Prostate cancer – a biomarker perspective

Despite early detection and reduced risk of death, prostate cancer still remains the second leading cause of cancer death in American men. There is currently no cure for advanced prostate cancer. The multistage, stochastic and highly heterogeneous nature of prostate cancer, coupled with genetic and epigenetic alterations that occur during disease progression and response to therapy, represent fundamental challenges in our quest to understand and control this complex and prevalent disease. Recent advances in drug development and breakthroughs in omics technologies have renewed our efforts to identify novel biomarkers for prostate cancer prognosis, prediction, and therapeutic response monitoring. In this perspective article, we overview the current status and highlight future prospects of biomarkers for prostate cancer, a disease that affects millions of men worldwide

Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling–informed personalized monitoring assay

IntroductionCirculating tumor DNA (ctDNA) detection postoperatively may identify patients with urothelial cancer at a high risk of relapse. Pragmatic tools building off clinical tumor next-generation sequencing (NGS) platforms could have the potential to increase assay accessibility.MethodsWe evaluated the widely available Foundation Medicine comprehensive genomic profiling (CGP) platform as a source of variants for tracking of ctDNA when analyzing residual samples from IMvigor010 (ClinicalTrials.gov identifier NCT02450331), a randomized adjuvant study comparing atezolizumab with observation after bladder cancer surgery. Current methods often involve germline sampling, which is not always feasible or practical. Rather than performing white blood cell sequencing to filter germline and clonal hematopoiesis (CH) variants, we applied a bioinformatic approach to select tumor (non-germline/CH) variants for molecular residual disease detection. Tissue-informed personalized multiplex polymerase chain reaction–NGS assay was used to detect ctDNA postsurgically (Natera).ResultsAcross 396 analyzed patients, prevalence of potentially actionable alterations was comparable with the expected prevalence in advanced disease (13% FGFR2/3, 20% PIK3CA, 13% ERBB2, and 37% with elevated tumor mutational burden ≥10 mutations/megabase). In the observation arm, 66 of the 184 (36%) ctDNA-positive patients had shorter disease-free survival [DFS; hazard ratio (HR) = 5.77; 95% confidence interval (CI), 3.84–8.67; P < 0.0001] and overall survival (OS; HR = 5.81; 95% CI, 3.41–9.91; P < 0.0001) compared with ctDNA-negative patients. ctDNA-positive patients had improved DFS and OS with atezolizumab compared with those in observation (DFS HR = 0.56; 95% CI, 0.38–0.83; P = 0.003; OS HR = 0.66; 95% CI, 0.42–1.05). Clinical sensitivity and specificity for detection of postsurgical recurrence were 58% (60/103) and 93% (75/81), respectively.ConclusionWe present a personalized ctDNA monitoring assay utilizing tissue-based FoundationOne® CDx CGP, which is a pragmatic and potentially clinically scalable method that can detect low levels of residual ctDNA in patients with resected, muscle-invasive bladder cancer without germline sampling

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab’)2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients

Study of inflammatory markers and BODE index in chronic obstructive pulmonary disease

Introduction: Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease characterized by progressive airflow limitation and associated with enhanced chronic inflammatory response of the airways to a variety of noxious stimuli. The current concept of COPD, however, extends beyond the respiratory system to include a variety of extrapulmonary manifestations which includes raised inflammatory markers. Methods: This was a single, center observational open-labeled case–controlled study which included fifty patients of diagnosed COPD and 50 age- and gender-matched controls. All patients were evaluated by detailed history taking, pulmonary function test, 6-min walk test, and calculation of BODE scores. Levels of serum inflammatory markers such as cortisol, tumor necrosis factor alpha, interleukin-6 (IL-6), lactate dehydrogenase, and C-reactive protein were estimated using standard quality equipments. Observations: Majority of the patients in the study and control groups were males and were aged above 40 years. Thirty-eight of the fifty COPD patients had BODE scores of more than 3. All the studied inflammatory markers were significantly higher in the COPD group as compared to the control group. Of all the studied markers, only IL-6 showed a significant correlation with BODE index, i.e., higher IL-6 values were associated with higher BODE scores. No correlation was seen between the other markers and BODE scores. Conclusions: Our data suggest that IL-6 is a biomarker that correlates with BODE score. IL-6 as a target for therapy in COPD needs to be further studied. Follow-up studies are needed to validate findings

Comprehensive management of complicated crown fracture in a 10-year-old child

Trauma to the maxillary anterior teeth is a common incidence in young patients. Pediatric dentists have to deal with such dental traumatic injuries on a regular basis in their daily routine practice. Some clinical studies have reported reattachment of fractured tooth segment using adhesive resin cement and dentine bonding agent with or without postplacement. This case report presents a comprehensive management of complicated crown fracture in the maxillary anterior teeth with reattachment of the fractured tooth segment with dual-cure adhesive resin and a prefabricated glass-reinforced composite fiber post followed by a permanent restoration

Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer.

