Shorter Progression-free Survival In Patients Research Articles

Potential of quantitative T1 mapping to serve as a novel prognostic predictor of clear cell renal cell carcinoma after nephrectomy.

Accurate preoperative risk stratification methods are important for clear cell renal cell carcinoma (ccRCC) patients to enable personalized treatment. However, there are still no accurate and quantitative prognostic factors. This study aimed to investigate the effectiveness of T1 mapping in predicting the progression-free survival (PFS) of ccRCC after nephrectomy. A retrospective cohort study was performed in a China tertiary care hospital. This study reviewed the clinical and magnetic resonance imaging (MRI) data of consecutive inpatients with pathologically confirmed ccRCCs between September 2014 and September 2021. PFS was evaluated by following patients until the first adverse event. Radiological features including T1 relaxation time of tumors were assessed by 2 radiologists. Cox regression and visual nomogram, Kaplan-Meier survival, and log-rank test were utilized for survival analysis. A total of 195 patients with pathologically confirmed ccRCCs (mean age ± standard deviation, 56.0±12.0 years; 133 men) with eligible data were included in the study. The median follow-up was 27.6 months (range, 1-88 months), and 22 (11.3%) patients experienced metastasis or recurrence. Univariate and multivariate survival analysis showed the higher post-contrasted T1 relaxation time [P=0.001; hazard ratio (HR), 2.077; 95% confidence interval (CI): 1.350-3.196] and the incomplete tumor capsule (P<0.001; HR, 7.849; CI: 2.614-23.570) were independently associated with a shorter PFS of patients. Patients with ≥222.73 ms post-contrasted T1 relaxation time ccRCCs had worse PFS than the lower post-contrasted T1 relaxation time group. The T1 mapping quantitative parameters may be a new potential biomarker for predicting PFS in patients with ccRCCs.

S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in melanoma through TLR4 signaling

BackgroundImmunotherapies for malignant melanoma are challenged by the resistance developed in a significant proportion of patients. Myeloid-derived suppressor cells (MDSC), with their ability to inhibit antitumor T-cell responses, are a...

Exploring the impact of BRCA1 and BRCA2 mutation type and location on Olaparib maintenance therapy in platinum-sensitive relapsed ovarian Cancer patients: A single center report

ObjectiveIn patients with platinum-sensitive relapsed ovarian cancer (PSROC) harboring pathogenic/likely pathogenic variants (PV) in BRCA1 and BRCA2 genes, olaparib maintenance monotherapy (OMT) is a viable option. Our study aimed to evaluate the impact of different BRCA1/2 PV in survival outcomes and safety of OMT in BRCA1/2-mutated PSROC patients, focusing on the type and location of PV. MethodsWe assessed the outcomes of 100 BRCA1/2-mutated PSROC patients treated at our institute, analyzing progression-free survival (PFS) and overall survival (OS). Germline and tumor BRCA1/2 genotyping was conducted using Illumina's next-generation sequencing (NGS). ResultsPFS and OS were significantly shorter in PSROC patients with PV in BRCA1 compared to those with PV in BRCA2 (PFS:14.0 vs. 38.8 months, p = 0.007, OS: 21.8 vs. 62.0 months, p = 0.011). Notably, there was a significant difference in PFS based on the intragenic location of BRCA1 PV, with shorter PFS in patients with 1st/2nd relapse, harboring PV in BRCA1 RING domain compared to those with PV in the DNA binding domain (DBD) and BRCT domains (12.4 vs. 23.0 months, p = 0.046). No differences in PFS and OS were observed between patients with germline versus somatic BRCA1/2 PV (PFS:14.9 vs.19.3, p = 0.316, OS: not reached vs. 25.8 months; p = 0.224). However, there were significant differences in the reasons for OMT discontinuation between patients with germline and somatic BRCA1/2 PV, primarily due to adverse side effects. ConclusionsIn summary, the type and location of BRCA1 and BRCA2 PV provide additional insight into the expected survival outcomes of olaparib MT in PSROC patients.Trial registration number: ISRCTN42408038, Name of registry: ISRCTN registry, Date of registration: 24/11/2015.

