MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients.

Background: This study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients. Methods: A high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in trastuzumab-treated HER2-positive NCI-N87 and HER2-negative FLO-1 oesophago-gastric cancer cell lines. NanoString nCounter® miR analysis was performed in NCI-N87, FLO-1, and MAGIC trial (ISRCTN93793971) formalin-fixed paraffin-embedded (FFPE) oesophago-gastric cancer patient samples. MiR-148a-3p copies in plasma samples were quantified using digital droplet polymerase chain reaction (ddPCR) from HER2-positive oesophago-gastric cancer patients treated with standard-of-care trastuzumab-based therapy within the FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. The primary endpoints were overall survival (OS) for plasma miR-148a-3p HIGH (>median) versus LOW (≤median). The secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFRs) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p). Results: The inhibition of miR-148a-3p reduced NCI-N87 relative cell viability (<0.6) and expression was high (>242) in NCI-N87 and HER2-positive MAGIC trial patients (n=5). Normalised-miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in 3-month PFRs (n=23; OR, 0.11 [0.02-0.78]; p=0.027; aOR, 0.03 [0.001-0.71], p=0.029) but no difference in OS or PFS. There was no statistically significant relationship between miR-148-3p LOW versus HIGH for OS (PLATFORM, n=62; hazard ratio [HR], 0.98 [0.57-1.66]; p=0.933; FOrMAT, n=8; HR, 0.54 [0.13-2.31]; p=0.322), PFS (n=62; HR, 1.08 [0.65-1.81]; p=0.759; FOrMAT, n=8; HR, 1.26 [0.31-5.07]; p=0.714), or PFRs (PLATFORM, n=31; odds ratio [OR], 0.67 [0.2-2.8]; p=0.577). Conclusion: Normalised miR-148a-3p may be a relevant biomarker for trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.

ctDNA guided adjuvant chemotherapy versus standard of care adjuvant chemotherapy after curative surgery in patients with high risk stage II or stage III colorectal cancer: a multi-centre, prospective, randomised control trial (TRACC Part C).

BACKGROUND: Circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) is emerging as a biomarker to predict recurrence in patients with curatively treated early stage colorectal cancer (CRC). ctDNA risk stratifies patients to guide adjuvant treatment decisions. We are conducting the UK's first multi-centre, prospective, randomised study to determine whether a de-escalation strategy using ctDNA to guide adjuvant chemotherapy (ACT) decisions is non-inferior to standard of care (SOC) chemotherapy, as measured by 3-year disease free survival (DFS) in patients with resected CRC with no evidence of MRD (ctDNA negative post-operatively). In doing so we may be able to spare patients unnecessary chemotherapy and associated toxicity and achieve significant cost savings for the National Health Service (NHS). METHODS: We are recruiting patients with fully resected high risk stage II and stage III CRC who are being considered for ACT into the study which uses results from a plasma-only ctDNA assay to guide treatment decisions. Eligible patients are randomised 1:1 to receive ctDNA-guided chemotherapy versus SOC chemotherapy. The primary endpoint is the difference in DFS at 3 years between the trial arms. Secondary endpoints include the proportion of patients in the ctDNA-guided arm who are ctDNA negative post-operatively and receive de-escalated ACT compared to the standard arm, the difference in overall survival (OS), neurotoxicity and quality of life between the arms, and the cost-effectiveness of ctDNA-guided therapy compared to SOC treatment. We hypothesise that using a ctDNA-guided approach to ACT decisions is non-inferior to SOC. Target accrual is 1621 patients over 4 years, which will provide a power of 80% with an alpha of 0.1 to demonstrate non-inferiority with a margin of 1.25 in survival of the ctDNA-guided approach compared to SOC. We anticipate approximately 50 UK centres will participate. The study opened with the Guardant Reveal plasma-only ctDNA assay in August 2022. DISCUSSION: The trial will determine whether ctDNA guided ACT is non-inferior to SOC ACT in patients with fully resected high risk stage II and stage III resected CRC, with the potential to significantly reduce unnecessary ACT and the toxicity associated with it. TRIAL REGISTRATION: NCT04050345.

