The optimal surgical margin for minimizing local recurrence (LR) and distant metastasis in phyllodes tumors (PTs) remains controversial. Despite multiple observational cohorts, variation among studies limits the interpretation of margin-outcome associations. We therefore performed a structured critical interpretative synthesis (CIS) to evaluate whether the current evidence supports specific margin thresholds. The CIS incorporated a systematic review, random-effects meta-analysis, an appraisal of existing meta-analyses and guidelines, and an expert interpretative analysis of 40 single-cohort studies from 2015 to 2025 evaluating surgical margin width and outcomes in PTs. Authors' recommendations regarding margin adequacy were extracted as interpretative "author conclusions." In parallel, LR and distant metastasis outcomes were pooled by tumor grade using random-effects models with prediction intervals. Final margin recommendations were derived by integrating CIS findings and multidisciplinary expert judgment. Current management guidelines do not recommend re-excision for positive or close margins in benign PTs. Contemporary guidelines are also concordant in advising negative margins for borderline and malignant PTs, although the specified margin width ranges from 1 to 10 mm. Within this range, no association has been established between increasing margin width and the risk of LR or malignant transformation upon LR. The estimated LR rates are 12.5% for borderline and 16.5% for malignant PTs. Malignant transformation on recurrence occurred in only 1% and 3% of all benign and borderline PTs, respectively. Approximately 14% of malignant PT metastasize, often without LR. Current heterogeneous evidence does not show lower recurrence with margins wider than a negative (≥1 mm) margin in PTs. For borderline and malignant PTs, a mandatory 10-mm threshold is insufficiently supported, as narrower negative margins may be adequate in selected cases. However, an optimal margin threshold cannot be defined from current data. These conclusions are practice-supporting rather than guideline-defining and reinforce the need for high-quality evidence to establish harmonized, grade-specific margin recommendations.

1061 Background: Combination of CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) is first-line (1L) standard of care for patients (pts) with HR+/HER2- advanced breast cancer (ABC). Treatment-free interval (TFI) is an established prognostic factor in ABC. Shorter TFI is associated with more aggressive disease biology, inferior treatment outcomes, and reduced overall survival (OS). Real-world (RW) evidence complements clinical trials by providing insights into pts underrepresented in clinical trials. We present interim analysis 5 (IA5) of the PERFORM study, evaluating outcomes by TFI in pts receiving 1L palbociclib + ET. Methods: The prospective, non-interventional study PERFORM (NCT04767594) enrolled pts across Germany and Austria receiving 1L palbociclib + ET. Primary endpoint is progression-free survival (PFS). Secondary endpoints include second line (2L) PFS, PFS2 (time from 1L start to progression on 2L or death) and OS. Tumor assessments followed local medical standards. Quality of life (QoL) was assessed using FACT-B questionnaires. Pts were stratified by TFI, defined as time from last (neo)adjuvant treatment to recurrence: >12 months, ≤12 months, and de novo advanced disease. Time-to-event endpoints were estimated using the Kaplan-Meier method. Results: At database cutoff (Sep 30th, 2025), 1268 pts were included in IA5 and 1010 pts had available TFI data for subgroup analysis (TFI >12 months: 373 pts; ≤12 months: 133 pts; de novo: 504 pts). Median age was 69.5, 64.4, and 68.8 years, respectively. Pts with TFI ≤12 months showed a more aggressive disease profile such as higher rates of G3 tumors, N2-3 nodal status and liver metastasis compared to other TFI subgroups. Overall median PFS was 25.5 months (95% CI: 23.0-28.6), while median PFS was 29.2 months (95% CI: 23.3-33.1) for TFI >12 months, 14.6 months (95% CI: 9.3-19.4) for TFI ≤12 months, and 31.5 months (95% CI: 26.5-36.7) for pts with de novo disease. Median PFS2 was 39.0 (95% CI:33.7-51.4), 21.2 (95% CI: 17.4-37.0), and 40.9 months (95% CI: 37.0-46.9) for TFI >12, ≤12, and de novo, respectively. Median OS was not reached for TFI>12 months and was 37.4 and 52.8 months for TFI ≤12 and de novo, respectively. QOL with 1L therapy was maintained in all subgroups. Conclusions: The PERFORM IA5 supports TFI as a relevant prognostic factor for pts treated with palbociclib + ET in the 1L RW setting. QOL was maintained in TFI subgroups. Longest clinical benefit was observed in pts with TFI > 12 months and those with de novo disease. Treatment was associated with shorter clinical outcome in pts with TFI≤12 months compared to those in other TFI subgroups. These results complement those in the RCT setting.