Assessing the Efficacy of Bortezomib and Dexamethasone for Induction and Maintenance Therapy in Relapsed/Refractory Cutaneous T-Cell Lymphoma: A Phase II CISL1701/BIC Study.

This multicenter, open-label, phase II trial evaluated the efficacy and safety of bortezomib combined with dexamethasone for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) in previously treated patients across 14 institutions in South Korea. Between September 2017 and July 2020, 29 patients with histologically confirmed CTCL received treatment, consisting of eight 4-week cycles of induction therapy followed by maintenance therapy, contingent upon response, for up to one year. The primary endpoint was the proportion of patients achieving an objective global response. Thirteen (44.8%) of the 29 patients achieved an objective global response, including two complete responses. The median progression-free survival (PFS) was 5.8 months, with responders showing a median PFS of 14.0 months. Treatment-emergent adverse events were generally mild, with a low incidence of peripheral neuropathy and hematologic toxicities. Despite the trend toward shorter PFS in patients with higher mutation burdens, genomic profiling before and after treatment showed no significant emergence of new mutations indicative of disease progression. This study supports the use of bortezomib and dexamethasone as a viable and safe treatment option for previously treated CTCL, demonstrating substantial efficacy and manageability in adverse effects. Further research with a larger cohort is suggested to validate these findings and explore the prognostic value of mutation profiles.

Prognostic impact of intraoperative rupture in early-stage epithelial ovarian cancer: an ancillary study of GORILLA-3002

ObjectiveTo evaluate whether intraoperative rupture affects oncological outcomes in patients with early-stage epithelial ovarian cancer (EOC). MethodsA multicenter retrospective study was conducted on patients with early-stage EOC based on surgical and final pathological reports between 2007 and 2021. Oncologic outcomes were compared between the unruptured group (International Federation of Gynaecology and Obstetrics [FIGO] stage IA/IB) and ruptured group (FIGO stage IC1). The primary endpoint was progression-free survival (PFS). Propensity score matching (PSM) was performed to adjust for the imbalance in prognostic factors between the groups. ResultsOverall, 197 (58.3 %) patients comprised the unruptured group (FIGO stage IA/IB), and 141 (41.7 %) were in the intraoperatively ruptured group (FIGO stage IC1). No significant difference in the 5-year PFS was observed between the two groups before PSM (92.65 % vs. 92.80 %, P = 0.93). After PSM, the 5-year PFS showed a noticeable decrease in the ruptured group compared to the unruptured group, although this difference showed borderline statistical significance (96.90 % vs. 89.82 %, P = 0.061). This trend was particularly discernible in cases with aggressive tumor characteristics; intraoperative rupture remained an independent prognostic factor for shorter PFS in patients with high-grade histology (adjusted hazard ratio = 14.4, 95 % confidence interval = 2.8–74.1). ConclusionsAlthough not statistically significant, intraoperative rupture may negatively affect PFS in these patients after PSM. Therefore, rupture during surgery should be avoided as it can cause upstaging and unnecessary chemotherapy.

Implications of unconventional histological subtypes on magnetic resonance imaging and oncological outcomes in patients who have undergone radical prostatectomy

The prognostic significance of unconventional histology (UH) subtypes including intraductal carcinoma of the prostate (IDC-P), ductal adenocarcinoma, and cribriform pattern has been investigated for prostate cancer (PCa). However, little is known about magnetic resonance imaging (MRI) features and the oncological impact of tumor localization in localized PCa with UH. Clinical data of 211 patients with acinar adenocarcinoma (conventional histology [CH]) and 82 patients with UH who underwent robotic-assisted radical prostatectomy (RARP) were reviewed. Patients with UH are more likely to be older and have higher Gleason grade group, higher Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 score, and larger tumor volume (TV) than those with CH. Multivariate analysis identified the presence of UH as an independent prognostic factor for progression-free survival (PFS) (hazard ration (HR) 2.41, 95% confidence interval (CI) 0.22–0.79, P = 0.0073). No significant difference in PFS was seen regarding tumor localization (transition zone [TZ] or peripheral zone [PZ]) in patients with UH (P = 0.8949), whereas PZ cancer showed shorter PFS in patients with CH (P = 0.0174). PCa with UH was associated with higher progression than PCa with CH among resection margin (RM)-negative cases (P < 0.0001). Further, increased PI-RADS v2.1 score did not correlate with larger TV in UH (P = 0.991), whereas a significant difference in TV was observed in CH (P < 0.0001). The prognostic significance of UH tumor was independent of tumor localization, and shorter PFS was observed even in RM-negative cases, indicating an aggressive subtype with micro-metastatic potential. Furthermore, UH tumors are more likely to harbor a large TV despite PI-RADS v2.1 score ≤ 3. These findings will help optimal perioperative management for PCa with UH.

