British Journal of Cancer

Li, Hanxiao; van der Merwe, P. Anton; Sivakumar, Shivan

doi: 10.1038/s41416-022-01743-4pmid: 35228677

The binding of T cell immune checkpoint proteins programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to their ligands allows immune evasion by tumours. The development of therapeutic antibodies, termed checkpoint inhibitors, that bind these molecules or their ligands, has provided a means to release this brake on the host anti-tumour immune response. However, these drugs are costly, are associated with potentially severe side effects, and only benefit a small subset of patients. It is therefore important to identify biomarkers that discriminate between responders and non-responders. This review discusses the determinants for a successful response to antibodies that bind PD-1 or its ligand PD-L1, dividing them into markers found in the tumour biopsy and those in non-tumour samples. It provides an update on the established predictive biomarkers (tumour PD-L1 expression, tumour mismatch repair deficiency and tumour mutational burden) and assesses the evidence for new potential biomarkers.

Pietrasz, Daniel; Sereni, Elisabetta; Lancelotti, Francesco; Pea, Antonio; Luchini, Claudio; Innamorati, Giulio; Salvia, Roberto; Bassi, Claudio

doi: 10.1038/s41416-022-01745-2pmid: 35197581

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the third leading cause of cancer-related mortality within the next decade. Management of PDAC remains challenging with limited effective treatment options and a dismal long-term prognosis. Liquid biopsy and circulating biomarkers seem to be promising to improve the multidisciplinary approach in PDAC treatment. Circulating tumour DNA (ctDNA) is the most studied blood liquid biopsy analyte and can provide insight into the molecular profile and individual characteristics of the tumour in real-time and in advance of standard imaging modalities. This could pave the way for identifying new therapeutic targets and markers of tumour response to supplement diagnostic and provide enhanced stratified treatment. Although its specificity seems excellent, the current sensitivity of ctDNA remains a limitation for clinical use, especially in patients with a low tumour burden. Increasing evidence suggests that ctDNA is a pertinent candidate biomarker to assess minimal residual disease after surgery but also a strong independent prognostic biomarker. This review explores the current knowledge and recent developments in ctDNA as a screening, diagnostic, prognostic and predictive biomarker in the management of resectable PDAC but also technical and analytical challenges that must be overcome to move toward “precision onco-surgery.”

Li, Yun; Liu, Chenying; Zhang, Xin; Huang, Xiaodi; Liang, Shujun; Xing, Feiyue; Tian, Han

doi: 10.1038/s41416-022-01747-0pmid: 35194191

BackgroundLymph node (LN) metastasis confers gastric cancer (GC) progression, poor survival and cancer-related death. Aberrant activation of Wnt/β-catenin promotes epithelial-mesenchymal transition (EMT) and LN metastasis, whereas the constitutive activation mutation of Wnt/β-catenin is rare in GC, suggesting that the underlying mechanisms enhancing Wnt/β-catenin activation need to be further investigated and understood.MethodsBioinformatics analyses and immunohistochemistry (IHC) were used to identify and detect LN metastasis-related genes in GC. Cellular functional assays and footpad inoculation mouse model illustrate the biological function of CCT5. Co-immunoprecipitation assays, western blot and qPCR elucidate the interaction between CCT5 and E-cadherin, and the regulation on β-catenin activity.ResultsCCT5 is upregulated in LN metastatic GCs and correlates with poor prognosis. In vitro assays prove that CCT5 markedly promotes GC cell proliferation, anti-anoikis, invasion and lymphatic tube formation. Moreover, CCT5 enhances xenograft GC growth and popliteal lymph node metastasis in vivo. Furthermore, CCT5 binds the cytoplasmic domain of E-cadherin and abrogates the interaction between E-cadherin and β-catenin, thereby releasing β-catenin to the nucleus and enhancing Wnt/β-catenin signalling activity and EMT.ConclusionCCT5 promotes GC progression and LN metastasis by enhancing wnt/β-catenin activation, suggesting a great potential of CCT5 as a biomarker for GC diagnosis and therapy.

Roque, Dana M.; Siegel, Eric R.; Buza, Natalia; Bellone, Stefania; Silasi, Dan-Arin; Huang, Gloria S.; Andikyan, Vaagn; Clark, Mitchell; Azodi, Masoud; Schwartz, Peter E.; Rao, Gautam G.; Reader, Jocelyn C.; Hui, Pei; Tymon-Rosario, Joan R.; Harold, Justin; Mauricio, Dennis; Zeybek, Burak; Menderes, Gulden; Altwerger, Gary;

Patel, Meera; Pennel, Kathryn A. F.; Quinn, Jean A.; Hood, Hannah; Chang, David K.; Biankin, Andrew V.; Rebus, Selma; Roseweir, Antonia K.; Park, James H.; Horgan, Paul G.; McMillan, Donald C.; Edwards, Joanne

doi: 10.1038/s41416-022-01729-2pmid: 35173303

BackgroundTo understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.MethodsImmunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.ResultsTwo patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete ‘punctate’ areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high ‘punctate’ IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.ConclusionsThese results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.

de Gregorio, Amelie; Janni, Wolfgang; Friedl, Thomas W. P.; Nitz, Ulrike; Rack, Brigitte; Schneeweiss, Andreas; Kates, Ronald; Fehm, Tanja; Kreipe, Hans; Christgen, Matthias; Kümmel, Sherko; Trapp, Elisabeth; Wuerstlein, Rachel; Hartkopf, Andreas; Clemens, Michael; Reimer, Toralf; Häberle, Lothar; Fasching, Peter A.; Gluz, Oleg;

