British Journal of Cancer

Lorenzoni, Giulia; Petracci, Elisabetta; Scarpi, Emanuela; Baldi, Ileana; Gregori, Dario; Nanni, Oriana

doi: 10.1038/s41416-022-02110-zpmid: 36572731

Sequential multiple assignments randomized trials (SMARTs) are a type of experimental design where patients may be randomised multiple times according to pre-specified decision rules. The present work investigates the state-of-the-art of SMART designs in oncology, focusing on the discrepancy between the available methodological approaches in the statistical literature and the procedures applied within cancer clinical trials. A systematic review was conducted, searching PubMed, Embase and CENTRAL for protocols or reports of results of SMART designs and registrations of SMART designs in clinical trial registries applied to solid tumour research. After title/abstract and full-text screening, 33 records were included. Fifteen were reports of trials’ results, four were trials’ protocols and fourteen were trials’ registrations. The study design was defined as SMART by only one out of fifteen trial reports. Conversely, 13 of 18 study protocols and trial registrations defined the study design SMART. Furthermore, most of the records considered each stage separately in the analysis, without considering treatment regimens embedded in the trial. SMART designs in oncology are still limited. Study powering and analysis is mainly based on statistical approaches traditionally used in single-stage parallel trial designs. Formal reporting guidelines for SMART designs are needed.

François, Alexia; Descarpentrie, Jean; Badiola, Iker; Siegfried, Géraldine; Evrard, Serge; Pernot, Simon; Khatib, Abdel-Majid

doi: 10.1038/s41416-022-02073-1pmid: 36522477

Immunotherapy is becoming an advanced clinical management for various cancers. Rebuilding of aberrant immune surveillance on cancers has achieved notable progress in the past years by either in vivo or ex vivo engineering of efficient immune cells. Immune cells can be programmed with several strategies that improves their therapeutic influence and specificity. It has become noticeable that effective immunotherapy must consider the complete complexity of the immune cell function. However, today, almost all immune cells can be transiently or stably reprogrammed against various cancer cells. As a consequence, investigations have interrogated strategies to improve the efficacy of cancer immunotherapies by enhancing T-cell infiltration into tumour tissues. Here, we review the emerging role of furin-like enzymes work related to T-cell reprogramming, their tumour infiltration and cytotoxic function.

Wang, Yuqing; Du, Jiang; Gao, Zhenyue; Sun, Haoyang; Mei, Mei; Wang, Yu; Ren, Yu; Zhou, Xuan

doi: 10.1038/s41416-022-02084-ypmid: 36522474

Immune checkpoint blockade therapy targeting programmed cell death protein 1 (PD-1) has revolutionized the landscape of multiple human cancer types, including head and neck squamous carcinoma (HNSCC). Programmed death ligand-2 (PD-L2), a PD-1 ligand, mediates cancer cell immune escape (or tolerance independent of PD-L1) and predicts poor prognosis of patients with HNSCC. Therefore, an in-depth understanding of the regulatory process of PD-L2 expression may stratify patients with HNSCC to benefit from anti-PD-1 immunotherapy. In this review, we summarised the PD-L2 expression and its immune-dependent and independent functions in HNSCC and other solid tumours. We focused on recent findings on the mechanisms that regulate PD-L2 at the genomic, transcriptional, post-transcriptional, translational, and post-translational levels, also in intercellular communication of tumour microenvironment (TME). We also discussed the prospects of using small molecular agents indirectly targeting PD-L2 in cancer therapy. These findings may provide a notable avenue in developing novel and effective PD-L2-targeted therapeutic strategies for immune combination therapy and uncovering biomarkers that improve the clinical efficacy of anti-PD-1 therapies.