Assessing the collection and reporting of patient-reported outcome data in interventional cancer trials: a single institution, retrospective systematic evaluation.

BACKGROUND: To understand our performance with respect to the collection and reporting of patient-reported outcome (PRO) measure (PROM) data, we examined the protocol content, data completeness and publication of PROs from interventional trials conducted at the Royal Marsden NHS Foundation Trust (RM) and explored factors associated with data missingness and PRO publication. DESIGN: From local records, we identified closed, intervention trials sponsored by RM that opened after 1995 and collected PROMs as primary, secondary or exploratory outcomes. Protocol data were extracted by two researchers and scored against the SPIRIT-PRO (PRO protocol content checklist; score 0-100, higher scores indicate better completeness). For studies with locally held datasets, the information team summarized for each study, PRO completion defined as the number of expected (as per protocol) PRO measurements versus the number of actual (i.e. completed) PRO measurements captured in the study data set. Relevant publications were identified by searching three online databases and chief investigator request. Data were extracted and each publication scored against the CONSORT-PRO (PRO manuscript content checklist; scored as SPIRIT-PRO above). Descriptive statistics are presented with exploratory comparisons of point estimates and 95% confidence intervals. RESULTS: Twenty-six of 65 studies were included in the review. Nineteen studies had accessible datasets and 18 studies published at least one article. Fourteen studies published PRO results. Most studies had a clinical (rather than PRO) primary outcome (16/26). Across all studies, responses in respect of 35 of 69 PROMs were published. Trial protocols scored on average 46.7 (range 7.1-92.9) on the SPIRIT-PRO. Among studies with accessible data, half (10/19) had less than 25% missing measurements. Publications scored on average 80.9 (range 36-100%) on the CONSORT-PRO. Studies that published PRO results had somewhat fewer missing measurements (19% [7-32%] vs 60% [- 26 to 146%]). For individual PROMs within studies, missing measurements were lower for those that were published (17% [10-24%] vs 41% [18-63%]). Studies with higher SPIRIT-PRO scores and PROs as primary endpoints (13% [4-22%] vs 39% [10-58%]) had fewer missing measurements. CONCLUSIONS: Missing data may affect publication of PROs. Extent of inclusion of SPIRIT-PRO protocol items and PROs as primary endpoints may improve data completeness. Preliminary evidence from the study suggests a future larger study examining the relationship between PRO completion and publication is warranted.

Visualising harms in publications of randomised controlled trials: consensus and recommendations.

OBJECTIVE: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes. DESIGN: Consensus study. SETTING: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ. PARTICIPANTS: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians. MAIN OUTCOME: measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached. RESULTS: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. CONCLUSIONS: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles.

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

OBJECTIVE: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785). DESIGN: EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients. RESULTS: EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA. CONCLUSION: EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.

Health-related quality Of Life In patients with advanced Soft TIssue sarcomas treated with Chemotherapy (The HOLISTIC study): protocol for an international observational cohort study.

