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Simple Summary: In preclinical studies, the epithelial-to-mesenchymal transition (EMT)-related transcription factor Slug indicated radio- and chemoresistance in head and neck squamous cell carcinoma (HNSCC). Here we show that Slug is a biomarker associated with treatment failure in HNSCC patients treated with primary radio- or radiochemotherapy, but not in patients undergoing upfront surgery and postoperative radio- or chemoradiotherapy. Slug may thus serve as a predictive biomarker to identify HNSCC patients who will benefit from upfront surgery. Slug status is an immunohistochemical (IHC) parameter that is easy to determine. If the predictive value observed here can be confirmed in validation studies with independent data, Slug immunohistochemistry may have significant clinical relevance in treatment planning for HNSCC patients. EMT promotes radio- and chemotherapy resistance in HNSCC in vitro. As EMT has been correlated to the transcription factor Slug in tumor specimens from HNSCC patients, we assessed whether Slug overexpression predicts radio- and chemotherapy resistance and favors upfront surgery in HNSCC patients. Slug expression was determined by IHC scoring in tumor specimens from patients with incident HNSCC. Patients were treated with either definitive radiotherapy or chemoradiotherapy (primary RT/CRT) or upfront surgery with or without postoperative RT or CRT (upfront surgery/PORT). Treatment failure rates and overall survival (OS) were compared between RT/CRT and upfront surgery/PORT in Slug-positive and Slug-negative patients. Slug IHC was positive in 91/354 HNSCC patients. Primary RT/CRT showed inferior response rates (univariate odds ratio (OR) for treatment failure, 3.6; 95% CI, 1.7 to 7.9; p = 0.001) and inferior 5-year OS (univariate, p < 0.001) in Slug-positive patients. The independent predictive value of Slug expression status was confirmed in a multivariable Cox model (p = 0.017). Slug-positive patients had a 3.3 times better chance of survival when treated with upfront surgery/PORT versus primary RT/CRT. For HNSCC patients, Slug IHC represents a novel and feasible predictive biomarker to support upfront surgery. [ABSTRACT FROM AUTHOR]

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials. [ABSTRACT FROM AUTHOR]

We conducted a systematic review for evidence of the clinical efficacy of cancer immunotherapies. We searched PubMed from inception to 14 February 2018 for meta-analyses of randomized controlled trials (RCTs) of cancer immunotherapies. Re-analyses were performed to estimate the summary effect size under random-effects, the 95% confidence interval (CI), heterogeneity, and the 95% prediction interval, and we determined the strength of the evidence. We examined publication bias and excess significance bias. 63 articles corresponding to 247 meta-analyses were eligible. Nine meta-analyses were classified to have convincing evidence, and 75 were classified as suggestive evidence. The clinical benefit of immunotherapy was supported by convincing evidence in the following settings: anti-PD-1/PD-L1 monoclonal antibody (mAb) therapy for treating advanced melanoma and non-small cell lung cancer (NSCLC), the combination of rituximab and chemotherapy for treating chronic lymphocytic leukemia and B-cell non-Hodgkin's lymphoma, adoptive cell immunotherapy for NSCLC, and the combination of interferon α and chemotherapy for metastatic melanoma. A further meta-analysis of 16 RCTs showed that anti-PD-1/PD-L1 mAb therapy had a benefit in patients with solid tumors (overall survival; hazard ratio = 0.73, 95% CI: 0.68–0.79; p < 0.001), supported by convincing evidence. In the future, rigorous approaches are needed when interpreting meta-analyses to gain better insight into the true efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02–3.49, p = 0.043), more than two metastatic sites (OR = 1.86, 1.34–2.57, p < 0.001), liver metastases (OR = 3.33, 2.07–5.34, p < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96–5.66, p < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36–0.99, p = 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD. [ABSTRACT FROM AUTHOR]