Kumegawa, Kohei; Saeki, Sumito; Takahashi, Yoko; Yang, Liying; Osako, Tomo; Nakadai, Tomoyoshi; Amino, Sayuri; Maeda, Tetsuyo; Takahata, Chikako; Mori, Seiichi; Noda, Tetsuo; Ohno, Shinji; Ueno, Takayuki; Maruyama, Reo

doi: 10.1038/s41416-023-02178-1pmid: 36725920

Geng, Qishun; Li, Lifeng; Shen, Zhibo; Zheng, Yuanyuan; Wang, Longhao; Xue, Ruyue; Xue, Wenhua; Peng, Mengle; Zhao, Jie

doi: 10.1038/s41416-022-02132-7pmid: 36646807

BackgroundMental stress-induced neurotransmitters can affect the immune system in various ways. Therefore, a better understanding of the role of neurotransmitters in the tumour immune microenvironment is expected to promote the development of novel anti-tumour therapies.MethodsIn this study, we analysed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments and experiments in vitro were used to reveal the specific mechanism of norepinephrine’s (NE) effect on immunotherapy.ResultsThe plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of C-X-C Motif Chemokine Ligand 9 (CXCL9) and adenosine (ADO) in tumour cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/β-catenin signalling pathway plays a crucial role in this progression.ConclusionNE can affect the secretion of CXCL9 and ADO in tumour cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD).

Zadran, Bassier; Sudhindar, Praveen Dhondurao; Wainwright, Daniel; Bury, Yvonne; Luli, Saimir; Howarth, Rachel; McCain, Misti Vanette; Watson, Robyn; Huet, Hannah; Palinkas, Fanni; Berlinguer-Palmini, Rolando; Casement, John; Mann, Derek A.; Oakley, Fiona; Lunec, John; Reeves, Helen; Faulkner, Geoffrey J.; Shukla, Ruchi

Du, Zhimin; Zhang, Hui; Feng, Yueyuan; Zhan, Dewen; Li, Shuya; Tu, Chenggong; Liu, Jinbao; Wang, Jinheng

doi: 10.1038/s41416-023-02175-4pmid: 36755063

BackgroundTumour-derived small extracellular vesicles (sEVs) play a crucial role in cancer immunomodulation. In addition to tumour immune microenvironment, the peripheral immune system also contributes significantly to cancer progression and is essential for anticancer immunity. However, a comprehensive definition of which and how peripheral immune lineages are regulated by tumour-derived sEVs during cancer development remains incomplete.MethodsIn this study, we used mass cytometry with extensive antibody panels to comprehensively construct the systemic immune landscape in response to tumour development and tumour-derived sEVs.ResultsSystemic immunity was dramatically altered by tumour growth and tumour-derived sEVs. Tumour-derived sEVs significantly and extensively affected immune cell population composition as well as intracellular pathways, resulting in an immunosuppressive peripheral and tumour immune microenvironment, characterised by increased myeloid-derived suppressor cells and decreased Ly6C+CD8 T cells. These sEVs largely promoted hematopoietic recovery and accelerate the differentiation towards myeloid-derived suppressor cells. The knockdown of Rab27a reduced sEV secretion from tumour cells and delayed tumour growth and metastasis in vivo.ConclusionsThese results highlight that tumour-derived sEVs function as a bridge between peripheral immunity regulation and the tumour microenvironment, and contribute to cancer progression through altering the composition and function of the global immune macroenvironment.

Bao, Jie; Hou, Ying; Qin, Lang; Zhi, Rui; Wang, Xi-Ming; Shi, Hai-Bin; Sun, Hong-Zan; Hu, Chun-Hong; Zhang, Yu-Dong

doi: 10.1038/s41416-022-02134-5pmid: 36646808

BackgroundTo develop and test a Prostate Imaging Stratification Risk (PRISK) tool for precisely assessing the International Society of Urological Pathology Gleason grade (ISUP-GG) of prostate cancer (PCa).MethodsThis study included 1442 patients with prostate biopsy from two centres (training, n = 672; internal test, n = 231 and external test, n = 539). PRISK is designed to classify ISUP-GG 0 (benign), ISUP-GG 1, ISUP-GG 2, ISUP-GG 3 and ISUP GG 4/5. Clinical indicators and high-throughput MRI features of PCa were integrated and modelled with hybrid stacked-ensemble learning algorithms.ResultsPRISK achieved a macro area-under-curve of 0.783, 0.798 and 0.762 for the classification of ISUP-GGs in training, internal and external test data. Permitting error ±1 in grading ISUP-GGs, the overall accuracy of PRISK is nearly comparable to invasive biopsy (train: 85.1% vs 88.7%; internal test: 85.1% vs 90.4%; external test: 90.4% vs 94.2%). PSA ≥ 20 ng/ml (odds ratio [OR], 1.58; p = 0.001) and PRISK ≥ GG 3 (OR, 1.45; p = 0.005) were two independent predictors of biochemical recurrence (BCR)-free survival, with a C-index of 0.76 (95% CI, 0.73–0.79) for BCR-free survival prediction.ConclusionsPRISK might offer a potential alternative to non-invasively assess ISUP-GG of PCa.