We tested cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc Δ716 /Smad4 +/- Kras G12D mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents

C-reactive protein reduction post treatment is associated with improved survival in atezolizumab (anti-PD-L1) treated non-small cell lung cancer patients.

PurposeOverall survival (OS) is the most significant endpoint for evaluation of treatment benefit with checkpoint inhibitors (CPI) in cancer. We evaluated serum C-reactive protein (CRP) in non-small cell lung cancer (NSCLC) trials with atezolizumab (anti-PD-L1) as an early OS surrogate.MethodsSerum from patients enrolled in randomized Phase II (n = 240) and Phase III (n = 701) trials of NSCLC patients (POPLAR, OAK) who progressed on prior-platinum chemotherapy, were analyzed for CRP levels over time. Patients were grouped by changes in CRP levels post-treatment as either increased (≥ 1.5 fold), decreased (≤ 1.5 fold) or unchanged (within +1.5 fold) relative to pre-treatment levels to assess association with progression free survival (PFS) and OS.ResultsDecrease in serum CRP levels at 6 weeks relative to pre-treatment were observed in patients with RECIST1.1 based complete or partial responses (CR/PR) to atezolizumab whereas patients with disease progression (PD) demonstrated an increase in CRP levels in the Phase II POPLAR study, and confirmed in the Phase III OAK study. Decrease in serum CRP as early as six weeks post treatment predicted improved PFS and OS, even in patients who were determined as stable disease (SD) in their first scan. This effect was not observed in the chemotherapy arms.ConclusionModulation of serum CRP correlates with clinical outcome post-atezolizumab treatment. This routine lab test may provide utility in informing OS signals as early as 6 weeks post-initiation of therapy with CPIs in NSCLC

Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer.

We tested cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors in cis-Apc Δ716 /Smad4 +/- Kras G12D mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-Apc Δ716 /Smad4 +/- and cis-Apc Δ716 /Smad4 +/- Kras G12D mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents

Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers

Programmed Death Ligand 1 (PD-L1) positivity rates differ between different metastatic sites and the primary tumor. Understanding PD-L1 expression characteristics could guide biopsy procedures and motivate research to better understand site-specific differences in the tumor microenvironment. The purpose of this study was to compare PD-L1 positivity on immune cells and tumor cells in primary and metastatic triple negative breast cancer (TNBC) tumors. Retrospective study utilizing the PD-L1 database of Foundation Medicine containing the SP142 companion diagnostic immunohistochemistry assay (SP142 CDx) and Food and Drug Administration guidelines for scoring. 340 TNBC cases (179 primary tumors and 161 unmatched metastatic lesions) were evaluated. The primary outcome measures were PD-L1 positivity rates in immune cells and tumor cells. χ2 test was used for comparisons. Spearman’s correlation coefficient was used for correlations. More primary tumors were positive for PD-L1 expression on immune cells than metastatic lesions (114 (63.7%) vs 68 (42.2%), p&lt;0.0001). This was driven by the lower PD-L1 positivity rates in skin (23.8%, 95% CI: 8.22% to 47.2%), liver (17.4%, 95% CI: 5.00% to 38.8%) and bone (16.7%, 95% CI: 2.10% to 48.4%) metastases. Lung (68.8%, 95% CI: 41.3% to 90.0%), soft tissues (65.2%, 95% CI: 42.7% to 83.6%) and lymph nodes (51.1%, 95% CI: 35.8% to 66.3%) had PD-L1 % positivity rates similar to primary tumors. PD-L1 expression was rare on tumor cells in both the breast and metastatic sites (8.3% vs 4.3%, p=0.13). The rate of PD-L1 positivity varies by metastatic location with substantially lower positivity rates in liver, skin and bone metastases compared with primary breast lesions or lung, soft tissue or lymph node metastases. This difference in PD-L1 positivity rates between primary tumors and different metastatic sites should inform physicians when choosing sites to biopsy and suggests a difference in the immune microenvironment across metastatic sites