Higher EpCAM-Positive Extracellular Vesicle Concentration in Ascites Is Associated with Shorter Progression-Free Survival of Patients with Advanced High-Grade Serous Carcinoma.

Platinum-resistant high-grade serous carcinoma (HGSC) is an incurable disease, so biomarkers that could help with timely treatment adjustments and personalized approach are extensively being sought. Tumor-derived extracellular vesicles (EVs) that can be isolated from ascites and blood of HGSC patients are such promising biomarkers. Epithelial cell adhesion molecule (EpCAM) expression is upregulated in most epithelium-derived tumors; however, studies on prognostic value of EpCAM overexpression in ovarian carcinoma have shown contradictory results. The aim of our study was to evaluate the potential of total and EpCAM-positive EVs as prognostic and predictive biomarkers for advanced HGSC. Flow cytometry was used to determine the concentration of total and EpCAM-positive EVs in paired pretreatment ascites and plasma samples of 37 patients with advanced HGSC who underwent different first-line therapy. We found that higher EpCAM-positive EVs concentration in ascites is associated with shorter progression-free survival (PFS) regardless of treatment strategy. We also found a strong correlation of EpCAM-positive EVs concentration between ascites and plasma. Our findings indicate that EpCAM-positive EVs in ascites of patients with advanced HGSC have the potential to serve as prognostic biomarkers for predicting early recurrence and thereby likelihood of more aggressive tumor biology and development of chemoresistance.

Factors Predicting Prognosis in Metastatic Grade 1 Gastro-entero-pancreatic Neuroendocrine Tumors

IntroductionThe incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied.Materials and MethodsRetrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS).ResultsOf the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017).ConclusionA higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.

Structural Elucidation and Prognostic Relevance of 297-11A-Sulfated Glycans in Ovarian Carcinoma

Ovarian carcinoma is usually diagnosed at an advanced stage with peritoneal dissemination and/or lymph node metastasis, and the prognosis for such advanced carcinoma is very poor. Therefore, new biomarkers to predict patient prognosis are needed. Miyamoto et al. previously showed that keratan sulfate (KS) detected by the 5D4 monoclonal antibody was expressed in ovarian carcinoma. However, the detailed structure of such KS was not determined, and the biological significance of this finding remained to be clarified. We previously generated the 297-11A monoclonal antibody, which recognizes galactose (Gal)-6-O-sulfated N-acetyllactosamine (LacNAc) located at the nonreducing terminus. Because the 297-11A epitope overlaps with that of 5D4, here we chose to use the 297-11A antibody as a tool to analyze KS and related structures. We conducted immunohistochemical analysis of 98 ovarian carcinoma cases with 297-11A antibody combined with a series of glycosidases and performed mass spectrometry analysis of the human serous ovarian carcinoma cell line OVCAR-3 to deduce the glycan structure of 297-11A-sulfated glycans. We also performed western blot analysis to assess a potential association of 297-11A-sulfated glycans with the mucin core protein mucin 16 (MUC16; also known as cancer antigen 125 (CA125)). Finally, we examined the relationship between 297-11A expression and patient prognosis. Consequently, 297-11A-sulfated glycans were primarily expressed in serous and endometrioid carcinomas and poorly expressed in mucinous and clear cell carcinomas. We reveal that structurally, 297-11A-sulfated glycans expressed in ovarian carcinoma are O-glycans carrying partially sialylated, Gal-6-O-sulfated LacNAc and that these glycans are likely displayed on MUC16 mucin core proteins. Of clinical importance is that expression of 297-11A-sulfated glycans correlated with shorter progression-free survival in patients. Thus, 297-11A-sulfated glycans may serve as a predictor of ovarian carcinoma recurrence.

