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Francesca Battaglin,1 Alberto Puccini,2 Selma Ahcene Djaballah,3 Heinz-Josef Lenz11Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; 2Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 3Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV - IRCCS, Padua 35128, ItalyAbstract: Panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR). It is currently approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC) in combination with chemotherapy in first- and second-line and as monotherapy in chemorefractory patients. This review will provide an overview of main efficacy data on panitumumab from its early development up to latest evidences, including novel perspectives on predictive biomarkers of anti-EGFRs efficacy and mechanisms of secondary resistance. Quality of life (QoL) related issues and panitumumab safety profile will be addressed as well.Keywords: panitumumab, colorectal cancer, EGFR, RAS, biomarker, quality of life

Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.

Purpose: The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of HER2 amplification and gene expression using next-generation sequencing (NGS) and NanoString data., Patients and Methods: Primary tumor DNA from 559 patients was profiled for HER2 amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points., Results: High HER2 expression (dichotomized at median) was associated with longer PFS (11.6 v 10 months, P = .012) and OS (32 v 25.3 months, P = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high HER2 expression group ( P = .02), whereas a worse PFS for cetuximab was seen in the low-expression group ( P = .019). When modeled as a continuous variable, increased HER2 expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted P = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted P = .0002), reaching a plateau effect after the median. In patients with HER2 expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted P = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted P = .03) compared with that with bevacizumab. A significant interaction between HER2 expression and the treatment arm was observed for OS ( P intx = .017), PFS ( P intx = .048), and objective response rate ( P intx = .001)., Conclusion: HER2 gene expression was prognostic and predictive in CALGB/SWOG 80405. HER2 tumor expression may inform treatment selection for patients with low HER2 favoring bevacizumab- versus cetuximab-based therapies.

Unlocking the full dimensionality of single-cell RNA sequencing data (scRNAseq) is the next frontier to a richer, fuller understanding of cell biology. We introduce q-diffusion, a framework for capturing the coexpression structure of an entire library of genes, improving on state-of-the-art analysis tools. The method is demonstrated via three case studies. In the first, q-diffusion helps gain statistical significance for differential effects on patient outcomes when analyzing the CALGB/SWOG 80405 randomized phase III clinical trial, suggesting precision guidance for the treatment of metastatic colorectal cancer. Secondly, q-diffusion is benchmarked against existing scRNAseq classification methods using an in vitro PBMC dataset, in which the proposed method discriminates IFN-γ stimulation more accurately. The same case study demonstrates improvements in unsupervised cell clustering with the recent Tabula Sapiens human atlas. Finally, a local distributional segmentation approach for spatial scRNAseq, driven by q-diffusion, yields interpretable structures of human cortical tissue., (© 2024. The Author(s).)

Background: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC)., Material and Methods: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs., Results: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature., Conclusions: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. EL reports research grants from the American Cancer Society (RSG-22–022-01-CDP) 2022–2026, and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; The Randy Shaver Cancer Research and Community Fund; honoraria and travel expenses for lab-based research talks 2018–21, and equipment for laboratory-based research 2018-present, Novocure, Ltd; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2 + gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to lab); compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); Scientific Advisory Board Member, Minnetronix, LLC, 2018–2019 (no financial compensation); consultant and speaker honorarium, Boston Scientific US, 2019. Institutional Principal Investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (no financial compensation). YB, JX, and WMK are employees of Caris Life Sciences. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5 / CCL5 expression in CRC and to determine whether CCR5 / CCL5 levels could impact treatment outcomes., Methods: 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial., Results: CCR5 / CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5 / CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5 / CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5 / CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone., Conclusions: Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment., Competing Interests: Competing interests: H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. JX, YB, JPA and WMK are employers of Caris Life Sciences. AFS reports funding for research, travel, and the speakers bureau from Caris Life Sciences. BAW reports receiving honoraria from Bayer, Sirtex, Lilly, Taiho, and HalioDx. RMG reports stock and other ownership interests from Advanced Chemotherapy Technologies and Compass Therapeutics, consulting/advisory role for AbbVie, G1 Therapeutics, GSK, Merck, Eisai, Compass Therapeutics, Inspirna, Taiho, Novartis, AstraZeneca, and Bayer, expert testimony from Taiho Pharmaceutical. FI is an AbbVie employee and receives stocks from the company. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment., Methods: Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n = 107; control cohort: FOLFIRI/cetuximab arm, n = 129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011-8 and 2015-7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n = 163) trials, was genotyped using the OncoArray-500 K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan-Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher's exact tests., Findings: In the discovery cohort, patients with FASN rs4485435 any C allele (n = 21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n = 62) in multivariable (HR = 2.87; 95%CI 1.4-5.9; p =  0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR = 2.07, 95%CI: 1.15-3.74; p =  0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 ( p =  0.017) on PFS ., Interpretation: Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment., Funding: This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892)., Competing Interests: H.-J.L. reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. S.S. reports receiving honoraria for talks and advisory board role: AMGEN, Bayer, BMS, Pierre-Fabre, Merck KGaA; MSD, Leo-Pharma, Lilly, Sanofi, Servier, Roche, Takeda, Taiho. A.F reports receiving honoraria as consultant/advisory board for Amgen, Bayer, Bristol, Daiichi Sankyo, Incyte, Lilly, Merck, MSD, Pierre-Fabre, Roche, Servier. C.M was a full time employee of Roche/Genentech when the MAVERICC data was generated. All remaining authors have declared no conflicts of interest., (© 2023 The Authors.)