3561 Background: The use of overall response rate (ORR) and progression-free survival (PFS) as surrogacy of overall survival (OS) has limitations in mCRC. Change in tumor load (ΔTL; tumor burden at progressive disease [PD] vs baseline) at treatment failure may reflect tumor aggressiveness and resistance biology. We evaluated the prognostic value of ΔTL in mCRC using IPD from twelve randomized first-line trials. Methods: IPD from ATEZOTRIBE, FIRE3, FIRE4, FIRE4.5, MACBETH, ML22011, MOMA, PANAMA, TRIBE, TRIBE2, TRIPLETE, and VALENTINO were pooled. ΔTL was defined as the ratio of the sum of longest target lesion diameters at PD vs baseline, per RECIST. Primary endpoint was OS; secondary endpoints included post-progression survival (PPS). Estimated marginal means were controlled for treatment type. Associations between ΔTL and outcomes were assessed using Cox models adjusted for prespecified baseline tumor burden and clinical covariates (ECOG, age, sex, sidedness, RAS/BRAF status, metastatic patterns, previous therapies). Incremental prognostic value beyond early tumor shrinkage (ETS) and depth of response (DpR) was assessed using likelihood ratio testing. Effect modification by treatment regimen was evaluated using ΔTL × treatment interaction terms for EGFR- vs VEGF-based therapy and for triplet vs doublet-chemotherapy across trials. Results: A total of 4852 patients evaluable for ΔTL were included. Mean ΔTL was 0.63 (SD 0.45) and significantly lower in patients receiving EGFR- vs VEGF-based therapy (0.58 vs 0.66, p<0.001) and triplet vs doublet chemotherapy (0.57 vs 0.67, p<0.001). Lower ΔTL (lower tumor load at PD vs baseline) was associated with better OS (HR 0.58 [95% CI 0.55–0.61], p<0.001) and PPS (HR 0.65 [0.61–0.69], p<0.001) after adjustment for baseline tumor burden and clinical covariates. For OS, ΔTL added prognostic information beyond ETS (likelihood ratio χ² = 282.13, p<0.001) and DpR (likelihood ratio χ² = 121.91, p<0.001). Lower ΔTL was associated with improved OS in patients receiving EGFR- (n = 1609; HR 0.62 [0.58–0.67], p<0.001) and VEGF-based therapy (n = 1916; HR 0.39 [0.35–0.43], p<0.001); doublet (n = 2177; HR 0.61 [0.57–0.65], p<0.001) and triplet (n = 1348; HR 0.34 [0.30–0.38], p<0.001) chemotherapy, with significant ΔTL × treatment interaction (VEGF vs EGFR: HR 0.50 [0.46–0.54], p<0.001; triplet vs doublet: HR 0.60 [0.54–0.66], p<0.001) after adjustment for treatment regimen, RAS/BRAF status and other clinical covariates. Conclusions: TL appears to be a strong, independent prognostic marker for OS and PPS in mCRC. ΔTL seems to vary by biologic and chemotherapy intensity, indicating it captures differential treatment effect/resistance not captured by ORR or PFS. Prospective validation as an early, treatment-sensitive prognostic endpoint is warranted.

Background and Purpose:The multicenter precision oncology registry INFINITY investigated biomarker-driven therapy and outcomes in patients with advanced malignancies not eligible for standard therapy in routine clinical care in Germany. Although programmed cell death (ligand) 1 (PD-(L)1) antibodies have changed the treatment landscape of several malignancies and PD-(L)1 expression level is predictive and therefore often used for treatment selection, existing predictive biomarkers are insufficient to identify patients who will benefit from PD-(L)1 inhibitor-based therapy. This project aimed to identify genomic tumor profiles predicting benefit from anti-PD-(L)1 therapy. Patients and Methods:Patients from the INFINITY registry treated with anti-PD-(L)1 monotherapy were stratified into two cohorts using a case-control design: clinical benefit (treatment duration >182 days) and no clinical benefit (treatment duration 22-63 days). Tumor tissue samples from the virtual biobank were requested from local pathologies and sent to the central pathology for next‑generation sequencing (NGS) using the OncomineTM Comprehensive Assay Plus panel (Thermo Fisher, NGS pan-cancer assay). Results:Of the 26 patients with clinical benefit and 24 patients without clinical benefit, NGS-based genetic tumor profiles were available for 11 and 8 patients, respectively. Only patients with clinical benefit from anti-PD-(L)1 therapy showed genetic alterations in KEAP1, PIK3CA and MRE11. Conclusion:Our analysis revealed a set of three genes (KEAP1, PIK3CA and MRE11) exclusively mutated in patients with clinical benefit from PD-(L)1-inhibitor therapy, possibly representing promising biomarker candidates. Given the small sample size and the heterogeneous tumor types included, these findings are exploratory, and validation in larger, preferably tumor-type-specific cohorts is required before any predictive value can be attributed to these genomic alterations.

INTRODUCTION:Leucine-rich α-2 glycoprotein 1 (LRG1) is a multifunctional pro-inflammatory signaling molecule that has been proposed as a promising biomarker and potential therapeutic target across various types of cancer. Prospective studies investigating LRG1 in breast cancer patients are scarce. The purpose of this study was to investigate whether circulating LRG1 levels are associated with overall survival in patients with metastatic breast cancer. METHODS:The present study encompassed 47 individuals with ER-positive/HER2-negative metastatic breast cancer who were scheduled to receive treatment with CDK4/6 inhibitors in combination with endocrine therapy as a first or second line of treatment. The primary endpoint was 3-year overall survival. Plasma LRG1 levels were measured using an enzyme-linked immunosorbent assay. RESULTS:LRG1 levels were significantly associated with advanced age, C-reactive protein, invasive lobular carcinoma, and the presence of lung metastases. During the 3-year follow-up period, 30% of participants died. Kaplan-Meier analysis based on the optimal cutoff indicated that patients with elevated LRG1 levels had a significantly higher risk of mortality compared to those with lower concentrations (log-rank p = 0.008), with a hazard ratio (HR) of 3.22 [95% CI: 1.32-11.05]; p = 0.013. This association remained significant after adjustment for potential confounders. Similarly, when modeled as a log2-transformed continuous variable, LRG1 levels were also significantly associated with overall survival (HR per doubling = 5.82 [95% CI: 1.35-25.13]; p = 0.018). CONCLUSION:LRG1 significantly predicted 3-year overall survival in patients with metastatic breast cancer, supporting its potential as a prognostic biomarker.

Macrophages are key in maintaining tissue homeostasis and controlling inflammation. To rapidly adapt their phenotype, they rely on JAK-STAT signaling pathways to convert extracellular cytokine cues into transcriptional responses. Understanding how macrophages interpret disease-associated cytokine environments is therefore key for deciphering how inflammation is resolved or sustained.