Low Tmtv Influences Response and Outcomes in R/R DLBCL 3L+ Patients Treated with CAR-T Cells : First Results of FDG-PET/CT Analysis in the French Descar-T Registry

Context : DESCAR-T is a French national registry designed by LYSA/LYSARC including real-life patients receiving commercial CAR T-cells for hematologic malignancies. We initiated a project to conduct a centralized review of Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography (FDG-PET/CT) performed before CAR T-cells infusion, and during follow-up, to evaluate the impact of several metabolic imaging parameters at baseline and response assessment. Materials and methods : Patients with relapsed/refractory (R/R) DLBCL who initiated at least a third line of therapy (3L+) from the DESCAR-T registry and treated with commercial anti-CD19 CAR T-cells, with at least one central reviewed PET before CAR T-cell infusion (PRE-CAR T), at one month (M1) or three months (M3) after infusion, were included. For each visit, Total Metabolic Tumor Volume (TMTV) and SUVmax of the tumor were measured. Deauville score (DS) and response according to 2014 Lugano classification were registered on follow-up FDG-PET/CT. TMTV optimal cut-off for survival prediction (PFS and OS) was determined using X-tile analysis and association of DS with prognosis was studied. Progression-free survival (PFS) was defined as the time between CAR T-cell infusion and progression during follow-up. Overall survival (OS) was defined as the time between CAR T-cell treatment and death during follow-up. Results : Our analysis included FDG-PET/CT data from 212 R/R DLBCL patients (59 treated with tisagenlecleucel and 153 with axicabtagene ciloleucel). Median follow-up was 24.1 months and overall response rate was 47.1% with 112 patients presenting progression or relapse. On PRECAR-T FDG-PET/CT, the median SUVmax was 16.1 (25th-75th percentiles, 8.55-25.30) and median TMTV was 43.91 cm3 (25th-75th percentiles, 12.79-140.43 cm3). Tumor burden significantly affected survival using a TMTV optimal cut-off of 30 cm3. It was associated with a shorter PFS in patients with PRECAR-T TMTV ≥30 cm3 compared with &amp;lt;30 cm3 (median of 3 vs 22.2 months; p=0.0001; respectively) and a shorter OS (median of 9.4 vs 32 months ; p=0.0001; respectively). Regarding metabolic response at M1, reported in 192 patients, DS 1-3 (n=120; 62.5%) was significantly associated with better PFS and OS than DS4-5 (n=72; 37.5%) (for PFS: median of 1.3 vs 21.8 months ; p&amp;lt;0.0001; for OS: median of 4.5 vs 30.6 months; p&amp;lt;0.0001). Of note, considering only DS5 (n=46; 24%) as unequivocally insufficient response onM1 evaluation, identified patients with the poorest outcomes (for PFS: median of 0 month vs 21.2 months ; p&amp;lt;0.0001; for OS: median of 4.5 months vs 31.1 months; p&amp;lt;0.0001). Conclusion : Low PRECAR-T TMTV influences response and retains its predictive and prognostic value in R/R DLBCL patients treated with anti-CD19 CAR T-cells. Moreover, metabolic response assessed with DS is significantly associated with patients' outcome.

Clinical utility of plasma ctDNA sequencing in metastatic urothelial cancer

BackgroundGenomic stratification may help improve the management of patients with metastatic urothelial cancer (mUC), given the recent identification of targetable alterations. However, the collection of tissue samples remains challenging. Here, we assessed the clinical utility of plasma circulating tumour DNA (ctDNA) sequencing in these patients. MethodsPatients with mUC were prospectively enroled in the STING trial (NCT04932525), in which ctDNA was profiled using the Foundation One Liquid CDx Assay (324 genes, blood tumour mutational burden [bTMB], microsatellite instability status). Each genomic report was reviewed by a multidisciplinary tumor board (MTB). ResultsBetween January 2021 and June 2022, 140 mUC patients underwent molecular profiling. The median time to obtain the assay results was 20 days ((confidence interval) CI95%: [20,21]). The ctDNA analysis reproduced the somatic genomic landscape of previous tissue-based cohorts. Concordance for serial ctDNA samples was strong (r = 0.843 CI95%: [0.631–0.938], p < 0.001). At least one actionable target was detected in 63 patients (45%) with a total of 35 actionable alterations, including bTMB high (≥10 mutations/Mb) (N = 39, 21.1%), FGFR3 (N = 20, 10.8%), and Homologous recombination deficiency (HRD) alterations (N = 14, 7.6%). MTB recommended matched therapy in 63 patients (45.0%). Eight patients (5.7%) were treated, with an overall response rate of 50% (CI95%: 15.70–84.30) and a median progression-free survival (PFS) of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with a shorter PFS in patients treated with immunotherapy. ConclusionOverall, we demonstrated that genomic profiling with ctDNAs in mUC is a reliable and feasible approach for the timely initiation of genotype-matched therapies.

Determinants of response to CDK4/6 inhibitors in the real-world setting

Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). Most of these patients had modified Scarff–Bloom–Richardson (SBR) scores, and ER, HER2, and PR immunohistochemistry. Both the SBR score and lack of PR expression were associated with shorter PFS in patients treated with AI combinations and remained significant in multivariate analyses (HR = 3.86, p = 0.008). Gene expression analyses indicated substantial changes in cell cycle and estrogen receptor signaling during the course of treatment. Furthermore, gene expression-based subtyping indicated that predominant subtypes changed with treatment and progression. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations when assessed in the pretreatment biopsies; however, they were not associated with OS. Using unbiased approaches, cell cycle-associated gene sets were strongly associated with shorter PFS in pretreatment biopsies irrespective of endocrine therapy. Estrogen receptor signaling gene sets were associated with longer PFS particularly in the AI-treated cohort. Together, these data suggest that there are distinct pathological and biological features of HR+/HER2− breast cancer associated with response to CDK4/6 inhibitors. Clinical trial registration number: NCT04526587.

Osteopontin is a prognostic circulating biomarker in patients with neuroendocrine neoplasms

PurposeOsteopontin (OPN), also called secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and which has been shown to be involved in tumorigenesis and metastasis in many malignancies. Its role in neuroendocrine neoplasms (NEN) remains to be established. The aim of the study was to analyze plasma concentrations of OPN in patients with NEN and to explore its diagnostic and prognostic value as a clinical biomarker.MethodsOPN plasma concentrations were measured in a total of 38 patients with histologically proven NEN at three different time points during the course of disease and therapy (at the start of the study, after 3 and 12 months, respectively) as well as in healthy controls. Clinical and imaging data as well as concentrations of Chromogranin A (CgA) and Neuron Specific Enolase (NSE) were assessed.ResultsOPN levels were significantly higher in patients with NEN compared to healthy controls. High-grade tumors (grade 3) showed the highest OPN levels. OPN levels were neither different between male and female patients nor between different primary tumor sites. OPN correlated significantly with corresponding NSE levels, while there was no correlation with Chromogranin A. High OPN levels above a cutoff value of 200 ng/ml at initial analysis predicted a worsened prognosis with significantly shorter progression-free survival of patients with NEN, which also held true within the subgroup of well-differentiated G1/G2 tumors.ConclusionOur data indicate that high baseline OPN levels in patients with NEN are predictive of an adverse outcome with shorter progression-free survival, even within the group of well differentiated G1/G2 tumors. Therefore, OPN may be used as a surrogate prognostic biomarker in patients with NEN.

Adipose tissue area is a predictive biomarker for the efficacy of pegylated liposomal doxorubicin in platinum-refractory/resistant ovarian cancer.

Pegylated liposomal doxorubicin (PLD), an anthracycline agent, is widely used as a treatment option for platinum-refractory/resistant epithelial ovarian cancer (EOC). Although only a subset of patients with platinum-refractory/resistant EOC derive benefit from PLD, predictive biomarkers for patients who will respond to the drug have not yet been established. Here, we evaluated the relationship between adipose tissue status and PLD efficacy in patients with platinum-refractory/resistant EOC. Patients with platinum-refractory/resistant EOC who were treated with single-agent PLD were included in this retrospective cohort study. Adipose tissue areas including visceral adipose tissue area (VATA), subcutaneous adipose tissue area (SATA), and visceral to subcutaneous adipose tissue area ratio (VSR) were calculated prior to the initiation of PLD using computed tomography images. The associations of adipose tissue areas with objective response rate (ORR) and patient survival were evaluated. Forty-four patients with platinum-refractory/resistant EOC who received single-agent PLD were included. Subjects were categorized into high and low groups according to the median VATA, SATA, and VSR values, and body mass index (BMI). The ORR of PLD was significantly lower in the VSR-high group than in the VSR-low group (p = 0.0089). Patients in the high VSR group showed significantly shorter progression-free survival (PFS) compared with patients in the low VSR group (median, 4.0 vs. 8.5 months; p = 0.020). In the multivariable analysis, high VSR was a significant prognostic factor for shorter PFS (hazard ratio, 2.07; 95% confidence interval, 1.05-4.19; p = 0.035). VATA, SATA, and BMI showed no significant association with ORR and survival of patients who received PLD. High VSR is associated with lower ORR and shorter PFS in patients with platinum-refractory/resistant EOC who received single-agent PLD. VSR is a robust predictive biomarker for the efficacy of PLD.

Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma

Background & AimsImmune checkpoint inhibitors (ICIs) alone or in combination with other ICIs or vascular endothelial growth factor pathway inhibitors are therapeutic options in unresectable/metastatic hepatocellular carcinoma (HCC). Whether antibiotic (ATB) exposure affects outcome remains unclear. MethodsThis study retrospectively analysed an FDA database including 4,098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or in combination (n = 584), tyrosine kinase inhibitor (TKI) (n = 1,968), vascular endothelial growth factor pathway inhibitors (n = 480), or placebo (n = 808) as part of nine international clinical trials. Exposure to ATB within 30 days before or after treatment initiation was correlated with overall survival (OS) and progression-free survival (PFS) across therapeutic modality before and after inverse probability of treatment weighting (IPTW). ResultsOf 4,098 patients with unresectable/metastatic HCC, of which 39% were of hepatitis B aetiology and 21% were of hepatitis C aetiology, 83% were males with a median age of 64 years (range 18–88), a European Collaborative Oncology Group performance status of 0 (60%), and Child–Pugh A class (98%). Overall, ATB exposure (n = 620, 15%) was associated with shorter median PFS (3.6 months in ATB-exposed vs. 4.2 months; hazard ratio [HR] 1.29; 95% CI 1.22, 1.36) and OS (8.7 months in ATB-exposed vs. 10.6 months; HR 1.36; 95% CI 1.29, 1.43). In IPTW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52; 95% CI 1.34, 1.73), TKI (HR 1.29; 95% CI 1.19, 1.39), and placebo (HR 1.23; 95% CI 1.11, 1.37). Similar results were observed in IPTW analyses of OS in patients treated with ICI (HR 1.22; 95% CI 1.08, 1.38), TKI (HR 1.40; 95% CI 1.30, 1.52), and placebo (HR 1.40; 95% CI 1.25, 1.57). ConclusionsUnlike other malignancies where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with worse outcomes in this study across different therapies for HCC including placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut–liver axis remains to be demonstrated in translational studies. Impact and ImplicationsA growing body of evidence suggests the host microbiome, frequently altered by antibiotic treatment, as an important outcome predictor in the context of immune checkpoint inhibitor therapy. In this study, we analysed the effects of early antibiotic exposure on outcomes in almost 4,100 patients with hepatocellular carcinoma treated within nine multicentre clinical trials. Interestingly, early exposure to antibiotic treatment was associated with worse outcomes not only in patients treated with immune checkpoint inhibitors but also in those treated with tyrosine kinase inhibitors and placebo. This is in contrast to data published in other malignancies, where the detrimental effect of antibiotic treatment may be more prominent in immune checkpoint inhibitor recipients, highlighting the uniqueness of hepatocellular carcinoma given the complex interplay between cirrhosis, cancer, risk of infection, and the pleiotropic effect of molecular therapies for this disease.