Background: Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours., Methods: Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS-TMB-H, dMMR/MSI-H, and MSS-TMB-low (L) tumours, using χ 2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort., Findings: MSS-TMB-H was observed in 1600 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS-TMB-L in 44 734 (92·03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18·77 months [95% CI 17·30-20·23] vs 7·03 months [5·73-8·34]; hazard ratio 0·55 [95% CI 0·31-0·99], p=0·044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1, FGF genes) was more prevalent in MSS-TMB-H tumours than in the dMMR/MSI-H or MSS-TMB-L subgroups., Interpretation: Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs., Funding: US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China., Competing Interests: Declaration of interests H-JL reports receiving honoraria from serving as a consultant or from advisory board membership for Merck Serono, Bayer, and Genentech. JX, AF, YB, MO, DS, and WMK are employees of Caris Life Sciences. AFS reports funding for research, travel, and speakers bureau participation from Caris Life Sciences. BAW reports receiving honoraria from Bayer, Sirtex, Lilly, Taiho, and HalioDx. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Exploring the relationship between various neurotransmitters and breast cancer cell growth has revealed their likely centrality to improving breast cancer treatment. Neurotransmitters play a key role in breast cancer biology through their effects on the cell cycle, epithelial mesenchymal transition, angiogenesis, inflammation, the tumor microenvironment and other pathways. Neurotransmitters and their receptors are vital to the initiation, progression and drug resistance of cancer and progress in our biological understanding may point the way to lower-cost and lower-risk antitumor therapeutic strategies. This review discusses multiple neurotransmitters in the context of breast cancer. It also discusses risk factors, repurposing of pharmaceuticals impacting neurotransmitter pathways, and the opportunity for better integrated models that encompass exercise, the intestinal microbiome, and other non-pharmacologic considerations. Neurotransmitters' role in breast cancer should no longer be ignored; it may appear to complicate the molecular picture but the ubiquity of neurotransmitters and their wide-ranging impacts provide an organizing framework upon which further understanding and progress against breast cancer can be based., (© 2023. The Author(s).)

Purpose: Chemokines are essential for immune cell trafficking and are considered to have a major impact on the composition of the tumor microenvironment. CX-chemokine receptor 4 (CXCR4) is associated with poor differentiation, metastasis, and prognosis in pancreatic ductal adenocarcinoma (PDAC). This study provides a comprehensive molecular portrait of PDAC according to CXCR4 mRNA expression levels., Experimental Design: The Cancer Genome Atlas database was used to explore molecular and immunologic features associated with CXCR4 mRNA expression in PDAC. A large real-word dataset (n = 3,647) served for validation and further exploratory analyses. Single-cell RNA analyses on a publicly available dataset and in-house multiplex immunofluorescence (mIF) experiments were performed to elaborate cellular localization of CXCR4., Results: High CXCR4 mRNA expression (CXCR4high) was associated with increased infiltration of regulatory T cells, CD8+ T cells, and macrophages, and upregulation of several immune-related genes, including immune checkpoint transcripts (e.g., TIGIT, CD274, PDCD1). Analysis of the validation cohort confirmed the CXCR4-dependent immunologic TME composition in PDAC irrespective of microsatellite instability-high/mismatch repair-deficient or tumor mutational burden. Single-cell RNA analysis and mIF revealed that CXCR4 was mainly expressed by macrophages and T-cell subsets. Clinical relevance of our finding is supported by an improved survival of CXCR4high PDAC., Conclusions: High intratumoral CXCR4 mRNA expression is linked to a T cell- and macrophage-rich PDAC phenotype with high expression of inhibitory immune checkpoints. Thus, our findings might serve as a rationale to investigate CXCR4 as a predictive biomarker in patients with PDAC undergoing immune checkpoint inhibition., (©2022 The Authors; Published by the American Association for Cancer Research.)