Brand, Adam; Sachs, Michael C.; Sjölander, Arvid; Gabriel, Erin E.

doi: 10.1038/s41416-023-02144-xpmid: 36690722

BackgroundMedical advances in the treatment of cancer have allowed the development of multiple approved treatments and prognostic and predictive biomarkers for many types of cancer. Identifying improved treatment strategies among approved treatment options, the study of which is termed comparative effectiveness, using predictive biomarkers is becoming more common. RCTs that incorporate predictive biomarkers into the study design, called prediction-driven RCTs, are needed to rigorously evaluate these treatment strategies. Although researched extensively in the experimental treatment setting, literature is lacking in providing guidance about prediction-driven RCTs in the comparative effectiveness setting.MethodsRealistic simulations with time-to-event endpoints are used to compare contrasts of clinical utility and provide examples of simulated prediction-driven RCTs in the comparative effectiveness setting.ResultsOur proposed contrast for clinical utility accurately estimates the true clinical utility in the comparative effectiveness setting while in some scenarios, the contrast used in current literature does not.DiscussionIt is important to properly define contrasts of interest according to the treatment setting. Realistic simulations should be used to choose and evaluate the RCT design(s) able to directly estimate that contrast. In the comparative effectiveness setting, our proposed contrast for clinical utility should be used.

Bottosso, Michele; Griguolo, Gaia; Sinoquet, Léa; Guarascio, Maria Cristina; Aldegheri, Vittoria; Miglietta, Federica; Vernaci, Grazia; Barbieri, Caterina; Girardi, Fabio; Jacot, William; Guarneri, Valentina; Darlix, Amélie; Dieci, Maria Vittoria

doi: 10.1038/s41416-023-02153-wpmid: 36717671

BackgroundBrain metastases (BM) are common among HER2+ breast cancer (BC) and prognostic stratification is crucial for optimal management. BC-GPA score and subsequent refinements (modified-GPA, updated-GPA) recapitulate prognostic factors. Since none of these indexes includes extracranial disease control, we evaluated its prognostic value in HER2+ BCBM.MethodsPatients diagnosed with HER2+ BCBM at Istituto Oncologico Veneto-Padova (2002–2021) and Montpellier Cancer Institute (2001–2015) were included as exploratory and validation cohorts, respectively. Extracranial disease control at BM diagnosis (no disease/stable disease/response vs. progressive disease) was evaluated.ResultsIn the exploratory cohort of 113 patients (median OS 12.2 months), extracranial control (n = 65, 57.5%) was significantly associated with better OS at univariate (median OS 17.7 vs. 8.7 months, p = 0.005) and multivariate analysis after adjustment for BC-GPA (HR 0.61, 95% CI 0.39–0.94), modified-GPA (HR 0.64, 95% CI 0.42–0.98) and updated-GPA (HR 0.63, 95% CI 0.41–0.98). The prognostic impact of extracranial disease control (n = 66, 56.4%) was then confirmed in the validation cohort (n = 117) at univariate (median OS 20.2 vs. 9.1 months, p < 0.001) and multivariate analysis adjusting for BC-GPA (HR 0.41, 95% CI 0.27–0.61), modified-GPA (HR 0.44, 95% CI 0.29–0.67) and updated-GPA (HR 0.42, 95% CI 0.28–0.63).ConclusionsExtracranial disease control provides independent prognostic information in HER2+ BCBM beyond commonly used prognostic scores.