Predictors Of Response Research Articles

Heterogeneity in PD-L1 expression between primary and metastatic lymph nodes: a predictor of EGFR-TKI therapy response in non-small cell lung cancer

BackgroundThere is inconclusive evidence to suggest that the expression of programmed cell death ligand 1 (PD-L1) is a putative predictor of response to EGFR-TKI therapy in advanced EGFR-mutant non-small cell lung cancer (NSCLC). We evaluated the heterogeneity in PD-L1 expression in the primary lung site and metastatic lymph nodes to analyze the association between PD-L1 expression and response for patients treated with EGFR-TKI.MethodsThis study reviewed 184 advanced NSCLC patients with EGFR mutations who received first-generation EGFR-TKI as first-line treatment from 2020 to 2021 at Shanghai Chest Hospital. The patients were divided into the primary lung site group (n = 100) and the metastatic lymph nodes group (n = 84) according to the biopsy site. The patients in each group were divided into TPS < 1%, TPS 1–49%, and TPS ≥ 50% groups according to PD-L1 expression.ResultsThe median PFS was 7 (95% CI: 5.7–8.3) months, and the median OS was 26 (95% CI: 23.5–28.5) months for all patients. No correlation existed between PFS or OS and PD-L1 expression. The median PFS in the primary lung site group was 11 months (95% CI: 9.6–12.4) in the TPS < 1% group, 8 months (95% CI: 6.6–9.4) in TPS 1–49% group, and 4 months (95% CI: 3.2–4.8) in TPS ≥ 50% group, with statistically significant differences (p = 0.000). The median OS of the TPS < 1% group and TPS ≥ 50% group showed a statistically significant difference (p = 0.008) in the primary lung site group. In contrast, PD-L1 expression in the lymph nodes of EGFR-mutant patients was unrelated to PFS or OS after EGFR-TKI therapy.ConclusionPD-L1 expression from the primary lung site might predict clinical benefit from EGFR-TKI, whereas PD-L1 from metastatic lymph nodes did not.Trial registration: This retrospective study was approved by the Ethics Committee of Shanghai Chest Hospital (ID: IS23060) and performed following the Helsinki Declaration of 1964 (revised 2008).

Exploring GZMK as a prognostic marker and predictor of immunotherapy response in breast cancer: unveiling novel insights into treatment outcomes

BackgroundGranzyme K (GZMK) is a crucial mediator released by immune cells to eliminate tumor cells, playing significant roles in inflammation and tumorigenesis. Despite its importance, the specific role of GZMK in breast cancer and its mechanisms are not well understood.MethodsWe utilized data from the TCGA and GEO databases and employed a range of analytical methods including GO, KEGG, GSEA, ssGSEA, and PPI to investigate the impact of GZMK on breast cancer. In vitro studies, including RT-qPCR, CCK-8 assay, cell cycle experiments, apoptosis assays, Celigo scratch assays, Transwell assays, and immunohistochemical methods, were conducted to validate the effects of GZMK on breast cancer cells. Additionally, Cox regression analysis integrating TCGA and our clinical data was used to develop an overall survival (OS) prediction model.ResultsAnalysis of clinical pathological features revealed significant correlations between GZMK expression and lymph node staging, differentiation grade, and molecular breast cancer subtypes. High GZMK expression was associated with improved OS, progression-free survival (PFS), and recurrence-free survival (RFS), as confirmed by multifactorial Cox regression analysis. Functional and pathway enrichment analyses of genes positively correlated with GZMK highlighted involvement in lymphocyte differentiation, T cell differentiation, and T cell receptor signaling pathways. A robust association between GZMK expression and T cell presence was noted in the breast cancer tumor microenvironment (TME), with strong correlations with ESTIMATEScore (Cor = 0.743, P < 0.001), ImmuneScore (Cor = 0.802, P < 0.001), and StromalScore (Cor = 0.516, P < 0.001). GZMK also showed significant correlations with immune checkpoint molecules, including CTLA4 (Cor = 0.856, P < 0.001), PD-1 (Cor = 0.82, P < 0.001), PD-L1 (Cor = 0.56, P < 0.001), CD48 (Cor = 0.75, P < 0.001), and CCR7 (Cor = 0.856, P < 0.001). Studies indicated that high GZMK expression enhances patient responsiveness to immunotherapy, with higher levels observed in responsive patients compared to non-responsive ones. In vitro experiments confirmed that GZMK promotes cell proliferation, cell division, apoptosis, cell migration, and invasiveness (P < 0.05).ConclusionOur study provides insights into the differential expression of GZMK in breast cancer and its potential mechanisms in breast cancer pathogenesis. Elevated GZMK expression is associated with improved OS and RFS, suggesting its potential as a prognostic marker for breast cancer survival and as a predictor of the efficacy of immunotherapy.

