Heinz-Josef Lenz

182Background: Sex-based disparities have been reported for mCRC both in incidence, males having higher incidence than females, and in outcome, younger females having better outcome than males of same age or older females. Tumor immune microenvironment is hypothesized to have role in this sexual dimorphic pattern. Herein, we explored the role of gene expression (exp) and genetic variation of IRGs on progression-free (PFS) and overall survival (OS) in mCRC pts. Methods: 21 IRGs with potential roles in CRC were identified from literature review. The association of tumor gene exp with PFS and OS was evaluated in pts with mCRC (433 pts, RNA seq) from CALGB/SWOG 80405. Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) / cetuximab [cet] (N = 207)) and sex (male (N = 271) / female (N = 162)). Further, the impact on outcome of 5 selected germline single nucleotide …

Background: Colorectal cancer (CRC) is the third most common cancer, and second cause of cancer death in the United States (US). Among US Hispanic/Latino/a/x (H/L) individuals, CRC represents the second and the third most common cancer and the most common cause of cancer death for men and women, respectively. Despite this, the tumor landscape, and key determinants of outcomes in CRC H/L patients are understudied. Methods: To address this need, we launched the ENLACE study, to engage H/L CRC patients in germline and somatic sequencing and identify the optimal approaches for patient participation. Through the Center for Patient Engagement in Cancer Characterization Studies (COPECC) patients were recruited from two healthcare facilities: a safety-net hospital (Los Angeles General Medical Center, LA Gen) and the USC Norris Comprehensive Cancer Center (Norris) a university medical …

174Background: Few genome-wide investigations have examined germline variants associated with mCRC outcomes following primary treatment. Here, we performed a GWAS meta-analysis to explore the impact of germline genetic variation on progression-free survival (PFS) and overall survival (OS) in four clinical trials of mCRC. Methods: The GWAS comprised 1,324 mCRC patients (pts) enrolled in four randomized Phase II/III trials for first line treatment: FIRE-3 (FOLFIRI-bevacizumab [bev]; FOLFIRI-cetuximab[cet]), MAVERICC (FOLFIRI-bev; FOLFOX6-bev), TRIBE (FOLFIRI-bev; FOLFOXIRI-bev), and TRIBE2 (mFOLFOX6-bev; FOLFOXIRI-bev). DNA isolated from blood was genotyped using the OncoArray and imputed against the Haplotype Reference Consortium panel. In each trial arm, associations between SNPs and PFS and OS were assessed using an additive coding in a Cox proportional hazard …

172Background: Lemur tail kinase 3 (LMTK3) plays a critical role in multiple cellular pathways such as Wnt signaling, KIT modulation, and the estrogen receptor pathway. We previously reported that LMTK3 gene polymorphisms are associated with clinical outcome in patients with CRC, and that LMTK3 and estrogen-mediated signaling play a crucial role in CRC tumorigenesis in vitro. Here, we aimed to characterize the molecular features associated with LMTK3 gene expression in CRC. Methods: 20,219 CRC were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS). Top quartile transcripts per million (TPM) for LMTK3 expression (Q4) were considered high while bottom quartile (Q1) low. Consensus molecular subtypes (CMS) were assessed using RNAseq. Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by QuantiSEQ. X2 and …

Background: Plant-based diet is recommended by multiple cancer survivorship guidelines and was reported to be associated with better survival among patients with non-metastatic colorectal cancer. However, the association between plant-based diet and survival in metastatic colorectal cancer is unknown. Methods: Using an NCI-sponsored systemic therapy trial conducted from 2005 to 2015 (CALGB/SWOG 80405), we included 1,279 patients who completed validated food frequency questionnaires at the initiation of treatment for metastatic colorectal cancer. To emphasize different impact of healthful plant foods, less healthful plant foods, and animal foods, we used 18 food groups to calculate three plant-based indexes (ranges: 18-90 points): overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). The primary outcome was overall survival, and …

PurposeProgrammed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease.Methods3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter.ResultsCompared to BrT, more LvM samples had a high TMB …

PURPOSECALGB (Alliance)/SWOG 80405 was a randomized phase III trial that in first-line patients with metastatic colorectal cancer (mCRC) treated with bevacizumab or cetuximab with chemotherapy. We aimed to discover novel mutated genes associated with prognosis and differential response to therapy with the biologics.METHODSPrimary tumor DNA from 548 patients was sequenced using FoundationOne. The effect of mutated genes and mutations on overall survival (OS) was tested adjusting for microsatellite instability status, BRAF V600E, all RAS mutations, arm, sex, and age.RESULTSThe median number (lower-upper quartile) of mutated genes was 5 (3-7), 5 (3-6) in microsatellite stable and 12.5 (4.5-32) in microsatellite instability-high tumors. Mutated KRAS and APC were more frequent in Black (53% and 85%) than White (27% and 65%, respectively) patients while BRAF V600E was less frequent in …

Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal relationship is unclear. To elucidate causality, we conduct a prospective observational study using magnetic resonance imaging (MRI)-measured IPFD data and also perform a Mendelian randomization study using genetic instruments for IPFD. In the observational study, we use UK Biobank data (N = 29,463, median follow-up: 4.5 years) and find that high IPFD (>10%) is associated with PDAC risk (adjusted hazard ratio [HR]: 3.35, 95% confidence interval [95% CI]: 1.60–7.00). In the Mendelian randomization study, we leverage eight out of nine IPFD-associated genetic variants (p < 5 × 10−8) from a genome-wide association study in the UK Biobank (N = 25,617) and find that genetically determined IPFD is associated with PDAC (odds ratio [OR] per 1 …