INTRODUCTION: Chemotherapy is the mainstay of treatment for patients with advanced soft tissue sarcomas (STS). Treatment intent is usually palliative, aiming to improve symptoms, stabilise or reduce tumour burden and extend life. Clinical trials have traditionally used radiological response, time to progression and survival as measures of treatment efficacy. Health-related quality of life (HRQoL) is at least equally important or more important than survival for many patients with advanced cancer. Systematically collecting HRQoL data during chemotherapy can provide greater insight into treatment efficacy from the patient perspective.The primary aims of this study are to evaluate HRQoL in patients with advanced STS treated with chemotherapy over time, explore the decision-making process and patient reflection post-treatment. METHODS AND ANALYSIS: This is an observational, international cohort study for 132 patients aged ≥18 years with advanced STS treated at eight centres (three in the UK, five in the Netherlands). Patients will be recruited prior to starting first-line or third-line chemotherapy and invited to complete questionnaires using the Patient-Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship registry (PROFILES); an established international registry for collection of cancer patient-reported outcomes. Online (or paper) questionnaires will be completed at baseline, each cycle of chemotherapy and 2-3 monthly during follow-up. The questionnaire package includes the Decisional Conflict Scale, Control Preferences Scale, Quality-Quantity Questionnaire, treatment expectations, European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30), EORTC financial toxicity items, Work Ability Index, Functional Assessment of Cancer Therapy-General (FACT-G) items and Decisional Regret Scale. Clinical data will be extracted from patient records and linked with questionnaire responses. The primary outcome measure is the change in global HRQoL from baseline to after cycle 4 of first-line chemotherapy (based on published data showing that patients with advanced STS complete a median number of four cycles of first-line chemotherapy). ETHICS AND DISSEMINATION: Heath Research Authority and Research Ethics Committee (REC 17/NI/0197). Results from the Health-related quality Of Life In patients with advanced Soft TIssue sarcomas treated with Chemotherapy (HOLISTIC) study will be published in peer-reviewed journals and disseminated at local, national and international conferences. We will also present our findings at any appropriate patient meetings and involve patients in study-related publications. TRIAL REGISTRATION NUMBER: NCT03621332.

International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct.

PURPOSE: To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen. PATIENTS AND METHODS: Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m2 (day 1) plus FU 1,000 mg/m2 (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m2 (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner. RESULTS: We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; P = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; P = .014). CONCLUSION: This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care.

R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial.

Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ≥ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ≥ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL.

Influence of sex on chemotherapy efficacy and toxicity in oesophagogastric cancer: A pooled analysis of four randomised trials.

BACKGROUND: Sex contributes to interpatient variability of chemotherapy metabolism and dose response, potentially influencing both efficacy and toxicity; however, comparative data on its effect on oesophagogastric cancer are lacking. PATIENTS AND METHODS: Data for patients with advanced oesophagogastric cancer randomised to comparable first-line chemotherapy regimens within four United Kingdom prospective trials were pooled, and key demographic and outcome measures were compared between males and females. RESULTS: A total of 1654 patients were included: 1328 (80.3%) males and 326 (19.7%) females. Female patients were younger, had a significantly higher proportion of gastric tumours as opposed to junctional or oesophageal tumours and experienced significantly higher rates of a number of toxicities including nausea and vomiting, diarrhoea, stomatitis and alopecia. When adjusting for potential confounding factors, the risk of female patients experiencing grade ≥III gastrointestinal toxicity was greater (adjusted odds ratio = 1.50; 95% confidence interval = 1.07-2.12). Females also had a significantly higher incidence of serious adverse events on treatment and received comparatively less cycles of chemotherapy overall than males. CONCLUSIONS: This represents the largest pooled analysis of the effect of sex on chemotherapy outcome and toxicity in advanced oesophagogastric cancer. The differential toxicity and adverse event rates observed suggest that sex may be an important modulator of treatment tolerability and safety in this tumour type.

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial.

PURPOSE: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs. EXPERIMENTAL DESIGN: miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination. RESULTS: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer). CONCLUSIONS: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.

Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial.

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies.Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270-85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213 This article is highlighted in the In This Issue feature, p. 1195.

Rapid access clinic for unexplained lymphadenopathy and suspected malignancy: prospective analysis of 1000 patients.

BACKGROUND: In patients presenting with peripheral lymphadenopathy, it is critical to effectively identify those with underlying cancer who require urgent specialist care. METHODS: We analyzed a large dataset of 1000 consecutive patients with unexplained lymphadenopathy referred between 2001 and 2009 to the Royal Marsden Hospital (RMH) rapid access lymph node diagnostic clinic (LNDC). RESULTS: Cancer was diagnosed in 14% of patients. Factors predictive for malignant disease were male sex, age, supraclavicular and multiple site involvement. Cancer-associated symptoms were present for a median of 8 weeks. The median time from referral to start of cancer therapy was 53 days. Fine needle aspiration (FNA) was performed in 83% of patients with malignancies. Sensitivity and specificity of FNA were limited (50 and 87%, respectively for any malignancy; 30 and 79%, respectively for lymphoma). The vast majority of cancer patients received diagnostic biopsies on the basis of suspicious clinical and ultrasound findings; the FNA result contributed to establishing the diagnosis in only 4 cases. CONCLUSIONS: In conclusion, we demonstrate that Oncologist-led rapid access clinics are successful concepts to assess patients with unexplained lymphadenopathy. Our data suggest that a routine use of FNA should be reconsidered in this setting.

Survival in Advanced Esophagogastric Adenocarcinoma Improves With Use of Multiple Lines of Therapy: Results From an Analysis of More Than 500 Patients.

BACKGROUND: Although progress has been made in the molecular stratification of esophagogastric adenocarcinoma, the outlook for advanced disease remains poor. The present evaluation of over 500 patients treated at a single European high-volume tertiary center during a 6-year period gives important information on current and developing "real-world" treatment patterns and outcomes. RESULTS: The overall survival for the whole cohort was 11.5 months, with a range of treatments used in first-, second-, and third-line settings. Treatment with sequential lines of therapy was associated with better outcomes, although only 39% and 14% of patients subsequently received treatment in the second- and third-line setting, respectively. Treatment within a therapeutic clinical trial was associated with significantly improved survival. CONCLUSION: At present, a substantial proportion of patients with advanced esophagogastric adenocarcinoma will not proceed beyond first-line therapy, and for this group refinement of initial systemic therapies are required to improve outcomes. Although a number of established first- and second-line treatment options are now available, the therapeutic landscape of the disease continues to change, most notably in the application of immunotherapy and increasing interest in establishing evidence-based interventions in the third-line setting and beyond. A small but growing proportion of patients will benefit from sequential treatment approaches incorporating multiple lines of therapy, and improved selection of such patients will be a key challenge for clinicians moving forwards. Data such as these provide an overview of current treatment patterns and outcomes which can be used to inform planning of future research effectively within existing treatment frameworks.

CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial.

BACKGROUND: Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. METHODS: We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0-3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1-5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1-5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). FINDINGS: Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6-38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21-1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. INTERPRETATION: The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. FUNDING: Bloodwise and the UK National Institute of Health Research.

Genomic loss of heterozygosity and survival in the REAL3 trial.

BACKGROUND: Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy. METHODS: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes. RESULTS: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 - 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low. CONCLUSION: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature's predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.

Outcomes following front-line chemotherapy in peripheral T-cell lymphoma: 10-year experience at The Royal Marsden and The Christie Hospital.

We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age >60 years, International Prognostic Index (IPI) ≥ 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit.

Treatment and Survival Outcome of BRAF-Mutated Metastatic Colorectal Cancer: A Retrospective Matched Case-Control Study.

BACKGROUND: Somatic v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation, present in approximately 10% of metastatic colorectal cancer (mCRC) cases, is associated with poor prognosis. Patient outcome outside of clinical trials has only been reported in small series. We report real-world data on treatment and survival for BRAF-mutated (MT) patients at a single tertiary center, compared with a matched BRAF wild type (WT) control group. PATIENTS AND METHODS: All colorectal cancer patients tested for BRAF mutation, from October 2010 to November 2014 were identified. BRAF-MT mCRC cases were compared with an age and sex-matched BRAF-WT control group. Clinicopathological data were collected and survival calculated using the Kaplan-Meier method and comparisons made using Cox regression. RESULTS: Forty-three of 503 patients (8.5%) tested had BRAF-MT mCRC and were compared with 88 BRAF-WT controls. Median overall survival (mOS) was 18.2 months for BRAF-MT and 41.1 months for BRAF-WT mCRC patients (hazard ratio, 2.74; 95% confidence interval, 1.60-4.70; P < .001). Progression-free survival for BRAF-MT and WT patients, respectively, was: 8.1 months versus 9.2 months (P = .571) first-line, 5.5 months versus 8.3 months (P = .074) second-line, and 1.8 months versus 5.6 months (P = .074) third-line. Treatment using sequential fluoropyrimidine-based doublet chemotherapy was similar between both groups. Anti-epidermal growth factor receptor (EGFR) therapy was mainly given third-line with progressive disease in 90% (n = 9 of 10) of BRAF-MT patients at first restaging. CONCLUSION: In this case-control study, the poor mOS of BRAF-MT mCRC was associated with reduced treatment benefit beyond first-line. Sequential doublet chemotherapy remains a reasonable option in appropriately selected patients. BRAF-MT patients did not benefit from anti-EGFR therapy in this study. Recruitment to clinical trials is recommended to improve outcomes in BRAF-MT mCRC.