The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGAS-STING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer., Methods: Genomic DNA from blood samples of patients enrolled in FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215) was genotyped using the OncoArray-500K bead chip panel. Seven selected single nucleotide polymorphisms in 3 genes (cGAS, STING and interferon B1 (IFNB1)) were analysed for the association with overall survival and progression-free survival., Results: In the cetuximab cohort, patients with STING rs1131769 any T allele showed significantly shorter overall survival (36.3 versus 56.1 months) than carriers of C/C in both univariate [hazard ratio (HR) = 2.08; 95% confidence interval (CI): 1.06-4.07; P = 0.03] and multivariate (HR = 2.98; 95% CI: 1.35-6.6; P = 0.0085) analyses; patients carrying IFNB1 rs1051922 G/A and A/A genotype showed a significantly shorter progression-free survival than carriers of G/G allele in both univariate (G/A versus G/G, 10.2 versus 14.1 months, HR = 1.84; 95% CI 1.23-2.76; A/A versus G/G, 10.7 versus 14.1 months, HR = 2.19; 95% CI 0.97-4.96; P = 0.0077) and multivariate analyses (G/A versus G/G, HR = 2; 95% CI 1.22-3.3; A/A versus G/G, HR = 2.19, 95% CI 0.92-5.26, P = 0.02). These associations were not observed in the bevacizumab arm of FIRE-3 or TRIBE., Conclusion: These results suggest for the first time that germline polymorphisms in STING and IFNB1 genes may predict the outcomes of cetuximab-based treatment in patients with metastatic colorectal cancer., Competing Interests: Conflict of interest statement H.-J.L. reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. S.S. reports receiving honoraria for talks and advisory board role: AMGEN, Bayer, BMS, Pierre-Fabre, Merck KGaA; MSD, Leo-Pharma, Lilly, Sanofi, Servier, Roche, Takeda, Taiho. A.F reports receiving honoraria as consultant/advisory board for Amgen, Bayer, Bristol, Daiichi Sankyo, Incyte, Lilly, Merck, MSD, Pierre-Fabre, Roche, Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Reactive oxygen species activate EGFR/RAS/MAPK signaling either through the inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in antioxidant genes link to the efficacy of cetuximab in patients with metastatic colorectal cancer (mCRC)., Patients and Methods: We analyzed genomic and clinical data from FIRE-3, a phase III trial comparing cetuximab and bevacizumab along with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped. Thirteen functional SNPs in antioxidant genes were tested for associations with clinical outcomes., Results: In total, 236 patients were included (FOLFIRI/cetuximab arm, n = 129; FOLFIRI/bevacizumab arm, n = 107). In univariate analysis, two SNPs (TXN2 rs4821494 and GPX4 rs4807542) were significantly associated with overall survival (OS) in the FOLFIRI/cetuximab arm. Multivariate analysis confirmed the significant association of TXN2 rs4821494 (T/T vs. any G allele, hazard ratio = 2.47, 95% confidence interval = 1.06-5.72, P = .03). In the FOLFIRI/bevacizumab arm, no SNPs were significantly associated with clinical outcomes. Treatment-by-SNP interaction test confirmed the predictive value of TXN2 rs4821494 (OS: P = .03)., Conclusion: TXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab-based first-line chemotherapy in mCRC, warranting further validation studies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Motivation: Approaches that control error by applying a priori fixed discovery thresholds such as 0.05 limit the ability of investigators to identify and publish weak effects even when evidence suggests that such effects exist. However, current false discovery rate (FDR) estimation methods lack a principled approach for post hoc identification of discovery thresholds other than 0.05., Results: We describe a flexible approach that hinges on the precision of a permutation-based FDR estimator. A series of discovery thresholds are proposed, and an FDR confidence interval selection and adjustment technique is used to identify intervals that do not cover one, implying that some discoveries are expected to be true. We report an application to a transcriptome-wide association study of the MAVERICC clinical trial involving patients with metastatic colorectal cancer. Several genes are identified whose predicted expression is associated with progression-free or overall survival., Availability and Implementation: Software is provided via the CRAN repository (https://cran.r-project.org/web/packages/fdrci/index.html)., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2022. Published by Oxford University Press.)

Signet ring cell carcinoma (SRCC) is rare: about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however the underlying molecular characteristics are unknown. SRCCs were analyzed using NGS, immunohistochemistry, and in situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. A total of 8500 CRC and 1100 GC were screened. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%); in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%). When compared to non-SRCC histology (N = 3522), CRC-SRCC (N = 37) more frequently had mutations in BRCA1 (11% vs 1%, P < 0.001) and less frequently mutations in APC (19% vs 78%, P < 0.001), KRAS (22% vs 51%, P = 0.001) and TP53 (47% vs 73%, P = 0.001). Among the GC cohort, SRCC (N = 54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, compared to non-SRCC (N = 540). Our data suggest that SRCCs harbor a similar molecular profile, regardless of the tumor location. Tailored therapy may become available for these patients., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)