Role of long non-coding RNA in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a group of recurrent chronic inflammatory diseases, including Crohn's disease (CD) and ulcerative colitis (UC). Although IBD has been extensively studied for decades, its cause and pathogenesis remain unclear. Existing research suggests that IBD may be the result of an interaction between genetic factors, environmental factors and the gut microbiome. IBD is closely related to non-coding RNAs (ncRNAs). NcRNAs are composed of microRNA(miRNA), long non-coding RNA(lnc RNA) and circular RNA(circ RNA). Compared with miRNA, the role of lnc RNA in IBD has been little studied. Lnc RNA is an RNA molecule that regulates gene expression and regulates a variety of molecular pathways involved in the pathbiology of IBD. Targeting IBD-associated lnc RNAs may promote personalized treatment of IBD and have therapeutic value for IBD patients. Therefore, this review summarized the effects of lnc RNA on the intestinal epithelial barrier, inflammatory response and immune homeostasis in IBD, and summarized the potential of lnc RNA as a biomarker of IBD and as a predictor of therapeutic response to IBD in the future.

Tighter is better: Can a simple and cost-free parameter predict response to cardiac synchronization therapy?

Several studies have evaluated the role of QRS duration (QRSd) or QRS narrowing as a predictor of response to cardiac resynchronization therapy (CRT) to reduce nonresponders. Our study aimed to determine the correlation between the relative change in QRS index (QI) compared to clinical outcome and prognosis in patients who underwent CRT implantation. A three-centers study involving 398 patients with a CRT device was conducted. Clinical, echocardiographic and pharmacological variables, QRSd before and after CRT implantation and QI were measured. In a 6-month follow-up, a significant improvement in left ventricular ejection fraction (LVEF), left ventricular end-diastolic and systolic volumes (LVEDV and LVESV) were observed. QI was related to reverse remodeling (multiple r-squared: 0.48, adjusted r-squared: 0.43, p=.001), and the cut-off value that best predicted LV reverse remodeling after 6 months of CRT was 12.25% (AUC 0.7, p=.001). At 24 months, a statistically significant difference was found between patients with a QI≤12.25% and those with a QI>12.25% regarding NYHA class worsening (p=.04). The mean of the QI of patients who died from cardiovascular causes was lower than patients who died of other causes (p=.0179). A correlation between pre-CRT QRSd/LVEDV and QI was observed (r=+ 0.20; p=.0003). A higher QRSd/LVEDV ratio was associated with an improved LVEF, LVEDV, and LVESV (p<.0001) at follow-up. QI narrowing after CRT was related to greater echocardiographic reverse remodeling and a lower rate of adverse events (death or cardiovascular hospitalizations). The QI can improve the prediction of adverse events in a population with CRT regardless of comorbidities according to the Charlson Comorbidity Index. QI could be used to predict CRT response.

Genome-wide in vivo CRISPR screen identifies TGFβ3 as actionable biomarker of palbociclib resistance in triple negative breast cancer

Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGFβ3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGFβ3 treatment can overcome this. This study defines TGFβ3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGFβ3 to propose a new combinatorial treatment for TNBC.

Efficacy and safety of induction chemotherapy in oral cavity cancer: An eight-year experience at a Portuguese reference center.

Induction chemotherapy has been described as an option in locally advanced oral cavity squamous cell carcinoma when the surgical morbidity is expected to be high. This work aimed to evaluate the outcome and safety of induction chemotherapy in this setting. We performed a retrospective and observational study including patients with oral cavity squamous cell carcinoma, treated with induction chemotherapy between January 2010 and December 2018. Outcomes included induction chemotherapy toxicity, treatment response, disease-free survival and overall survival. A total of 108 oral cavity squamous cell carcinoma patients were included. Ninety-six (88.9%) had stage IV disease, while 12 (11.1%) had stage III. Eighty-four patients (80.8%) achieved at least a partial response to induction chemotherapy at clinical evaluation, and 75 (72.1%) at radiological evaluation. Seventy-eight patients have been proposed for subsequent definitive treatments, with no differences obtained in prognosis, when comparing surgical to non-surgical approaches. In patients treated with definitive treatments, improved five-year disease-free survival was obtained if at least a clinical (56.3%; p=0.001) or radiological (52.9%; p=0.001) partial response was achieved after induction chemotherapy. Similarly, superior five-year overall survival was verified for those achieving at least clinical (51.1%; p<0.0001) or radiological (52.6%; p=0.001) partial response. Also, accomplishing a pathologic complete response (n=22.6%) significantly improved disease-free survival (p=0.039) and overall survival (p=0.005). Grade 3 and 4 toxicities were observed in 52 patients (41.8%). Responses to induction chemotherapy predicted prognosis in our population, however important toxicities were observed. Further studies are necessary to identify induction chemotherapy response predictors and subgroups who may benefit from this approach.

Predictors of response and surgical approach after neoadjuvant chemotherapy in receptor-positive/HER2-negative stage II-III breast cancer patients treated in two private cancer care centers in Lima, Peru: Real-world data.

e12659 Background: The role of neoadjuvant chemotherapy (NAC) in hormone receptor-positive HER2-negative breast cancer (BC) is controversial, its main benefit being to improve the surgical outcome in both breast and axilla. The aim of this study was to evaluate the response to NAC, as well as possible predictors and the type surgery performed after primary treatment. Methods: Observational, retrospective study from a database of 1356 consecutive cases of BC between 2016 and 2022 in two private oncology centers in Lima Metropolitana. There were 726 new cases of hormone receptor-positive HER2-negative BC (53.5%), of which those patients with clinical stage II-III who received NAC were considered (n=122, 16.8 % of luminal HER2-negative). Results: The average age of the sample was 46.6 years (range 25-72) with a predominance of luminal B subtype (60.7%) and clinical stage II disease (51.6%), as well as an average delay time to treatment of 33.9 days. Chemotherapy choice was AC every 3 weeks followed by weekly paclitaxel (98.4%). The pathological complete response (pCR) rate was of 16.4% in the breast, 29.1% in the lymph nodes and 13.9% in both. None of the variables studied (age, histologic grade and type, clinical stage, tumor size, number of nodes, hormone receptors, Ki-67 and HER2 low) were predictors of pCR. According to RECIST criteria, tumor shrinking in the breast occurred in the majority of patients (partial and complete response: 86.1%) and eight out of ten patients achieved a tumor size reduction of more than 50%. The rate of mastectomy was 67.2% and radical axillary dissection, 70.5%. Conclusions: In our cohort, we found a pCR rate similar to that reported in the world literature. No predictors of pCR were found. Despite the high proportion of tumor response at breast and node level, the surgical approach was mostly radical. The multidisciplinary BC committee in our setting should be strengthened in order to make better decisions on the surgical approach for patients with hormone receptor-positive HER2-negative stage II-III BC who receive NAC.

Immune checkpoint inhibitors in advanced malignant peritoneal mesothelioma: Clinical insights, immunopathologic profiling, and prognostic implications from a single-center study.

e14665 Background: Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the peritoneum. In patients with advanced disease, therapeutic options are limited, and prognosis is usually poor. While the role of immune-checkpoint inhibitors (ICI) in MPM is evolving, clinical data is scarce and there are currently no biomarkers to predict response to ICI therapy in this population. Methods: Patients treated at the Sheba Medical Center between 2016-2022 have been examined with the aim of delineating the clinical and immunopathologic characteristics of MPM, including programmed-death ligand-1 (PDL-1) status. Results: Forty-two patients with MPM were treated at Sheba during the study period. Eight patients (19%) have received immunotherapy as a single treatment in our cohort, all as ≥2 line of treatment. Of these patients, 3 patients (37.5%) had complete response (CR) or partial response (PR) as their best response, 3 patients (37.5%) had stable disease (SD), and 2 patients (25%) had progressive disease. Median overall survival (OS) among responding patients (CR/PR) and patients with clinical benefit (CR/PR/SD) were 6.8 years and 5.2 years, respectively, noticeably higher than the median OS for MPM (2.5 years). PDL-1 status was available for 23 patients: 17/23 (74%) had negative PDL-1 status and 6/23 (26%) had positive PDL-1 status. No correlation was observed in PDL-1 status among patients experiencing clinical benefit from treatment with ICIs. Conclusions: ICI therapy could be considered as a reasonable option for second-line therapy and beyond for MPM, with selected patients who may substantially benefit from these treatments. PDL-1 status did not correlate with treatment benefit, which highlights the limitation of this biomarker as a predictor of response in MPM patients.

TERT-associated DNA polymerases genes link CAF and CD8+ T Cells to improve immunotherapy response rate across multiple cancers.

e14669 Background: The cancer cells exhibit heightened basal levels of responses to DNA breaks, accumulating DNA polymerases family (DNA-pol) as repair protein, thereby increasing DNA mutation and neoantigens. Based on this, we investigated the potential of DNA-pol as an immunotherapy biomarker and its underlying mechanism. Methods: We conducted a pan-cancer analysis of DNA-pol gene dysregulation in 6366 samples. Normal fibroblast, cancer-associated fibroblast, and CD8+ T cells were cultured from cancer patients (3 esophagus, 5 lung, 5 renal, and 3 liver cancer), then treated them with PD-L1 inhibitor or overexpressing TERT for RNA-seq and proteomics. 996 multiple cancer cases with ICIs were collected to test biomarker efficiency. A phase II clinical trial is evaluating and exploring our biomarker in mechanism prospectively. Results: We defined a distinct signature score of DNA-pol genes upregulated in cancer (DNA-pol-up) and linked to worse prognosis (HR=1.2). DNA-pol-up program dysregulation led to immune processes alteration and was related to upstream activation of TERT signaling (z-score=3.6) in ingenuity pathway analysis and linked to immunologically active tumors by recruiting CD8+ T cell and downregulating CAF. DNA-pol-up score was elevated in PD-L1-treated CAF and TERT-overexpressed CD8+ T cell, in MSI-H cancer, also related to more neoepitope peptides, TMB (Rho=0.54), cancer stemness (Rho=0.78), and tumor purity (Rho=0.29). Cancers that activate this program carried distinct genomic profiles with PIK3CA, KRAS, and TP53 mutations. This signature was an independent predictor for ICIs response (OR=2.52), even outperforming cytolytic activity, MSI, TMB (OR=0.9). In 12 clinical trial datasets, this signature could stratify the responding patients (maxAUC=0.762). In our phase II clinical trial, 34 liver cancer were enrolled with 4-year follow-up, it also has a satisfactory performance in predicting the ORR (AUC=0.699) and classifies mortality rate (HR=2.5), meanwhile verified its relationship with detailed potential molecular mechanism. Conclusions: Our findings identify a distinct transcriptional pattern of DNA-pol genes across cancers, which highlighted the role of DNA-pol family genes in predicting the immunotherapy response for the first time, and TERT could be a novel vaccine candidate for improving immunotherapy response.

Circulating tumor DNA as a predictor of treatment response to neoadjuvant chemotherapy in stage 2/3 rectal cancer without high risks: Subset analysis from the COPEC trial.

e15623 Background: Circulating tumor DNA (ctDNA) serves as a valuable tool for minimal residual disease (MRD) assessment. It has been reported as a promising noninvasive biomarker for the dynamic monitoring of treatment response of metastatic colorectal cancers to chemotherapy and locally advanced rectal cancers (LARC) to neoadjuvant chemoradiotherapy. However, the potential role of ctDNA in neoadjuvant chemotherapy (NCT) in LARC remains unexplored. The present study aims to investigate the value of ctDNA in NCT based on a prospective, multicentered, non-inferior, randomized, controlled trial (ClinicalTrials.gov ID, NCT04922853). The COPEC trial enrolls stage 2/3 LARC with low or intermediate and is designed to determine the optimal time (after 2 or 4 cycles of CAPOX) to evaluate treatment response based on pathological regression grades. Methods: Colonoscopy biopsy was taken before neoadjuvant therapy. Peripheral blood samples were collected before neoadjuvant (baseline, BL), one cycle (C1) and two cycles (4-cycle group, C2) after NCT, before surgery (BS), and within one month after surgery (postoperative, OP). All tissue biopsy and plasma specimens were analyzed by NGS assays using the MinerVA platform (Genecast Biotechnology Co., Ltd). MRI tumor regression grade (mrTRG) was assessed after 2 and 4 cycles (4-cycle group) of NCT. The primary outcome was the accuracy of ctDNA in the prediction of pathological tumor regression grade (pTRG). Results: A total of 151 LARC patients were enrolled, including 82 in the 2-cycle group and 69 in the 4-cycle group. The ctDNA was detectable in 87.4% (132/151), 39.6% (55/139), 29.0% (18/62), 38.4% (58/151), and 4.4% (6/138) at BL, C1, C2, BS and OP, respectively. The ctDNApositivity rates were significantly lower in good responders determined by mrTRG (mrTRG 1-3) compared to mrTRG 4-5 group at C1 (29% vs. 63.89%, p &lt; 0.001), C2 (20% vs.56.25%, p = 0.011), and BS time points (23.85% vs. 74.36%, p &lt; 0.001). Furthermore, the ctDNA-positivity rates at C1 in the good response group determined by TRG (pTRG 0-1) were 6.25%, significantly lower than that in the pTRG 2-3 group (49.53%). At neither C2 nor BS time point, patients in the pTRG 0-1 subgroup were detected as ctDNA positive while the ctDNA positivity rates for patients in pTRG 2-3 subgroup were 39.13% and 50%, respectively. Additionally, the mean of hGE/ml was 0.045 in pTRG 0-1 group at C1, significantly lower comparing to 1.337 in pTRG 2-3 group (p &lt; 0.001). Conclusions: We find that dynamic monitoring of ctDNA status was a useful tool in early predicting the effect of (treatment response to) NCT in LARC patients with low/intermediate risks. The monitoring of ctDNA status can supplement MRI in determining the NCT response and could potentially help identify poor responders to discontinue the treatment with inadequate efficacy. Clinical trial information: NCT04922853 .

Pretreatment neutrophil to lymphocyte ratio as a predictor of pathological complete response to neoadjuvant immunotherapy in early breast cancer.

e12545 Background: Neoadjuvant immunotherapy has been increasingly used in early breast cancer, while lack of accessible predictive biomarkers of response remains an open question. High pretreatment neutrophil to lymphocyte ratio (NLR) was associated with worse prognosis and treatment responses to neoadjuvant chemotherapy in multiple cancers including breast cancer. However, it remains unclear whether NLR was associated with response to neoadjuvant immunotherapy in early breast cancer. Methods: We retrospectively analyzed 89 early breast cancer patients who received neoadjuvant chemotherapy in combination with at least 4 cycles of immunotherapy and subsequent breast surgery in Sun Yat-sen University Cancer Center. Pretreatment NLR was calculated, and Miller-Payne grade 5 in primary tumor site was considered pathological complete response (pCR) to neoadjuvant therapy. Univariate and multivariate analyses were used to evaluate the associations between clinicopathological markers and pCR. Results: 49.4% (44/89) of the patients achieved pCR. Compared to non-pCR patients, pCR patients had significantly lower pretreatment NLR (1.93 vs 2.87, p&lt;0.001) and lower percentage of pretreatment cT3/T4 stage (11.4% vs 37.7%, p=0.006), and received more cycles of neoadjuvant immunotherapy (6.5 vs 6.0, p&lt;0.05). More pCR patients received TCb based neoadjuvant therapy (86.4% vs 51.1%, p&lt;0.001). In multivariate analysis, the pretreatment NLR (p=0.002) and cT3/T4 (p=0.010, as compared to cT1/T2) were independent predictive factors for pCR. Conclusions: Lower pretreatment NLR was associated with higher possibility of achieving pCR in early breast cancer treated with neoadjuvant immunotherapy. [Table: see text]

Effect of trabecular architectures on the mechanical response in osteoporotic and healthy human bone.

Research at the mesoscale bone trabeculae arrangement yields intriguing results that, due to their clinical resolution, can be applied in clinical field, contributing significantly to the diagnosis of bone-related diseases. While the literature offers quantitative morphometric parameters for a thorough characterization of the mesoscale bone network, there is a gap in understanding relationships among them, particularly in the context of various bone pathologies. This research aims to bridge these gaps by offering a quantitative evaluation of the interplay among morphometric parameters and mechanical response at mesoscale in osteoporotic and non-osteoporotic bones. Bone mechanical response, dependent on trabecular arrangement, is defined by apparent stiffness, computationally calculated using the Gibson-Ashby model. Key findings indicate that: (i) in addition to bone density, measured using X-ray absorptiometry, trabecular connectivity density, trabecular spacing and degree of anisotropy are crucial parameters for characterize osteoporosis state; (ii) apparent stiffness values exhibit strong correlations with bone density and connectivity density; (iii) connectivity density and degree of anisotropy result the best predictors of mechanical response. Despite the inherent heterogeneity in bone structure, suggesting the potential benefit of a larger sample size in the future, this approach presents a valuable method to enhance discrimination between osteoporotic and non-osteoporotic samples.

TBCRC 048 (olaparib expanded) expansion cohorts: Phase 2 study of olaparib monotherapy in patients (pts) with metastatic breast cancer (MBC) with germline (g) mutations in PALB2 or somatic (s) mutations in BRCA1 or BRCA2.

1021 Background: TBCRC 048 is an investigator-initiated proof of principle phase II trial that demonstrated responses with monotherapy olaparib in MBC pts with g PALB2 or s BRCA mutations. Here we report results of the expansion cohorts for additional pts with g PALB2(Cohort 1a) or s BRCA (Cohort 2a) mutations. Methods: 24 MBC pts with g PALB2m and 30 pts with s BRCAm were enrolled in the expansion cohorts from Sept 2020 to Oct 2023.Eligibility included: MBC with measurable disease; documented g PALB2m or s BRCAm (with normal g BRCA testing); progression on &lt; 2 metastatic chemotherapy regimens. Prior PARP inhibitor or progression on platinum was not allowed. Patients received olaparib 300 mg bid until progression or unacceptable toxicity. The null hypothesis for each expansion cohort [≤ 30% objective response rate (ORR)] would be rejected if &gt; 13 responses were seen. Secondary endpoints include clinical benefit rate (CBR) at 18 weeks, progression-free survival (PFS), duration of response (DOR) and whether the mutant allele frequency (MAF) is significantly higher in responders than in non-responders. Enrollment to the g PALB2 cohort was closed early due to slow enrollment. PFS and DOR were estimated using the Kaplan-Meier method. Association between MAF and response status was assessed using Wilcoxon rank sum test. Results: In Cohort 1a (g PALB2, n=24), median age was 52.5 years (range: 26-86). 19 pts had ER+ HER2-negative, 2 HER2-positive, and 3 triple-negative breast cancer (TNBC). There were 18 confirmed responses for ORR of 75% (80% CI: 60.2%-86.3%); CBR at 18 weeks was 83.3% (90% CI: 65.8%-94.1%). Median PFS was 9.6 months (90% CI: 8.3-12.4). Median DOR was 7.1 months (90% CI: 5.6-11.0). In Cohort 2a (s BRCA1/2, n=30) 15 pts had s BRCA1m and 15 s BRCA2m. 23 pts had ER+ HER2-negative, 3 HER2-positive, and 4 TNBC. There were 11 confirmed responses for ORR of 36.7% (80% CI: 24.8%-50%). CBR was 53.3% (90% CI: 37%-69.2%) and median PFS was 5.6 months (90% CI: 3.0-8.3). Median DOR was 12.4 months (90% CI: 4.3-not reached). One additional pt with a s BRCAm had a PR, which was not confirmed. Clinical and molecular factors associated with response to olaparib are being evaluated. MAF was available and evaluable for 33 of the 46 pts in Cohorts 2 plus 2a who had s BRCAm identification by tumor biopsy. The mean MAF was 43% in responders and 39 % in non-responders (p=0.7), which was not significantly different. Conclusions: The notable ORR (75%) with olaparib in this second cohort of women with MBC and g PALB2m was again demonstrated.Olaparib activity inMBC pts with s BRCAm was also confirmed, though identifying predictors of response for these pts is of critical importance to distinguish those more likely to respond to PARP inhibition. Clinical trial information: NCT02032823 .

Transcriptome-based response predictor to identify potential responders among patients with negative standard markers for response to immune checkpoint blockers.

2666 Background: Immune checkpoint blockers (ICB) are revolutionizing cancer treatment, and are being approved for an increasingly wide range of cancer types. The most common biomarkers currently in use to select patients for ICB are PD-L1 expression on tumor cells, as measured by IHC, and tumor mutational burden (TMB) and microsatellite instability (MSI), both measured by NGS. However, some patients that are negative for these markers still respond to ICB. This calls for complementary biomarkers to better identify responders to ICB, especially in patients that are negative to current biomarkers. Here, we focus on predicting response to anti-PD1 in patients with negative PD-L1, TMB or MSI. Methods: We employ ENLIGHT, our transcriptome-based precision oncology platform, which identifies and utilizes clinically relevant genetic interactions to predict a patient’s response to a wide range of targeted drugs, including ICB. ENLIGHT generates an individual ICB response score calculated from a 10-gene expression signature - the ENLIGHT Matching Score (EMS). Patients with EMS above a predetermined threshold are considered matched by ENLIGHT to anti-PD-1 treatments. We have previously shown, based on more than 1000 cases analyzed retrospectively, that this signature can identify responders to anti-PD-1 with high accuracy. Here, we use ENLIGHT to perform a retrospective analysis of 125 cases from three different datasets, who had low PD-L1 presentation (&lt;1%), low TMB (&lt; 10) or microsatellite stable tumors (MSS), and were treated with anti-PD-1, to specifically assess ENLIGHT’s performance in this biomarker-negative sub-population. Results: Patients who responded to anti-PD-1 treatments had significantly higher EMS in all three datasets. Correspondingly, ENLIGHT is highly predictive of response to anti-PD-1 in patients with negative ICB markers in the three datasets (ROC AUCs of 0.80, 0.84, 0.77, respectively, for low PDL1, low TMB and MSS). It is important to note that ENLIGHT was not trained on any of these datasets, and is applied as-is using previously published parameters. Overall, we find that patients who are ENLIGHT-Matched to anti-PD1 in this biomarker-negative cohort are almost 3 times more likely to respond than patients who are not (31% vs. 11%, p=5e-13). Conclusions: ENLIGHT is a powerful tool for predicting response to anti-PD-1 treatment in patients with negative standard biomarkers for ICB, a currently unmet need with considerable clinical importance.

ARHGAP4 as a Prognostic Biomarker for Colon Liver Metastases After Surgical Resection.

To select and stratify patients for optimal treatment plans is challenging. Identification of cancer-related biomarkers that serve as predictors for prognosis and treatment response is essential to better predict treatment outcome and find future targets for therapy. Previous data has suggested ARHGAP4 as a relevant biomarker in colorectal cancer (CRC). The purpose of this study was to assess how ARHGAP4 expression affected patients undergoing surgery for colon liver metastasis (CLM) in terms of overall survival (OS). A total of 251 patients undergoing resection of CLM from 2006 to 2017 were included. Corresponding resected tumor specimens were examined for ARHGAP4 expression levels by immunohistochemistry (IHC). The correlation between ARHGAP4 expression and postoperative survival was analyzed. High expression levels of ARHGAP4 were seen in 60% of patients. High expression levels of ARHGAP4 were correlated with adverse prognosis after hepatectomy due to CLM. Survival data generated using Cox proportional hazard model showed a statistically significant difference between high and low ARHGAP4 expression groups by univariate (HR=1.5, 95% CI=1.1-2.2) and multivariate (HR=1.5, 95% CI=1.0-2.1) analysis. In multivariate Cox regression, high ARHGAP4 expression, preoperative CEA levels and presence of vascular invasion by pathological examinations were independent predictive factors of overall survival. ARHGAP4 is a novel prognostic biomarker after resection of CLM.

Clinical Features and Predictors of Treatment Outcome in Patients with Ocular Tuberculosis from the Netherlands and Indonesia: The OculaR TB in Low versus High Endemic Countries (ORTEC) Study

ABSTRACT Purpose To describe and compare clinical features, treatment approaches, and treatment outcomes of ocular tuberculosis (OTB) patients in the Netherlands, a low tuberculosis (TB)-endemic country, and Indonesia, a high TB-endemic country. We also aimed to identify predictors of treatment outcomes. Methods A medical chart review of 339 OTB patients (n = 93 from the Netherlands and n = 246 from Indonesia) was performed. The primary outcome was response to treatment, whether with or without anti-tubercular treatment, after six months of treatment initiation (good versus poor responders). Results Indonesian OTB patients displayed a higher prevalence of chest radiograph findings indicative of TB infection (p < 0.001) and concurrent active systemic TB (p = 0.011). Indonesian cohort exhibited a more acute and severe disease profile, including uveitis duration ≤ 3 months (p < 0.001), blindness (p < 0.001), anterior chamber (AC) cells ≥ 2+ (p < 0.001), and posterior synechiae (p < 0.001). Overall proportions of good responders to treatment were 67.6% in the Netherlands and 71.5% in Indonesia. Presence of AC cell ≥ 2+ (adjusted odds ratio (aOR): 2.12, 95% CI: 1.09–4.14), choroidal lesions other than serpiginous-like choroiditis (SLC) or tuberculoma (aOR: 4.47, 95% CI: 1.18–16.90), and retinal vasculitis (aOR: 2.32, 95% CI: 1.10–4.90) at baseline were predictors for poor response to treatment. Conclusions Despite a more severe initial clinical presentation in the Indonesian cohort, the overall treatment outcomes of OTB was comparable in both cohorts. Three baseline clinical features were identified as predictors of treatment outcomes.

PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-β pathway.

Sunitinib has emerged as the primary treatment for advanced or metastatic clear cell renal cell carcinoma (ccRCC) due to its significant improvement in patients' average survival time. However, drug resistance and adverse effects of sunitinib pose challenges to its clinical benefits. The differentially expressed genes (DEGs) associated with sunitinib sensitivity and resistance in ccRCC were investigated. Cell counting kit-8, plate colony formation, flow cytometry and subcutaneous xenograft tumor model assays were employed to explore the effects of PDZK1 on ccRCC. Further research on the molecular mechanism was conducted through western blot, co-immunoprecipitation, immunofluorescence co-localization and immunohistochemical staining. We elucidated that PDZK1 is significantly downregulated in sunitinib-resistant ccRCC specimens, and PDZK1 negatively regulates the phosphorylation of PDGFR-β and the activation of its downstream pathways through interaction with PDGFR-β. The dysregulated low levels of PDZK1 contribute to inadequate inhibition of cell proliferation, tumor growth, and insensitivity to sunitinib treatment. Notably, our preclinical investigations showed that miR-15b antagomirs enhance sunitinib cytotoxic effects against ccRCC cells by upregulating PDZK1 levels, suggesting their potential in overcoming sunitinib resistance. Our findings establish the miR-15b/PDZK1/PDGFR-β axis as a promising therapeutic target and a novel predictor for ccRCC patients' response to sunitinib treatment.

Insights from an Italian Delphi panel: exploring resistance to first-generation somatostatin receptor ligands and guiding second-line medical therapies in acromegaly management.

First-line medical therapy for acromegaly management includes first-generation somatostatin receptor ligands (fgSRLs), but resistance limits their use. Despite international guidelines, the choice of second-line therapy is debated. We aim to discuss resistance to fgSRLs, identify second-line therapy determinants and assess glycemia's impact to provide valuable insights for acromegaly management in clinical practice. A group of Italian endocrinologists expert in the pituitary field participated in a two-round Delphi panel between July and September 2023. The Delphi questionnaire encompassed a total of 75 statements categorized into three sections: resistance to fgSRLs therapy and predictors of response; determinants for the selection of second-line therapy; the role of glycemia in the therapeutic management. The statements were rated on a 6-point Likert scale. Fifty-nine (79%) statements reached a consensus. IGF-1 levels resulted central for evaluating resistance to fgSRLs, that should be defined considering also symptomatic clinical response, degree of tumor shrinkage and complications, using clinician- and patient-reported outcome tools available. Factors to be evaluated for the choice of second-line medical therapy are hyperglycemia-that should be managed as in non-acromegalic patients-tumor remnant, resistant headache and compliance. Costs do not represent a main determinant in the choice of second-line medical treatment. The experts agreed on a holistic management approach to acromegaly. It is therefore necessary to choose currently available highly effective second-line medical treatment (pegvisomant and pasireotide) based on the characteristics of the patients.

C-Reactive Protein-Albumin Ratio Predicts Objective Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma.

Enfortumab vedotin (EV), an antibody-drug conjugate that targets Nectin-4, is used for patients with metastatic urothelial carcinoma who have experienced progression on platinum-based chemotherapy and checkpoint inhibitors. Despite the widespread use of the drug, evidence remains scarce regarding clinical indicators that can predict the response to EV treatment. We aimed to explore the predictive value of clinical indicators derived from peripheral blood tests for treatment responses to EV. We utilized records of 109 patients with metastatic urothelial carcinoma treated by EV from our multi-institutional dataset. Receiver operating characteristic curve analyses for predicting objective responses including several indicators from blood examinations, such as C-reactive protein-albumin ratio (CAR), hemoglobin, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and lactate dehydrogenase, were performed. The optimal cutoff points were determined by the Youden index. Logistic regression analyses for achieving objective responses to EV treatment were performed among these indicators. The median age of the cohort was 74 years, and the median follow-up duration was 10 months for the entire group. Median overall survival and progression-free survival from the initiation of EV were 12 and 6 months, respectively. The objective response rate and disease control rate were 48% and 70%, respectively. The receiver operating characteristic curve analysis aimed at predicting the achievement of an objective response to EV showed that the concordant index for the CAR was 0.774, significantly surpassing other indicators such as hemoglobin level, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and serum lactate dehydrogenase. The Youden index identified an optimal cutoff value of 1 for CAR (mg/L for C-reactive protein and g/dL for serum albumin level) in predicting the objective response to EV treatment. Using the cutoff value for the CAR, the cohort was divided into 32 patients (29%) with lower CAR and 77 patients (71%) with higher CAR. The objective response rate was observed to be 84% in the lower CAR group and 32% in the higher CAR group (p < 0.0001). A logistic regression analysis revealed that an Eastern Cooperative Oncology Group Performance Status ≥1 (p = 0.04) and a CAR ≥1 (p < 0.001) were identified as independent predictors for the objective response to EV. The evaluation of the CAR from a concise blood examination at the initiation of EV could effectively predict the treatment response to EV in patients with metastatic urothelial carcinoma after the progression of platinum-based chemotherapy and checkpoint inhibitors.

Cancer Prevention Among Firefighters: Examining Lifestyle, Screening Behavior, and Beliefs.

Firefighters are at increased risk of developing cancer due to occupational exposures, but they may also face increased risk due to their lifestyle, such as the quality of their diet and physical activity. Cancer beliefs and screening behavior could also influence their cancer risk. The current study aimed to identify individual differences associated with lifestyle behaviors, cancer screening, and cancer beliefs among firefighters; to describe the strategies firefighters use to adapt to their work schedule; and to describe topics firefighters believe are the most important to address in their workplace. Career firefighters (N = 171) in a medium-sized U.S. city completed an online survey. Logistic regression analyses identified age, education, racial identity, years of fire service, perceived stress, and rank as predictors of responses to items addressing cancer screening, lifestyle behaviors, and cancer beliefs. Although results varied, age, education, and racial identity were associated with most of the outcomes. Strategies related to sleep such as getting the right amount and napping, exercise, and getting family/roommate support were selected as the top adaptive strategies for work. Sleep, mental health/well-being, and work-life balance were selected most often as the most important topics to address in the fire service, with topics related to reducing occupational exposures receiving less attention. The findings suggest individual differences, such as age, education, and racial identity, should be considered when developing occupational health interventions for firefighters. Interventions related to mental health, work-life balance, and sleep may be desired most by those in the fire service.