Pharmacogenetic Analysis of the UK MRC (Medical Research Council) MAGIC Trial: Association of Polymorphisms with Toxicity and Survival in Patients Treated with Perioperative Epirubicin, Cisplatin, and 5-fluorouracil (ECF) Chemotherapy.

Purpose: Germline polymorphisms may affect chemotherapy efficacy and toxicity. We examined the effect of polymorphisms in drug metabolism and DNA repair genes on pathologic response rates, survival, and toxicity for patients randomized to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial.Experimental Design: DNA was extracted from nontumor resection formalin-fixed paraffin-embedded (FFPE) blocks. ERCC1, ERCC2, XRCC1, DYPD, and OPRT SNPs were evaluated using Sequenom, GSTP1, GSTT1 deletion, and TYMS (TS) 5' 2R/3R using multiplex PCR. Post PCR amplification, TS 2R/3R and GSTT1 samples underwent gel electrophoresis.Results: Polymorphism data were available for 289 of 456 (63.4%) operated patients. No polymorphism was statistically significantly associated with pathologic response to chemotherapy. Median overall survival (OS) for patients treated with surgery alone with any TS genotype was not different (1.76 years 2R/2R, 1.68 years 2R/3R, 2.09 years 3R/3R). Median OS for patients with a TS 2R/2R genotype treated with chemotherapy was not reached, whereas median OS for 2R/3R and 3R/3R patients were 1.44 and 1.60 years, respectively (log rank P value = 0.0053). The P value for the interaction between treatment arm and genotype (3R/3R and 3R/2R vs. 2R/2R) was 0.029. No polymorphism was statistically significantly associated with chemotherapy toxicity.Conclusions: In MAGIC, patients with a TS 2R/2R genotype appeared to derive a larger benefit from perioperative ECF chemotherapy than patients with 3R containing genotypes. Further exploration of this potential predictive biomarker in this patient population is warranted. Clin Cancer Res; 23(24); 7543-9. ©2017 AACR.

Comparison between MRI and pathology in the assessment of tumour regression grade in rectal cancer.

BACKGROUND: Limited data exist regarding the correlation between MRI tumour regression grade (mrTRG) and pathological TRG (pTRG) in rectal cancer. METHODS: mrTRG and pTRG were compared in rectal cancer patients from two phase II trials (EXPERT and EXPERT-C). The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan-Meier method was used to estimate survival outcomes. RESULTS: One hundred ninety-one patients were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range (IQR): 3.7-4.7) and 6.6 weeks (IQR: 5.9-7.6), respectively. Fair agreement was found between mrTRG and pTRG when regression was classified according to standard five-tier systems (κ=0.24) or modified three-tier systems (κ=0.25). Sensitivity and specificity of mrTRG 1-2 (complete/good radiological regression) for the prediction of pathological complete response was 74.4% (95% CI: 58.8-86.5) and 62.8% (95% CI: 54.5-70.6), respectively. Survival outcomes of patients with intermediate pathological regression (pTRG 2) were numerically better if complete/good regression was also observed on imaging (mrTRG 1-2) compared to poor regression (mrTRG 3-5) (5-year recurrence-free survival 76.9% vs 65.9%, P=0.18; 5-year overall survival 80.6% vs 68.8%, P=0.22). CONCLUSIONS: The agreement between mrTRG and pTRG is low and mrTRG cannot be used as a surrogate of pTRG. Further studies are warranted to assess the ability of mrTRG to identify pathological complete responders for the adoption of non-operative management strategies and to provide complementary prognostic information to pTRG for better risk-stratification after surgery.