Taxonomic reclassification of Kaposi Sarcoma identifies disease entities with distinct immunopathogenesis.

BACKGROUND: The taxonomy of Kaposi Sarcoma (KS) is based on a classification system focused on the description of clinicopathological features of KS in geographically and clinically diverse populations. The classification includes classic, endemic, epidemic/HIV associated and iatrogenic KS, and KS in men who have sex with men (MSM). We assessed the medical relevance of the current classification of KS and sought clinically useful improvements in KS taxonomy. METHODS: We reviewed the demographic and clinicopathological features of 676 patients with KS, who were referred to the national centre for HIV oncology at Chelsea Westminster hospital between 2000 and 2021. RESULTS: Demographic differences between the different subtypes of KS exist as tautological findings of the current classification system. However, no definitive differences in clinicopathological, virological or immunological parameters at presentation could be demonstrated between the classic, endemic or MSM KS patients. Reclassifying patients as either immunosuppressed or non-immunosuppressed, showed that the immunosuppressed group had a significantly higher proportion of adverse disease features at presentation including visceral disease and extensive oral involvement, classified together as advanced disease (chi2 P = 0.0012*) and disseminated skin involvement (chi2 P < 0.0001*). Immunosuppressed patients had lower CD4 counts, higher CD8 counts and a trend towards higher HHV8 levels compared to non-immunosuppressed patients, however overall survival and disease specific (KS) survival was similar across groups. CONCLUSION: The current system of KS classification does not reflect meaningful differences in clinicopathological presentation or disease pathogenesis. Reclassification of patients based on the presence or absence of immunosuppression is a more clinically meaningful system that may influence therapeutic approaches to KS.

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer.

BACKGROUND: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. PATIENTS AND METHODS: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. RESULTS: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. CONCLUSIONS: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.

Antibiotic-exposed patients with non-small-cell lung cancer preserve efficacy outcomes following first-line chemo-immunotherapy.

BACKGROUND: Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes to chemo-immunotherapy combinations is still unknown. PATIENTS AND METHODS: In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions. RESULTS: Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 [95% confidence interval (CI): 0.91-2.22]; P = 0.1207} and PFS [HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552], compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS [HR = 1.29 (95% CI: 0.91-1.84); P = 0.149] and PFS [HR = 1.20 (95% CI: 0.89-1.63); P = 0.222] when evaluated as time-varying covariate in multivariable analysis. CONCLUSIONS: In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed.

The systemic pro-inflammatory response: targeting the dangerous liaison between COVID-19 and cancer.

Inflammation is an established driver of severe SARS-CoV-2 infection and a mechanism linked to the increased susceptibility to fatal COVID-19 demonstrated by patients with cancer. As patients with cancer exhibit a higher level of inflammation compared with the general patient population, patients with cancer and COVID-19 may uniquely benefit from strategies targeted at overcoming the unrestrained pro-inflammatory response. Targeted and non-targeted anti-inflammatory therapies may prevent end-organ damage in SARS-CoV-2-infected patients with cancer and decrease mortality. Here, we review the clinical role of selective inhibition of pro-inflammatory interleukins, tyrosine kinase modulation, anti-tumor necrosis factor agents, and other non-targeted approaches including corticosteroids in their roles as disease-modulating agents in patients with COVID-19 and cancer. Investigation of these therapeutics in this highly vulnerable patient group is posited to facilitate the development of tailored therapeutics for this patient population, aiding the transition of systemic inflammation from a prognostic domain to a source of therapeutic targets.

The albumin-bilirubin grade uncovers the prognostic relationship between hepatic reserve and immune dysfunction in HIV-associated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of liver-related mortality in people living with HIV, where co-infection with hepatotropic viruses accelerates the course of chronic liver disease. AIM: To evaluate whether the albumin-bilirubin (ALBI) grade, a more accurate marker of liver dysfunction in HCC, might identify patients with progressive liver dysfunction in the context of HIV/hepatitis co-infection. METHODS: Using uni- and multi-variable analyses, we studied the albumin-bilirubin grade as a predictor of overall survival (OS) in a large, multi-center cohort of patients with HIV-associated HCC recruited from 44 centres in 9 countries within the Liver Cancer in HIV study group. Patients who underwent liver transplantation were excluded. RESULTS: A total of 387 patients, predominantly HCV co-infected (78%) with balanced representation of all Barcelona Clinic Liver Cancer (BCLC) stages (A = 33%, B = 18%, C = 37%, D = 12%) were recruited. At HCC diagnosis, 84% had been on anti-retrovirals for a median duration of 8.8 years. The albumin-bilirubin grade identified significant differences in median survival of 97 months for grade 1 (95% CI 13-180 months), 17 months for grade 2 (95% CI 11-22 months) and 6 months for grade 3 (95% CI 4-9 months, P < .001). A more advanced albumin-bilirubin grade correlated with lower CD4 counts (464/373/288 cells/mm3 for grades 1/2/3) and higher HIV viraemia (3.337/8.701/61.845 copies/mL for grades 1/2/3, P < .001). CONCLUSIONS: In this large, multi-center retrospective study, the albumin-bilirubin grade highlights the interplay between liver reserve and immune dysfunction as prognostic determinants in HIV-associated HCC.

Review article: delivering precision oncology in intermediate-stage liver cancer.

BACKGROUND: Intermediate-stage hepatocellular carcinoma (HCC), for which trans-arterial chemoembolization (TACE) constitutes the standard of care, is a patient subgroup with significant heterogeneity in clinical outcome. Sources of variation relate to differences in tumour burden, hepatic reserve, ethnicity and treatment modalities. Increasing research efforts have been dedicated to minimise the clinical diversity of this patient population and enhance optimal provision of treatment. AIM: To comprehensively review the diverse prognostic models that have been proposed to refine the prognostic prediction of patients with HCC undergoing TACE. RESULTS: A number of prognostic algorithms (HAP, ART, ABCR score and many others) have shown potential to address the clinical heterogeneity characterising patients with intermediate-stage HCC and facilitate early identification of patients with poor prognostic features in whom alternative treatments or best supportive care might be more appropriate than TACE. CONCLUSIONS: While an improved characterisation of intermediate-stage HCC is a highly important clinical aim, current evidence suggests that novel prognostic algorithms in this patient population may offer potential benefits but non-negligible challenges in the provision of TACE. This review summarises the currently available evidence to facilitate the development of precision oncology in intermediate-stage HCC.

On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable. AIM: To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC. METHODS: In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively. RESULTS: A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child-Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8-18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61-0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37-0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51-0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose. CONCLUSION: Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.

The albumin-bilirubin grade improves hepatic reserve estimation post-sorafenib failure: implications for drug development.

BACKGROUND: Drug development in hepatocellular carcinoma (HCC) is limited by disease heterogeneity, with hepatic reserve being a major source of variation in survival outcomes. The albumin-bilirubin (ALBI) grade is a validated index of liver function in patients with HCC. AIM: To test the accuracy of the ALBI grade in predicting post-sorafenib overall survival (PSOS) in patients who permanently discontinued treatment. METHODS: From a prospectively maintained international database of 447 consecutive referrals, we derived 386 eligible patients treated with sorafenib within Barcelona Clinic Liver Cancer C stage (62%), 75% of whom were of Child class A at initiation. Clinical variables at sorafenib discontinuation were analysed for their impact on post-sorafenib overall survival using uni- and multivariable analyses. RESULTS: Median post-sorafenib overall survival of the 386 eligible patients was 3.4 months and median sorafenib duration was 2.9 months, with commonest causes of cessation being disease progression (68%) and toxicity (24%). At discontinuation, 92 patients (24%) progressed to terminal stage, due to worsening Child class to C in 40 (10%). Median post-sorafenib overall survival in patients eligible for second-line therapies (n = 294) was 17.5, 7.5 and 1.9 months according respectively to ALBI grade 1, 2 and 3 (P < 0.001). CONCLUSIONS: The ALBI grade at sorafenib discontinuation identifies a subset of patients with prolonged stability of hepatic reserve and superior survival. This may allow improved patient selection for second-line therapies in advanced HCC.

TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition.

TAM (Tyro3-Axl-Mer) receptor tyrosine kinases and Met are implicated in several hallmarks of cancer progression including sustained angiogenesis, enhanced motility, tissue invasion and acquisition of metastatic potential through the upregulation of epithelial-to-mesenchymal transition. Increasing evidence has confirmed Axl and Met as emerging central drivers of adaptive resistance to targeted therapies across a wide variety of cancers. In this issue of Oncogene, Zhou et al. describe the mechanisms linking Axl and Met activation to acquired resistance to sunitinib in renal cell carcinoma (RCC), providing a pre-clinical rationale for the development of Axl and Met inhibitors including cabozantinib in anti-angiogenic resistant RCC.

Dynamic changes of the inflammation-based index predict mortality following chemoembolisation for hepatocellular carcinoma: a prospective study.

BACKGROUND: Transarterial chemoembolisation (TACE) is a standard treatment for unresectable, intermediate stage hepatocellular carcinoma (HCC). Survival after TACE, however, can be highly variable, with no suitable biomarker predicting therapeutic outcome. The inflammation-based index (IBI) has previously been shown to independently predict overall survival (OS) in all stages of HCC. AIM: To explore the prognostic ability of IBI as a predictor of survival after TACE. METHODS: Baseline staging, biochemical and clinicopathological features including IBI were studied in a derivation set of 64 patients undergoing TACE for intermediate stage HCC. Dynamic changes in IBI before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model and further validated in two independent patient cohorts from Korea (n = 76) and Japan (n = 577). RESULTS: Pre-treatment IBI predicted for OS in the derivation set (P = 0.001). Other univariate predictors of OS included radiological response to TACE (P < 0.001), pre-TACE CLIP score (P < 0.01), tumour diameter >5 cm (P = 0.05) and AFP ≥400 (P < 0.001). Normalisation of IBI post-TACE was associated with radiological response by mRECIST criteria and improved OS (P < 0.001). Normalisation of IBI remained a significant multivariate predictor of OS in both the derivation and validation sets (P < 0.001). CONCLUSIONS: Normalisation of IBI after TACE is shown to be an independent predictor of survival and may be integrated into the retreatment criteria for repeat TACE in intermediate stage HCC. IBI and its dynamic changes after treatment are validated as a biomarker allowing the stratification of patients with a significant survival advantage following initial TACE.

Prognostic performance of inflammation-based prognostic indices in primary operable non-small cell lung cancer.

BACKGROUND: At least 30% of patients with primary resectable non-small cell lung cancer (NSCLC) will experience a relapse in their disease within 5 years following definitive treatment. Clinicopathological predictors have proved to be suboptimal in identifying high-risk patients. We aimed to establish whether inflammation-based scores offer an improved prognostic ability in terms of estimating overall (OS) and recurrence-free survival (RFS) in a cohort of operable, early-stage NSCLC patients. METHODS: Clinicopathological, demographic and treatment data were collected prospectively for 220 patients operated for primary NSCLC at the Hammersmith Hospital from 2004 to 2011. Pretreatment modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were tested together with established prognostic factors in uni- and multivariate Cox regression analyses of OS and RFS. RESULTS: Half of the patients were male, with a median age of 65. A total of 57% were classified as stage I with adenocarcinoma being the most prevalent subtype (60%). Univariate analyses of survival revealed stage (P<0.001), grade (P=0.02), lymphovascular (LVI, P=0.001), visceral pleural invasion (VPI, P=0.003), mGPS (P=0.02) and NLR (P=0.04) as predictors of OS, with stage (P<0.001), VPI (P=0.02) and NLR (P=0.002) being confirmed as independent prognostic factors on multivariate analyses. Patients with more advanced stage (P<0.001) and LVI (P=0.008) had significantly shorter RFS. CONCLUSIONS: An elevated NLR identifies operable NSCLC patients with a poor prognostic outlook and an OS difference of almost 2 years compared to those with a normal score at diagnosis. Our study validates the clinical utility of the NLR in early-stage NSCLC.

Inflammation as a validated prognostic determinant in carcinoma of unknown primary site.

BACKGROUND: Carcinoma of unknown primary (CUP) is a clinical presentation with a poor prognosis. Inflammation-based prognostic systems are stage-independent prognostic predictors in various malignancies. We aimed to assess the accuracy of the modified Glasgow Prognostic Score (mGPS), neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) as objective prognostic models in CUP. METHODS: We derived inflammatory scores in 60 consecutive CUP referrals to the Imperial College oncology unit between 1996 and 2011. Patient demographics, treatment and staging data and full blood profiles were collected. An independent cohort of 179 patients presenting to the Taipei Veterens Hospital between 2000 and 2009 were used as a 'validation' data set. Uni- and multivariate survival analysis was used to predict the overall survival (OS). RESULTS: Sixty patients were included: median age 61 (range: 33-86); 51% men; median OS 5.9 months (0.7-42.9); 88% with distant metastases. On univariate analysis NLR >5 (P=0.04) and mGPS (score 1-2) (P=0.03) correlated with OS. Multivariate analysis demonstrated significant hazard ratios for NLR; 2.02 (CI 1.0-4.1) (P=0.04) and mGPS; 1.52 (CI 1.0-2.3) (P=0.03). These findings were reinforced by analysis of the validation data. CONCLUSION: NLR and mGPS are independent, externally validated prognostic markers in CUP, with superior objectivity compared with performance status.

An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1-5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan-Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16-82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up.