Purpose: To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing. Experimental Design: Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated. Results: cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit. Conclusions: cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate. See related commentary by Wang and Ajani, p. 6887

Objective:The main objective of this retrospective work was the study of three-dimensional (3D) heterogeneity measures of post-contrast pre-operative MR images acquired with T1 weighted sequences of patients with glioblastoma (GBM) as predictors of clinical outcome.Methods:79 patients from 3 hospitals were included in the study. 16 3D textural heterogeneity measures were computed including run-length matrix (RLM) features (regional heterogeneity) and co-occurrence matrix (CM) features (local heterogeneity). The significance of the results was studied using Kaplan–Meier curves and Cox proportional hazards analysis. Correlation between the variables of the study was assessed using the Spearman's correlation coefficient.Results:Kaplan–Meyer survival analysis showed that 4 of the 11 RLM features and 4 of the 5 CM features considered were robust predictors of survival. The median survival differences in the most significant cases were of over 6 months.Conclusion:Heterogeneity measures computed on the post-cont...

Tumor Treating Fields (TTFields), low intensity alternating electric fields with antimitotic activity, have demonstrated survival benefit in patients with glioblastoma. This phase 2 PANOVA study was conducted to examine the combination of TTFields plus chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). Forty patients with newly-diagnosed, locally advanced or metastatic PDAC received continuous TTFields (150 KHz for ≥18 h/day) plus gemcitabine (1000 mg/m2), or gemcitabine plus nab-paclitaxel (125 mg/m2). The primary endpoint was safety and secondary endpoints included compliance to TTFields, progression-free survival (PFS), and overall survival (OS). Seventeen patients (85%) in each cohort reported Grade ≥3 adverse events (AEs). No increase in serious AEs (SAEs) was observed compared to that anticipated with systemic chemotherapy alone. Twenty-one patients reported TTFields-related skin toxicity, of which 7 were Grade 3; all resolved following temporary reduction of daily TTFields usage. No TTFields-related SAEs were reported. Compliance to TTFields was 68-78% of the recommended average daily use in both cohorts. Median PFS was 8.3 months (95% CI 4.3, 10.3) and median OS was 14.9 months (95% CI 6.2, NA) in the TTFields + gemcitabine cohort. In the TTFields + gemcitabine + nab-paclitaxel cohort, the median PFS was 12.7 months (95% CI 5.4, NA); median OS has not been reached. The PANOVA trial demonstrated that the combination of TTFields and systemic chemotherapy is safe and tolerable in patients with advanced PDAC. Based on the safety and preliminary efficacy results of this phase 2 study, a randomized phase 3 study (PANOVA-3) is underway.

In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups. Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59-0.81; P = 0.0001). Median OS in the three regions was 6.5-7.8 months in the trifluridine/tipiracil arm and 4.3-6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34-0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48-0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57-1.00; P = 0.0470). Median PFS was 2.0-2.8 months for trifluridine/tipiracil and 1.7-1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957.

Biliary tract cancer (BTC) is an uncommon and highly fatal malignancy. It is composed of three main different entities; Gall bladder carcinoma (GBC), intrahepatic cholangiocarcinoma (iCC) and extrahepatic cholangiocarcinoma (eCC) sharing different genetic, risk factors and clinical presentation. Multidetector-row computed tomography (MDCT) and magnetic resonance cholangio-pancreatography (MRCP) are the more important diagnostic techniques. Surgery is the only potentially curative therapy but disease recurrence is frequent. Treatment with chemotherapy, radiotherapy or both has not demonstrated survival benefit in the adjuvant setting. Cisplatin plus gemcitabine constitutes the gold standard in metastatic disease. New ongoing studies mainly in the adjuvant and neoadjuvant setting along with molecular research will hopefully help to improve survival and quality of life of this disease.

Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases.