Jenny F. Seligmann

Mucinous tumours of the ovary

Mucinous epithelial ovarian cancers (mEOC) are a relatively rare subset of ovarian cancers. Despite a relatively favourable outcome in early disease, the more frequent advanced presentation is associated with poorer response to platinum/taxane chemotherapies, and poorer survival, compared to serous ovarian cancers. We consider some of the fundamental clinico-pathological and molecular features, and existing clinical trial data regarding mEOC. Underlying molecular differences, between mEOC and serous cancers may contribute to the observed clinical differences, including an increased prevalence of K-RAS mutations in mEOC, more in keeping with gastrointestinal tumours. This observation contributes to the rationale for a trial (“mEOC”) investigating the use of “ovarian” versus “gastrointestinal” style chemotherapy. Looking to potential future approaches, we speculate upon the potential impact of emerging technologies on the future investigation and management of mEOC.

Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: Analysis from 2530 patients in randomised clinical trials

Background To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types. Patients and methods 2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status. Results 231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months. Conclusions BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression.

Ovarian Cancer: Advances in First-Line Treatment Strategies with a Particular Focus on Anti-Angiogenic Agents

Ovarian cancer is an important health concern worldwide. The majority of patients present with advanced disease, and despite initial chemosensitivity, most relapse and die from their disease. Better therapeutic options are urgently required. Maximal surgical debulking in combination with platinum/taxane chemotherapy has been the standard of care in advanced ovarian cancer since the mid-1990s. Trials investigating the addition of a third chemotherapeutic agent have disappointingly failed to demonstrate benefit. Intra-peritoneal therapy demonstrated improvements in outcomes in some trials, but at the cost of increased toxicity and inconvenience. Encouragingly, prospective data has now demonstrated benefits with bevacizumab in both the first-line and relapsed settings; however, interpretation is complex, particularly considering recent data demonstrating non-inferiority of neo-adjuvant chemotherapy with delayed primary surgery, and other data demonstrating a substantial improvement in outcome as a result of first-line paclitaxel dose fractionation. This article reviews the recent advances in ovarian cancer treatment and discusses current management and key areas for future research.

Association of Tumor HER3 Messenger RNA Expression With Panitumumab Efficacy in Advanced Colorectal Cancer

Importance Epidermal growth factor receptor (EGFR) (HER1) signaling depends on ligand binding and dimerization with itself or other HER receptors. We previously showed in a randomized trial that high EGFR ligand expression is predictive of panitumumab benefit in advanced colorectal cancer. Tumor expression of HER3 may further refine the RAS wild-type (wt) population benefitting from anti-EGFR agents. Objective To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab. Design, Setting, and Participants The study was a prospectively planned retrospective biomarker study of pretreatment samples from the PICCOLO trial that tested the addition of panitumumab to irinotecan therapy in patients with KRAS wt advanced colorectal cancer who experienced failure with prior fluoropyrimidine treatment. HER3 was assessed as a prognostic marker, then as a predictive biomarker in patients with RAS wt, first as a continuous variable and then as a binary (high vs low) variable. Relationship with MEK-AKT pathway mutations and EGFR ligands epiregulin and amphiregulin (EREG/AREG) were also assessed. Main Outcomes and Measures Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS). Results In 308 patients (mean age at randomization, 61.6 years; 193 men) higher HER3 was weakly prognostic for OS (hazard ratio [HR] per 2-fold change, 0.91; 95% CI, 0.83-0.99; P = .04) but not PFS (HR, 0.93; 95% CI, 0.83-1.05; P = .25). Higher HER3 was predictive, being associated with prolonged PFS on irinotecan plus panitumumab (IrPan) (HR, 0.71; 95% CI, 0.61-0.82; P < .001), but not irinotecan (HR, 0.96; 95% CI, 0.82-1.13; P = .65) in patients with RAS wt, with significant interaction between biomarker and treatment (P = .001). Similar interaction was seen for OS (P = .004). In an exploratory binary model, dividing the population at the 66th percentile, HER3 was predictive of panitumumab benefit: in patients with high HER3 expression, median PFS was 8.2 months (IrPan) vs 4.4 months (irinotecan) (HR, 0.33; 95% CI, 0.19-0.58; P < .001). Patients with low HER3 expression gained no benefit in PFS: 3.3 months (IrPan) vs 4.3 months (irinotecan) (HR, 0.96; 95% CI, 0.67-1.38; P = .84), with significant interaction (P = .002). The binary model was also predictive for OS, with significant interaction (P = .01). Combining HER3 and ligand data, patients with HER3-high, AREG/EREG-high tumors gained markedly from panitumumab (PFS HR, 0.24; 95% CI, 0.11-0.51; P < .005 and OS HR, 0.36; 95% CI, 0.18-0.73; P = .004). Conversely, patients with HER3-low, AREG/EREG-low tumors did not benefit (PFS HR, 1.14; 95% CI, 0.73-1.79; P = .57 and OS HR, 1.44; 95% CI, 0.92-2.26; P = .11). Conclusions and Relevance High HER3 expression identified patients with RAS wt who gained markedly from panitumumab, and those who did not, with statistically significant biomarker-treatment interactions for PFS and OS. This finding provides insight into the mechanism of anti-EGFR agents and is of potential clinical utility.

Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D) : a phase 2–3 randomised trial

Summary Background A substantial change in trial methodology for solid tumours has taken place, in response to increased understanding of cancer biology. FOCUS4 is a phase 2–3 trial programme testing targeted agents in patients with advanced colorectal cancer in molecularly stratified cohorts. Here, we aimed to test the hypothesis that combined inhibition of EGFR, HER2, and HER3 signalling with the tyrosine kinase inhibitor AZD8931 will control growth of all wild-type tumours. Methods In FOCUS4-D, we included patients from 18 hospitals in the UK with newly diagnosed advanced or metastatic colorectal cancer whose tumour was wild-type for BRAF, PIK3CA, KRAS, and NRAS. After 16 weeks of first-line therapy, patients with stable or responding tumours were randomised to oral AZD8931 (40 mg twice a day) or placebo. Randomisation was done by minimisation with a random element of 20%, minimisation by hospital site, site of primary tumour, WHO performance status, 16-week CT scan result, number of metastatic sites, and first-line chemotherapy regimen. The primary outcome was progression-free-survival. CT scans were assessed by local radiologists according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Preplanned interim analyses were assessed per protocol and were agreed using multiarm multistage (MAMS) trial design methodology triggered by occurrence of progression-free survival events in the placebo group. The final analysis was assessed by intention to treat. This trial is registered at controlled-trials.com, ISRCTN 90061546. Findings Between July 7, 2014, and March 7, 2016, 32 patients were randomised to study treatment, 16 to AZD8931 and 16 to placebo. At the first preplanned interim analysis (March, 2016), the independent data monitoring committee (IDMC) recommended closure of FOCUS4-D because of a lack of activity. At the final analysis (Aug 1, 2016), 31 patients had had a progression-free survival event (15 with AZD8931 and 16 with placebo). Median progression-free survival was 3·48 months (95% CI 1·51–5·09) in the placebo group and 2·96 months (1·94–5·62) in the AZD8931 group. No progression-free survival benefit of AZD8931 compared with placebo was noted (hazard ratio [HR] 1·10, 95% CI 0·47–3·57; p=0·95). The most common grade 3 adverse event in the AZD8931 group was skin rash (three [20%] of 15 patients with available data vs none of 16 patients in the placebo group), and in the placebo group it was diarrhoea (one [7%] vs one [6%]). No grade 4 adverse events were recorded and no treatment-related deaths were reported. Interpretation The MAMS trial design for FOCUS4 has shown efficiency and effectiveness in trial outcome delivery, informing the decision to proceed or stop clinical evaluation of a targeted treatment within a molecularly defined cohort of patients. The overarching FOCUS4 trial is now aiming to open a replacement arm in the cohort with all wild-type tumours. Funding Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme, Cancer Research UK, NIHR Clinical Trials Research Network, Health and Care Research Wales, and AstraZeneca.

Role of derived neutrophil lymphocyte ratio as a biomarker in advanced colorectal cancer