Forster, Alice S.; Herbert, Annie; Koo, Minjoung Monica; Taylor, Rachel M.; Gibson, Faith; Whelan, Jeremy S.; Lyratzopoulos, Georgios; Fern, Lorna A.

doi: 10.1038/s41416-022-01698-6pmid: 35190694

BackgroundThe association of diagnostic intervals and outcomes is poorly understood in adolescents and young adults with cancer (AYA). We investigated associations between diagnostic intervals and health-related quality of life (HRQoL), anxiety and depression in a large AYA cohort.MethodsParticipants aged 12–24 completed interviews post-diagnosis, providing data on diagnostic experiences and the patient-reported outcomes (PROs) HRQoL, anxiety and depression. Demographic and cancer information were obtained from clinical and national records. Six diagnostic intervals were considered. Relationships between intervals and PROs were examined using regression models.ResultsEight hundred and thirty participants completed interviews. In adjusted models, across 28 of 30 associations, longer intervals were associated with poorer PROs. Patient intervals (symptom onset to first seeing a GP) of ≥1 month were associated with greater depression (adjusted odds ratio (aOR):1.7, 95% Confidence Interval (CI):1.1–2.5) compared to <1 month. ≥3 pre-referral GP consultations were associated with greater anxiety (aOR:1.6, CI:1.1–2.3) compared to 1–2 consultations. Symptom onset to first oncology appointment intervals of ≥2 months was associated with impaired HRQoL (aOR:1.8, CI:1.2–2.5) compared to <2 months.ConclusionsProlonged diagnostic intervals in AYA are associated with an increased risk of impaired HRQoL, anxiety and depression. Identifying and delivering interventions for this high-risk group is a priority.

Li, Zhuyue; Wang, Kang; Shivappa, Nitin; Hébert, James R.; Chen, Hong; Liu, Hui; Jiang, Xiaolian

doi: 10.1038/s41416-022-01731-8pmid: 35136208

BackgroundAcknowledging the role of inflammation in colorectal carcinogenesis, this study aimed to evaluate the associations between diet-associated inflammation, as measured by the energy-adjusted dietary inflammatory index (E-DIITM), and distinct stages of colorectal carcinogenesis.MethodsThe Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial enrolled participants without a colorectal cancer history, who were asked to complete baseline questionnaires and food frequency questionnaires. To estimate the associations between the E-DII and risks of newly incident colorectal adenoma, recurrent adenoma, and colorectal cancer, multivariable-adjusted Cox proportional hazards regression models were employed.ResultsAmong 101,680 participants, with an average age of 65 years, a total of 1177 incident colorectal adenoma cases, 895 recurrent adenoma cases and 1100 colorectal cancer cases were identified. Higher E-DII scores from food and supplement (HRQ5 vs Q1: 0.86 [0.69–1.06], Ptrend: 0.27) or from food only (HRQ5 vs Q1: 0.82 [0.64–1.05], Ptrend: 0.06) were not associated with higher risks of incident adenoma. However, the elevated risk of recurrent adenoma was found in the highest category of E-DII from food plus supplement (HRQ5 vs Q1: 1.63 [1.28–2.03], Ptrend: < 0.001) when compared with the lowest category. A significant association between colorectal cancer risk and E-DII from food plus supplement (HRQ5 vs Q1: 1.34 [1.09–1.65], Ptrend: 0.009) was found, where this association was only pronounced in distal colorectal cancer.ConclusionHigher E-DII scores from diet plus supplement but not from diet only were associated with a higher risk of recurrent adenoma and distal colorectal cancer. The role of nutrient supplements on cancer risk, especially when combined with diet, needs to be elucidated in future studies.

Harewood, Rhea; Wooldrage, Kate; Robbins, Emma C.; Kinross, James; von Wagner, Christian; Cross, Amanda J.

doi: 10.1038/s41416-022-01719-4pmid: 35149853

BackgroundColorectal cancer (CRC) screening is less effective at reducing cancer incidence in the proximal colon compared to the distal colorectum. We aimed to identify adenoma characteristics associated with proximal colon cancer (PCC).MethodsEndoscopy and pathology data for patients with ≥1 adenoma detected at baseline colonoscopy were obtained from 17 UK hospitals between 2001 and 2010. Multivariable Cox regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for PCC, and, for comparison, distal CRC incidence, by adenoma characteristics.ResultsAmong 18,431 patients, 152 and 105 developed PCC and distal CRC, respectively, over a median follow-up of 9.8 years. Baseline adenoma characteristics positively associated with PCC incidence included number (≥3 vs. < 3: aHR 2.10, 95% CI: 1.42–3.09), histology (tubulovillous/villous vs. tubular: aHR 1.61, 95% CI: 1.10–2.35) and location (any proximal vs. distal only: aHR 1.70, 95% CI: 1.20–2.42), for which there was borderline evidence of heterogeneity by subsite (p = 0.055). Adenoma dysplasia (high vs. low grade) was associated with distal CRC (aHR 2.42, 95% CI: 1.44–4.04), but not PCC (p-heterogeneity = 0.023).ConclusionsBaseline adenoma number, histology and proximal location were independently associated with PCC and may be important to identify patients at higher risk for post-polypectomy PCC.

Dalmartello, Michela; Turati, Federica; Zhang, Zuo-Feng; Lunet, Nuno; Rota, Matteo; Bonzi, Rossella; Galeone, Carlotta; Martimianaki, Georgia; Palli, Domenico; Ferraroni, Monica; Yu, Guo-Pei; Morais, Samantha; Malekzadeh, Reza; López-Carrillo, Lizbeth; Zaridze, David;