: Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit. RESULTS: Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05). CONCLUSION: Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.

The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis.

To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.

Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis.

Sulphasalazine (SSA) is a disease modifying anti-rheumatic drug (DMARD) that is commonly used to treat rheumatoid arthritis (RA). Plasma levels of SSA and its metabolite sulphapyridine are influenced by common polymorphisms in genes that encode N-acetyl transferase 2 (NAT2) and ATP-binding cassette protein G2 (ABCG2). Study participants had early RA that was treated with a combination DMARD regimen that included SSA. Toxicity was defined by cessation of SSA due to adverse effects and response as remission after 12 months of treatment. The effect of variables on toxicity was assessed by a Cox-proportional Hazard model and response by logistic regression. After correction for conventional variables, toxicity in 229 participants was influenced by NAT2 phenotype (hazard ratio=1.74 (95% confidence interval (CI) 1.01-3.21), P=0.044) and remission in 141 participants was associated with ABCG2 genotype (odds ratio=3.34 (95% CI 1.18-9.50), P=0.024). In our sample of early RA patients who were primarily treated with a combination of DMARDs, common variants in genes that encode NAT2 and ABCG2 were associated respectively with toxicity and response to SSA.

Prasugrel vs. clopidogrel for cytochrome P450 2C19-genotyped subgroups: integration of the TRITON-TIMI 38 trial data.

BACKGROUND: Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON-TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced-function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for individuals with unstable angina or non-ST segment elevation myocardial infarction is currently uncertain. METHODS AND RESULTS: An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON-TIMI 38 trial. Individuals with a CYP2C19 reduced-metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57; 95% confidence interval (CI) 0.39-0.83]. For CYP2C19 extensive metabolizers (∼70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98; 95% CI 0.80-1.20). CONCLUSIONS: Integration of the TRITON-TIMI 38 data suggests that the CYP2C19 genotype can discriminate between individuals who receive extensive benefit from using prasugrel instead of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.