British Journal of Cancer

doi: 10.1038/s41416-020-01208-6pmid: 33398062

BackgroundPatients with refractory colorectal (CRC) cancer have few treatment options. This trial tests the combination of metformin and irinotecan in this setting.MethodsA phase 2 single-arm trial was conducted, patients received metformin 2500 mg orally a day plus irinotecan 125 mg/m2 intravenously weekly D1 and D8 every 21 days. The primary endpoint was the disease control rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks.ResultsBetween December 2015 and January 2018, 41 patients were enrolled. Seventeen patients (41%) met the primary endpoint of disease control in 12 weeks; hence, the study was deemed positive. The median progression-free survival was 3.3 months (CI 95%, 2.0–4.5 months), and the median overall survival was 8.4 months (CI 95%, 5.9–10.8 months). Both mutation RAS status and disease control at 12 weeks impacted overall survival in the multivariate model (HR 2.28, CI 95%, 1.12–4.7, p = 0.02; and HR 0.21, CI 95%, 0.08–0.5, p = 0.001, respectively). The most common adverse event was diarrhoea (29.2% grade 3).ConclusionsIn this trial, metformin plus irinotecan demonstrated disease control in patients with refractory CRC. Further trials with optimised diarrhoea control are needed to confirm these results.

BackgroundRapid Diagnostic Clinics (RDC) are being expanded nationally by NHS England. Guy’s RDC established a pathway for GPs and internal referrals for patients with symptoms concerning for malignancy not suitable for a site-specific 2WW referral. However, little data assessing the effectiveness of RDC models are available in an English population.MethodsWe evaluated all patients referred to Guy’s RDC between December 2016 and June 2019 (n = 1341) to assess the rate of cancer diagnoses, frequency of benign conditions and effectiveness of the service.ResultsThere were 96 new cancer diagnoses (7.2%): lung (16%), haematological (13%) and colorectal (12%)—with stage IV being most frequent (40%). Median time to definitive cancer diagnosis was 28 days (IQR 15–47) and treatment 56 days (IQR 32–84). In all, 75% were suitable for treatment: surgery (26%), systemic (24%) and radiotherapy (14%). Over 180 serious non-neoplastic conditions were diagnosed (35.8%) of patients with no significant findings in two-third of patients (57.0%).ConclusionsRDCs provide GPs with a streamlined pathway for patients with complex non-site-specific symptoms that can be challenging for primary care. The 7% rate of cancer diagnosis exceeds many 2WW pathways and a third of patients presented with significant non-cancer diagnoses, which justifies the need for rapid diagnostics. Rapid Diagnostic Centres (RDCs) are being rolled out nationally by NHS England and NHS Improvement as part of the NHS long-term plan. The aim is for a primary care referral pathway that streamlines diagnostics, patient journey, clinical outcomes and patient experience. This pilot study of 1341 patients provides an in-depth analysis of the largest single RDC in England. Cancer was diagnosed in 7% of patients and serious non-cancer conditions in 36%—justifying the RDC approach in vague symptom patients.

doi: 10.1038/s41416-020-01222-8pmid: 33414540

BackgroundThe characterisation of desmoplastic reaction (DR) has emerged as a new, independent prognostic determinant in colorectal cancer. Herein, we report the validation of its prognostic value in a randomised controlled study (SACURA trial).MethodsThe study included 991 stage II colon cancer patients. DR was classified by the central review as Mature, Intermediate or Immature based on the presence of hyalinised collagen bundles and myxoid stroma at the desmoplastic front. All clinical and pathological data, including DR characterisations, were prospectively recorded and analysed 5 years after the completion of the registration.ResultsThe five-year relapse-free survival (RFS) rate was the highest in the Mature group (N = 638), followed by the Intermediate (N = 294) and Immature groups (N = 59). Multivariate analysis revealed that DR classification was an independent prognostic factor, and based on Harrell’s C-index, the Cox model for predicting RFS was significantly improved by including DR. In the conditional inference tree analysis, DR categorisation was the first split factor for predicting RFS, followed by T-stage, microsatellite instability status and budding.ConclusionsHistological categorisation of DR provides important prognostic information that could contribute to the efficient selection of stage II colon cancer patients who would benefit from postoperative adjuvant therapy.