Abstract B005: Hypoxic sarcoma spheroid on a chip: Insights into treatment response

Abstract Context: Hypoxia is found in at least 47% of soft-tissue sarcoma (STS) patients and is known to be a major contributor to treatment resistance, metastasis progression and associated with poor prognosis. Indeed, expression of hypoxic proteins (HIF1-α, CAIX) in STS is associated with a shorter overall survival, and a shorter progression-free survival in patients. Specifically, Yang et al. demonstrated in 2017 that patients stratified by a 24-gene hypoxia signature had a poorer distant metastasis free survival. Nevertheless, hypoxia is seldom considered during treatment development due to the lack of a user-friendly way to culture naturally hypoxic 3D tumor models. Therefore, we developed a user-friendly in vitro preclinical tool allowing the study of natural chronic hypoxia and its effect on treatment response. Methods: Microfabrication technologies were used to design a microfluidic chip allowing culture, maintenance, treatment, and analysis of 240 STS naturally hypoxic spheroids (750µm of diameter). SK-LMS-1 Human leiomyosarcoma and STS117 (human primary undifferentiated pleomorphic sarcoma cells) spheroids were formed 48h after seeding. Gold-standard hypoxic protein Hypoxia Inducible Factor 1 alpha (HIF1- α) and Carbonic Anhydrase IX (CAIX) expression was assessed by Western Blot (WB). Spatial distribution of CAIX was assessed by immunofluorescence (IF). Based on the IF, an in silico model of the oxygen consumption of the spheroids was built using COMSOL. As a proof of concept, the spheroids were treated using two oxygen-dependent treatment: RT and hypoxia prodrug Tirapazamine (TPZ). DNA-damages were quantified using yH2AX in IF to assess treatment efficacy. Results: These spheroids on-a-chip are the largest to date (&amp;gt;750µm), and express gold-standard hypoxic protein CAIX in their core only, a feature absent in spheroids of 450µm of diameter of the same cell lines. HIF1-α expression patterns were cell line dependent. CAIX expression in SK-LMS-1 and STS117 large spheroids was respectively 7.8 and 24 times higher than in 450µm spheroids. Quantification of DNA damages (count of yH2AX foci/nuclei area in mm²) demonstrated that TPZ preferentially targets the hypoxic core. However, the response (DNA damages) to RT alone showed no evidence of radioresistance of the hypoxic regions, on samples fixed 24h after irradiation. A possible explanation could be that, in 24h, the oxygen-dependent DNA repair and the accumulation of DNA damages in hypoxic regions hide the oxygen-dependent radioresistance. Therefore, quantification of DNA damages with yH2AX 30min after irradiation is currently being investigated, as maximum DNA damage response has been shown to be observed at this time point. Our 750µm spheroids naturally display a hypoxic core expressing gold-standard hypoxic protein CAIX at 120µm of depth, a feature absent in smaller spheroids. Together, these results cement our microfluidic device and our spheroids as a potent fundamental and pre-clinical tool to explore the biology of hypoxia on 3D tumor model, its effects on treatment response. Citation Format: Elena Refet-Mollof, Ouafa Najyb, Rodin Chermat, Audrey Glory, Julie Lafontaine, Philip Wong, Thomas Gervais. Hypoxic sarcoma spheroid on a chip: Insights into treatment response [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B005.

Antibiotic therapy and association with oncological outcomes from targeted and immune-based therapy in hepatocellular carcinoma (HCC).

4089 Background: Immune checkpoint inhibitors (ICI) alone or in combination with tyrosine kinase (TKI) or VEGF pathway inhibitors (VEGFi) are therapeutic options in unresectable HCC (uHCC). Whether exposure to antibiotics (ATB), a consolidated adverse prognostic factor in ICI recipients, affects outcome in HCC remains unclear. Methods: FDA analysed patient-level data of 4098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or combinations (n = 584), TKI (N = 1968), VEGFi (n = 480) or placebo (n = 808) as part of 9 international clinical trials submitted to the US Food and Drug Administration in support of marketing applications. Associations for ATB exposure within 30 days before or after initiation of anti-cancer treatment (ATB) with overall (OS) and progression-free survival (PFS) were examined across therapeutic modality. Estimates were weighted by propensity score (PSW) using clinically relevant covariates. Results: Out of 4098 patients with uHCC mostly secondary to Hepatitis B (39%) or C (21%) infection, the majority were males (83%) with a median age of 64 (range 18-88), ECOG performance status of 0 (60%) and Child-Pugh A class (98%). Most patients had metastases (68%) but did not have macrovascular invasion (71%). Overall, 620 patients (15%) were ATB+, with comparable rates across placebo (12%), TKI (16%), VEGFi (15%), and ICI (16%). In the overall population, ATB was associated with shorter PFS (2.8 vs 3.9 months [m], HR 1.29, 95%CI 1.22-1.36) and OS (6.4 vs. 8.8 m; HR 1.36, 95%CI 1.29-1.43). In PSW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52, 95%CI 1.34-1.73), TKI (HR 1.29, 95%CI 1.19-1.39) and placebo (HR 1.23, 95%CI 1.11-1.37). Similar results were observed in PSW analyses of OS in patients treated with ICI (HR 1.22, 95%CI 1.08-1.38), TKI HR 1.40, 95%CI 1.30-1.52), and placebo (HR 1.40, 95%CI 1.25-1.57). Consistent outcomes were observed for ATB+ patients within ICI treatment subgroups, including patients treated with anti-PD-1 monotherapy (PFS HR 1.49, 95%CI 1.22-1.80; OS HR 1.31 1.02-1.68) and ICI combinations (PFS HR 1.50, 95%CI 1.26-1.77; OS HR 1.14 0.99-1.32). Conclusions: Unlike other oncological indications where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with inferior outcomes across a broad range of anti-cancer therapies for HCC and placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut liver axis remains to be demonstrated in translational studies.

The prognostic value of prognostic nutritional index inadvanced cancer receiving PD-1/L1 inhibitors: A meta-analysis.

PurposeTo study the prognostic value of the prognostic nutritional index (PNI) in advanced cancers receiving programmed death‐1/programmed death‐ligand 1 (PD‐1/L1) inhibitors.MethodsOnline electronic databases were comprehensively searched and available literature was retrieved. We extracted available data from included researches and pooled the hazard ratios (HRs) and 95% confidence intervals (CIs) to learn the prognostic value of PNI on overall survival (OS) or progression‐free survival (PFS); and meanwhile calculated the relative risk (RR) with 95% CI to study the relationship between PNI and treatment efficacy (objective response rate [ORR] or disease control rate [DCR]) in late staged cancer receiving PD‐1/L1 inhibitors.ResultsNine studies were finally selected for this meta‐analysis. We obtained data regarding PNI on OS from all nine studies, and the pooled HR was 2.31 (95% CI 1.81–2.94, p = 0.000), showing a correlation between low PNI and worse OS. Eight studies reported a relationship between PNI and PFS, and combined results revealed shorter PFS in patients with lower PNI, with an HR of 1.75 (95% CI 1.40–2.18, p = 0.000). Four studies explored the association between PNI and ORR and two studies explored the influence of PNI on DCR. An association between PNI and ORR (RR = 0.47, p = 0.003) was observed, while no association between PNI and DCR (RR = 0.49, p = 0.103) was observed by pooling these studies.ConclusionIn summary, this meta‐analysis indicated that a lower PNI was significantly correlated with decreased OS and PFS and played adverse roles in ORR in advanced cancer patients receiving PD‐1/L1 inhibitors. Therefore, PNI could be promising for predicting prognosis and treatment response in advanced malignancies treated with PD‐1/L1 inhibitors.

HLA-A*03 and response to immune checkpoint blockade in cancer: an epidemiological biomarker study.

Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20-1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05-1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01-1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01-1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16-2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0·76) INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. National Institutes of Health, Merck KGaA, and Pfizer.

Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis

IntroductionDespite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown. MethodsPatients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined. ResultsIn total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0–108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2–15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0–43.1 months). No unexpected toxicities were observed. ConclusionChemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma.