Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.

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.

Differential responses to immune checkpoint inhibitors are governed by diverse mismatch repair gene alterations.

PURPOSE: The response to immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR) colorectal cancer (CRC) and endometrial cancer (EC) is variable. Here, we explored the differential response to ICIs according to different MMR alterations. EXPERIMENTAL DESIGN: CRC (N=13701) and EC (N=3315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan-Meier. The prediction of high, intermediate and low affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2) Results: Compared to mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all CRC (54.6m vs. 36m; p=0.0.025) and EC (81.5m vs. 48.2m; p<0.001) patients. In ICIs-treated patients, the mOS was longer in mutS co-loss in CRC (not reached (NR) vs. 36m; p=0.011). In EC, the mOS was NR vs. 42.2m; p=0.711). The neoantigen load (NAL) in mutS co-loss compared to mutL co-loss was higher in CRC (high-affinity epitopes: 25.5 vs 19; q=0.017, intermediate: 39 vs. 32; q=0.004, low: 87.5 vs. 73; q<0.001) and EC (high-affinity epitopes: 15 vs. 11; q=0.002, intermediate: 27.5 vs. 19; q<0.001, low: 59 vs. 41; q<0.001) respectively. R2 ranged from 0.25 in mutS co-loss CRC to 0.95 in mutL co-loss EC. CONCLUSIONS: Patients with mutS co-loss experienced longer mOS in CRC and EC and better response to ICIs in CRC. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.

CCR5 and CCL5 gene expression in colorectal cancer: comprehensive profiling and clinical value.

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.

Subcutaneous Administration of Monoclonal Antibodies: Pharmacology, Delivery, Immunogenicity, and Learnings From Applications to Clinical Development.

Subcutaneous (s.c.) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared with intravenous (i.v.) infusion through shorter administration times, made possible by convenient, patient-centric devices. A deeper understanding of clinical pharmacology principles related to efficacy and safety of s.c.-administered mAbs over the past decade has streamlined s.c. product development. This review presents learnings from key constituents of the s.c. mAb development pathway, including pharmacology, administration variables, immunogenicity, and delivery devices. Restricted mAb transportation through the hypodermis explains their incomplete absorption at a relatively slow rate (pharmacokinetic (PK)) and may impact mAb-cellular interactions and/or onset and magnitude of physiological responses (pharmacodynamic). Injection volumes, formulation, rate and site of injection, and needle attributes may affect PKs and the occurrence/severity of adverse events like injection-site reactions or pain, with important consequences for treatment adherence. A review of immunogenicity data for numerous compounds reveals that incidence of anti-drug antibodies (ADAs) is generally comparable across i.v. and s.c. routes, and complementary factors including response magnitude (ADA titer), persistence over time, and neutralizing antibody presence are needed to assess clinical impact. Finally, four case studies showcase how s.c. biologics have been clinically developed: (i) by implementation of i.v./s.c. bridging strategies to streamline PD-1/PD-L1 inhibitor development, (ii) through co-development with i.v. presentations for anti-severe acute respiratory syndrome-coronavirus 2 antibodies to support rapid deployment of both formulations, (iii) as the lead route for bispecific T cell engagers (BTCEs) to mitigate BTCE-mediated cytokine release syndrome, and (iv) for pediatric patients in the case of dupilumab.

Invasive squamous cell carcinoma of the breast associated with breast augmentation implant capsule.

Primary squamous cell carcinoma (SCC) of the breast is rare, representing less than 0.1% of all breast cancers. To date, there have been 20 reported cases of SCC associated with breast augmentation, usually in patients with long-standing implants. A patient is reported here with primary squamous carcinoma of the breast associated with textured saline implants. Due to the paucity of cases, there is limited information on the incidence and management of implant-associated SCC of the breast.

BRAF V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors.

BACKGROUND: We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). PATIENTS AND METHODS: Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. RESULTS: Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. CONCLUSION: In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.

Axillary lymph node recurrence following wire-directed sentinel lymph node dissection for breast cancer patients with biopsy-proven axillary metastases prior to neoadjuvant chemotherapy at a safety net medical center.

BACKGROUND: Although sentinel lymph node dissection (SLND) after neoadjuvant chemotherapy (NAC) is feasible, axillary management for patients with pretreatment biopsy-proven axillary metastases and who are clinically node-negative after NAC (ycN0) remains unclear. This retrospective study was performed to determine the rate of axillary lymph node recurrence for such patients who had wire-directed (WD) SLND. METHODS: Patients treated with NAC from 2015 to 2020 had axillary nodes evaluated by pretreatment ultrasound. Core biopsies were done on abnormal nodes, and microclips were placed in nodes during biopsy. For patients with biopsy-proven node metastases who received NAC and were ycN0 by clinical exam, WD SLND was done. Patients with negative nodes on frozen section had WD SLND alone; those with positive nodes had WD SLND plus axillary lymph node dissection (ALND). RESULTS: Of 179 patients receiving NAC, 62 were biopsy-proven node-positive pre-NAC and ycN0 post-NAC. Thirty-five (56%) patients were node-negative on frozen section and had WD SLND alone. Twenty-seven (43%) patients had WD SLND + ALND. Forty-seven patients had postoperative regional node irradiation. With median follow-up of 40 months, there were recurrences in 4 (11%) of 35 patients having WD SLND and 5 (19%) of 27 having WD SLND + ALND, but there was only one axillary lymph node recurrence, identified by CT scan. CONCLUSIONS: Axillary node recurrence was very uncommon after WD SLND for patients who had pretreatment biopsy-proven node metastases and were ypN0 after NAC. These patients would be unlikely to derive clinical benefit from the addition of completion ALND to SLND.

Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions.

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.

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs. METHODS: We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models. RESULTS: Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two's effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, 'aggregated' burden scores were developed to distinguish 'protective' (endocrine and musculoskeletal) and 'harmful' (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS. CONCLUSIONS: Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.

Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by decreased or absent dystrophin gene leading to progressive muscle degeneration and weakness in young boys. Disease progression models for the North Star Ambulatory Assessment (NSAA), a functional measurement widely used to assess outcomes in clinical trials, were developed using a longitudinal population modeling approach. The relationship between NSAA total score over time, loss of ambulation, and potential covariates that may influence disease progression were evaluated. Data included individual participant observations from an internal placebo-controlled phase II clinical trial and from the external natural history database for male patients with DMD obtained through the Cooperative International Neuromuscular Research Group (CINRG). A modified indirect response model for NSAA joined to a loss of ambulation (LOA) time-to-event model described the data well. Age was used as the independent variable because ambulatory function is known to vary with age. The NSAA and LOA models were linked using the dissipation rate constant parameter from the NSAA model by including the parameter as a covariate on the hazard equation for LOA. No covariates were identified. The model was then used as a simulation tool to explore various clinical trial design scenarios. This model contributes to the quantitative understanding of disease progression in DMD and may guide model-informed drug development decisions for ongoing and future DMD clinical trials.

Diversity in Clinical Pharmacology: A Call to Action.

Prioritization of diversity, equity, and inclusion in all facets of our work is long overdue for the clinical pharmacology community. Increasing diversity in clinical research will deepen our understanding of nuanced patient populations and help improve all patient outcomes. Fostering an inclusive and diverse workforce will lead to broader perspectives that can better inform critical decisions and create work environments where everyone can thrive. In this call to action, we invite you to join us.

Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment.

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.

Modeling the Probability of HIV Infection over Time in High-Risk Seronegative Participants Receiving Placebo in Five Randomized Double-Blind Placebo-Controlled HIV Pre-Exposure Prophylaxis Trials: A Patient-Level Pooled Analysis.

The World Health Organization recommends pre-exposure prophylaxis (PrEP) for individuals at substantial risk of HIV infection. The aim of this analysis is to quantify the individual risk of HIV infection over time, using a large database of high-risk individuals (n = 5583). We used data from placebo recipients in five phase III PrEP trials: iPrEx, conducted in men who have sex with men and transgender women; VOICE, conducted in young women at high sexual risk; Partners PrEP, conducted in HIV serodiscordant heterosexual couples; TDF2, conducted in high-risk heterosexual men and women; and BTS, conducted in persons who inject drugs. The probability of HIV infection over time was estimated using NONMEM7.4. We identified predictors of HIV risk and found a substantial difference in the risk of infection among and within trial populations, with each study including a mix of low, moderate, and high-risk individuals (p < 0.05). Persons who were female at birth were at a higher risk of HIV infection than people who were male at birth. Final models were integrated in a tool that can assess person-specific risk and simulate cumulative HIV risk over time. These models can be used to optimize future PrEP clinical trials by identifying potential participants at highest risk.

Prognostic impact of performance status on the outcomes of immune checkpoint inhibition strategies in patients with dMMR/MSI-H metastatic colorectal cancer.

BACKGROUND: Immune checkpoint inhibitors yielded unprecedented outcomes in patients with mismatch repair deficient/ microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), but clinical decision-making in this rapidly evolving treatment landscape is challenging. Since performance status (PS) represents a well-established prognostic factor in clinical practice, we investigated whether worse PS, overall or related to either patients' frailty or high tumour burden, could affect the outcomes in this whole patients' population and according to immune checkpoint inhibitor treatment type. METHODS: We conducted a global study at Tertiary Cancer Centres and collected data of patients with dMMR/MSI-H mCRC treated with anti- programmed-death (ligand)-1 (PD(L)-1) monotherapy or anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination. RESULTS: The cohort included 502 patients. At a median follow-up of 31.2 months, worse PFS and OS were reported in patients with patient-related PS ≥ 1 (adjusted-HRs: 1.73, 95%CI: 1.06-2.83, p = 0.004 and 2.06, 95%CI: 1.13-3.74, p = 0.001, respectively) and cancer-related PS ≥ 1 (adjusted-HRs: 1.61, 95%CI: 1.19-2.17, p = 0.004 and 1.87, 95%CI: 1.32-2.66, p = 0.001, respectively). Anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination did not provide significantly better survival compared to anti-PD(L)-1 monotherapy in PS 0 subgroup (PFS HR = 0.62, 95%CI: 0.37-1.02, p = 0.059; OS HR = 0.59, 95%CI: 0.32-1.11, p = 0.100) and in patient-related PS ≥ 1 (PFS HR 0.93, 95%CI: 0.31-2.83, p = 0.899; OS HR 1.22, 95%CI: 0.34-4.37, p = 0.760), but the difference was significant and clinically meaningful in the subgroup with cancer-related PS ≥ 1 (PFS HR = 0.32, 95%CI: 0.19-0.53, p < 0.001; OS HR = 0.26, 95%CI: 0.14-0.48, p < 0.001). CONCLUSIONS: In patients with dMMR/MSI-H mCRC, an extensive evaluation of clinical variables including PS may be implemented in the therapy decision-making.

fdrci: FDR confidence interval selection and adjustment for large-scale hypothesis testing.

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.

Germline Polymorphisms in Genes Involved in the Antioxidant System Predict the Efficacy of Cetuximab in Metastatic Colorectal Cancer Patients Enrolled in FIRE-3 Trial.

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.

Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials.

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.