BackgroundDiffusion-weighted magnetic resonance imaging (DW-MRI) potentially interrogates site-specific response to neoadjuvant chemotherapy (NAC) in epithelial ovarian cancer (EOC).MethodsParticipants with newly diagnosed EOC due for platinum-based chemotherapy and interval debulking surgery were recruited prospectively in a multicentre study (n = 47 participants). Apparent diffusion coefficient (ADC) and solid tumour volume (up to 10 lesions per participant) were obtained from DW-MRI before and after NAC (including double-baseline for repeatability assessment in n = 19). Anatomically matched lesions were analysed after surgical excision (65 lesions obtained from 25 participants). A trained algorithm determined tumour cell fraction, percentage tumour and percentage necrosis on histology. Whole-lesion post-NAC ADC and pre/post-NAC ADC changes were compared with histological metrics (residual tumour/necrosis) for each tumour site (ovarian, omental, peritoneal, lymph node).ResultsTumour volume reduced at all sites after NAC. ADC increased between pre- and post-NAC measurements. Post-NAC ADC correlated negatively with tumour cell fraction. Pre/post-NAC changes in ADC correlated positively with percentage necrosis. Significant correlations were driven by peritoneal lesions.ConclusionsFollowing NAC in EOC, the ADC (measured using DW-MRI) increases differentially at disease sites despite similar tumour shrinkage, making its utility site-specific. After NAC, ADC correlates negatively with tumour cell fraction; change in ADC correlates positively with percentage necrosis.Clinical trial registrationClinicalTrials.gov NCT01505829.

doi: 10.1038/s41416-020-01218-4pmid: 33402737

BackgroundAdoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation.MethodsPD-1− and PD-1+ CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation.ResultsTumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137+ cells within the PD-1+CD8+ TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products.ConclusionWe have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1+ TILs.

doi: 10.1038/s41416-020-01216-6pmid: 33414541

BackgroundThere is limited knowledge about DCIS cellular composition and relationship with breast cancer events (BCE).MethodsImmunofluorescence multiplexing (MxIF) was used to image and quantify 32 cellular biomarkers in FFPE DCIS tissue microarrays. Over 75,000 DCIS cells from 51 patients (median 9 years follow-up for non-BCE cases) were analysed for profiles predictive of BCE. K-means clustering was used to evaluate cellular co-expression of epithelial markers with ER and HER2.ResultsOnly ER, PR and HER2 significantly correlated with BCE. Cluster analysis identified 6 distinct cell groups with different levels of ER, Her2, cMET and SLC7A5. Clusters 1 and 3 were not significant. Clusters 2 and 4 (high ER/low HER2 and SLC7A5/mixed cMET) significantly correlated with low BCE risk (P = 0.001 and P = 0.034), while cluster 6 (high HER2/low ER, cMET and SLC7A5) correlated with increased risk (P = 0.018). Cluster 5 (similar to cluster 6, except high SLC7A5) trended towards significance (P = 0.072). A continuous expression score (Escore) based on these 4 clusters predicted likelihood of BCE (AUC = 0.79, log-rank test P = 5E–05; LOOCV AUC = 0.74, log-rank test P = 0.006).ConclusionMultiplexed spatial analysis of limited tissue is a novel method for biomarker analysis and predicting BCEs. Further validation of Escore is needed in a larger cohort.

BackgroundHigher dairy intake during adulthood has been associated with lower colorectal cancer risk. As colorectal carcinogenesis spans several decades, we hypothesised that higher dairy intake during adolescence is associated with lower risk of colorectal adenoma, a colorectal cancer precursor.MethodsIn 27,196 females from the Nurses’ Health Study 2, aged 25–42 years at recruitment (1989), who had completed a validated high school diet questionnaire in 1998 and undergone at least one lower bowel endoscopy between 1998 and 2011, logistic regression for clustered data was used to calculate odds ratios (ORs) and 95% confidence intervals (CI).ResultsColorectal adenomas were diagnosed in 2239 women. Dairy consumption during adolescence was not associated with colorectal adenoma risk (OR highest vs. lowest [≥4 vs. ≤1.42 servings/day] quintile [95% CI] 0.94 [0.80, 1.11]). By anatomical site, higher adolescent dairy intake was associated with lower rectal (0.63 [0.42, 0.95]), but not proximal (1.01 [0.80, 1.28]) or distal (0.97 [0.76, 1.24]) colon adenoma risk. An inverse association was observed with histologically advanced (0.72 [0.51, 1.00]) but not non-advanced (1.07 [0.86, 1.33]) adenoma.ConclusionsIn this large cohort of younger women, higher adolescent dairy intake was associated with lower rectal and advanced adenoma risk later in life.