Abstract Background The discovery and validation of prognostic and predictive biomarkers in advanced colorectal cancer is crucial for the personalisation of therapy. Inflammation-based prognostic scores have been developed, including the neutrophil lymphocyte ratio (NLR), and the derived NLR (dNLR) calculated using a differential white cell count. The NLR has been assessed in several cancers; in a retrospective series of advanced colorectal cancer, higher NLR was associated with reduced survival and poorer outcomes with chemotherapy. We aimed to validate the usefulness of the dNLR as a prognostic and a predictive biomarker to anti-epidermal growth factor receptor (EGFR) agents in advanced colorectal cancer. Methods We studied patients from a phase 3, open-label, randomised controlled trial that assessed the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer (PICCOLO trial). The prognostic analysis included all patients for whom dNLR data were available; a subset with KRAS wild-type tumours randomised to standard irinotecan with or without panitumumab was also analysed for predictive value. The dNLR was calculated from the prerandomisation blood count and categorised as high (≥2) or low ( Findings 1159 patients were included in the prognostic analysis, and 444 in the predictive analysis. In multivariate analysis, high dNLR was independently associated with reduced overall survival compared with low dNLR (hazard ratio 1·59, 95% CI 1·32–1·78; p KRAS, BRAF, NRAS , and PIK3CA ), and in the subset of 323 patients in this all-wild-type category panitumumab had a more marked effect on tumour response rate in patients with low dNLR (odds ratio 7·4, p Interpretation The dNLR seems to offer the clinician useful prognostic information. Since this information can easily be calculated from routine clinical data, its integration into routine patient assessment should be considered after further validation. We did not demonstrate significant predictive value for anti-EGFR therapy, but our finding of higher response with panitumumab in patients with a low dNLR is hypothesis generating. Further investigation in datasets from randomised controlled trials and exploratory translational work are warranted. Funding Cancer Research UK, Yorkshire Cancer Research.

509PDPRIMARY TUMOUR LOCATION (PTL) AS A PROGNOSTIC AND PREDICTIVE FACTOR IN ADVANCED COLORECTAL CANCER (ACRC): DATA FROM 2075 PATIENTS (PTS) IN RANDOMISED TRIALS

ABSTRACT Aim: Variations in tumour biology and outcomes depending upon PTL have been reported in aCRC. We tested effects of PTL in two phase III randomised trials. Methods: We studied 2075 pts, from FOCUS (1st-line; n = 1390; Lancet 370: 143-52) and PICCOLO (2nd-line; n = 685; Lancet Oncol 14:749-59). We compared: (1) right colon (RC) vs [left colon (LC) or rectum] and (2) LC vs rectum. Association of PTL with RAS/RAF, AREG/EREG and MMR was assessed where available. PTL was tested as a prognostic factor, then for predictive utility by testing PTL/treatment interactions on OS and PFS for: 1st line FU vs doublet (FOCUS); 1st-line irinotecan doublet vs oxaliplatin doublet (FOCUS); 2nd line irinotecan (Ir) +/- panitumumab (Pan) (KRAS-wt pts, PICCOLO). Results: PTL was RC in 575 (28%), LC in 801 (39%) and rectum in 699 (34%) pts. RC tumours had more BRAF mutations (n = 1136, 22% vs 6%, p Interaction test p-values for treatment comparisons Comparison Interaction Test p-values RC vs LC/rectum LC vs Rectum OS PFS OS PFS 1st line doublet vs single-agent FU (1334 pts) 0.39 0.84 0.48 0.8 1st line OxFU doublet vs IrFU doublet (452 pts) 0.99 0.67 0.18 0.50 2nd line Ir +/- Pan KRAS-WT (450 pts) 0.35 0.13 0.63 0.46 2nd line Ir +/- Pan KRAS/BRAF-WT (341 pts) 0.72 0.89 0.83 0.19 Conclusions: We confirm that RC tumours are biologically distinct, and have worse outcomes with 1st-line therapy. We did not find PTL to be predictive for the benefit of the drugs under test in these trials, so cannot recommend its use for selection of therapy. Better objective predictive biomarkers are required. Disclosure: All authors have declared no conflicts of interest.

Editorial: Use of Gene Expression Profiles to Distinguish Molecular Subtypes in Colorectal Cancer: Progression Toward Primetime

Stratified medicine has already transformed the paradigm of drug therapy for some cancers and is set to underpin future developments across all of cancer therapeutics. Some stratified medicine approaches are specific: a single molecular biomarker corresponding to the molecular target of a specific treatment (such as vemurafenib in BRAF V600E-mutated melanoma). A key alternative concept in stratified medicine is that different patients’ cancers, while individual and heterogeneous, may have disruptions to the same cellular pathways or functions, leading to similarities in tumor behavior and, crucially, similar response to specific treatments. So, while recognizing that no two patients’ cancers are identical, we may still develop molecular classifications that identify quasi-consistent groups for whom distinct treatment strategies may be needed, or in whom different novel targeted therapies might logically be tested. RNA expression arrays offer an important platform from which to develop disease stratification, and since 2012 several colorectal cancer schemes have been published based on Affymetrix or Agilent arrays, each resulting in three to six patient strata, but with wide differences between the contributing genes (1–6). In an important collaboration in 2015, data sets from six published algorithms were then co-analyzed to generate a single Consensus Molecular Subtype (CMS) scheme (7). CMS classification using a 273-gene expression classifier defines four groups (CMS1-CMS4), each with a set of pathway alterations and clinicopathological features. For example, CMS4 or “mesenchymal-type” tumors are characterized by upregulation of genes implicated in epithelial-to-mesenchymal transition, TGFb signaling, angiogenesis, and matrix proteins and are rich in stromal cells such as fibroblasts. Perhaps the most immediate potential clinical application of CMS status is where it can be shown to correlate with prognosis and so contribute to decisions about existing standard treatments. In the consensus study data set, patients with CMS4 tumors had statistically significantly inferior postoperative relapse-free and overall survival compared with CMS1-3 (7). Evaluation of CMS4 status alongside other known prognostic factors (TNM stage, vascular invasion, primary tumor location, etc.) is needed to evaluate whether it adds to these factors in decision-making for adjuvant chemotherapy. Second and perhaps more importantly, CMS stratification, by identifying tumors with a degree of biological commonality, has the potential to be used to select groups of patients for evaluation of novel targeted therapies, where the known biological characteristics of the CMS group provide a rationale for a specific treatment approach. Currently no targeted systemic therapies are used as standard in the treatment of early-stage colorectal cancer. For example, CMS1 is characterized by genes associated with T-cell infiltration and immune evasion pathways, with high rates of microsatellite instability and CIMP, making this a promising subpopulation for evaluation of immunotherapy. However, prospective use of CMS status to stratify our treatment decisions, whether in research or for future standard practice, requires that patients be assessed rapidly, reliably, cost-effectively, and preferably without the need for additional biopsies, none of which can be listed as defining features of array-based RNA assays. There is therefore a strong rationale to develop rapid, low-cost, reliable techniques that correlate with CMS strata and are better suited for the routine laboratory. In this issue of the Journal, Ubink and colleagues propose a method to identify one of the CMS types, CMS4, using a fourgene reverse transcription polymerase chain reaction (RT-PCR) assay (8). Their approach was to select five candidate genes

Can D-Dimer Measurement Reduce the Frequency of Radiological Assessment in Patients Receiving Palliative Imatinib for Gastrointestinal Stromal Tumor (GIST)?

ABSTRACT Imatinib therapy has improved outcomes in advanced GISTs. Current guidelines suggest monitoring with CT scanning every 12 weeks. There are no validated biomarkers to assist disease evaluation. We identified 50 patients treated with imatinib for GIST in a single tertiary center. We assessed the prognostic value of D-dimers by Cox regression, and the utility as a biomarker for radiological progression (rPD) using receiver-operator curve (ROC) analysis. In asymptomatic patients with D-dimer levels <1,000 and falling levels, the negative predictive value for rPD was 92%. D-dimers may reduce the burden of CT scanning in a proportion of patients in this setting.

553PTHE DERIVED NEUTROPHIL LYMPHOCYTE RATIO (DNLR) AS A BIOMARKER IN ADVANCED COLORECTAL CANCER (ACRC)

ABSTRACT Aim: Links between inflammation, the immune response and cancer outcomes are compelling. The dNLR, calculated from a standard blood count, is a simple measure of inflammatory response, and in retrospective series high dNLR has been reported to be associated with poorer outcomes in aCRC. We examined dNLR as a prognostic marker, and assessed its predictive utility for two treatments in large phase III trials in aCRC. Methods: 2484 patients (pts) were studied, from the FOCUS (Lancet 370:143, 2007) and PICCOLO trials (Lancet Oncol 14:749, 2013). dNLR was calculated from the pre-randomisation blood count and prospectively defined as “high” (≥2) or “low” ( Results: 52.8% pts had high dNLR; 47.2% had low dNLR. High dNLR was independently associated with reduced OS in both trials (FOCUS: n = 1810 HR 1.51, p 25% after 6 weeks of chemotherapy was associated with a higher risk of disease progression at 12 weeks (OR = 1.6, p = 0.02) and inferior PFS (HR = 1.34, p Conclusions: The dNLR provides prognostic information and may provide an early warning when chemotherapy is failing. It might also help identify patients who could be treated safely with less intensive 1st line chemotherapy, but confirmatory data are required. Given that dNLR is readily and freely calculated from routine clinical data, its integration into routine patient evaluation should be considered following further validation. Disclosure: All authors have declared no conflicts of interest.