Artificial intelligence (AI) is rapidly transforming histopathology, with applications ranging from workflow optimisation and quality assurance to tumour diagnosis, grading, biomarker assessment and estimation of prognosis. While numerous AI algorithms have demonstrated promising analytical and clinical performance, pathology laboratories are increasingly adopting commercially available AI systems with regulatory-approval rather than developing their own algorithms. Existing guidance largely focuses on AI development, validation and regulatory approval, with comparatively little practical direction on the local verification, governance and ongoing assurance required for safe routine clinical implementation. This paper proposes a practical framework for the clinical implementation of AI specifically within pathology laboratories. Rather than addressing AI development, it focuses on the responsibilities of laboratories adopting established AI systems into clinical practice. The framework distinguishes AI applications according to their intended clinical function, recognising that diagnostic applications, biomarker evaluation, workflow optimisation and generative AI applications require different implementation, verification, governance and quality assurance strategies. It further distinguishes algorithm validation, local verification and continuous assurance as complementary stages of implementation and advocates a function-based, risk-proportionate approach integrated within existing laboratory quality management systems. Practical recommendations are provided for workflow integration, interoperability, human oversight, user competency, performance monitoring, incident management, software updates and proportionate re-verification throughout the AI operational lifecycle. By extending implementation beyond regulatory approval, this guidance complements existing AI development and regulatory frameworks rather than replacing them. It provides a practical governance framework for pathology laboratories, professional organisations, accreditation bodies, and healthcare providers to support the safe, standardised, and sustainable integration of AI into routine histopathology while maintaining diagnostic quality, patient safety, and clinical governance.

Interferon-γ (IFNγ) is a key cytokine that activates macrophages and is essential for the defence against intracellular pathogens. Beyond its immediate effects, IFNγ also shapes macrophages for subsequent encounters with pathogen-associated molecules by multiple mechanisms, including chromatin remodelling. Here, we employed integrated epigenomic and transcriptomic approaches utilizing primary macrophages from gene-modified mice to explore the role of STAT1 and its naturally occurring isoforms in these processes. Using ChIP-seq for histone modifications (H3K27ac and H3K4me1) and RNA-seq, we demonstrate that STAT1 isoforms differentially modulate macrophage responses to lipopolysaccharide (LPS) following IFNγ conditioning. We provide genetic evidence that STAT1 isoforms exhibit distinct capacities to mediated IFNγ-induced changes in H3K27 acetylation at promoter and enhancer regions, thereby shaping transcriptional responses to LPS. We show that the STAT1β isoform, which lacks the C-terminal transactivation domain (TAD), is unable to mediate the repressive effect of IFNγ on transcriptional regulation by LPS but retains significant collaborative activity. Furthermore, we show that IFNγ attenuates the induction of a subset of antiviral genes and represses LPS-induced negative feedback loops, thereby amplifying the inflammatory response to pathogens. These effects are dependent on the presence of the STAT1 C-terminal TAD, highlighting its importance in fine-tuning the balance between inflammatory and antiviral responses. Our findings uncover isoform-specific roles of STAT1 in IFNγ-driven epigenetic regulation and macrophage conditioning, providing new insights into the control of inflammation and innate immunity.

Cancer patients prone to toxicities might benefit from dose reduction over fixed-dose recommendations. We develop a predictive index to identify patients with increased probability of dose reduction, intolerable toxicities, or therapy discontinuation (hereafter: dose reduction) in metastatic breast cancer (MBC) and compare real-world effectiveness of reduced (RSD) versus full starting dose (FSD) using this index. This analysis included 618 patients with HR-positive, HER2-negative MBC from the prospective, observational, multicenter registry OPAL (NCT03417115), receiving first-line palbociclib (n = 386) or ribociclib (n = 232) plus endocrine therapy. A logistic regression model was employed to derive the predictive index. Inverse probability of treatment weighting was used to emulate a head-to-head comparison of RSD and FSD by analyzing progression-free (PFS) and overall survival (OS). Within 6 months, 215 patients (35%) underwent dose reduction, including 109 (51%) with RSD. Predictors for dose reduction were age ≥65 years and Charlson comorbidity index (CCI) ≥1. Among patients with increased probability of dose reduction (index ≥1: ≥65 years and/or CCI ≥ 1), median PFS and OS were 30.1 [21.7, 54.0] and 57.6 [40.0, NA] months with RSD vs. 29.3 [24.9, 32.0] and 43.1 [38.8, 50.3] months with FSD. For low-probability patients (index = 0: <65 years and CCI = 0), median PFS and OS were 17.6 [9.1, 29.8] and 32.9 [23.1, 40.9] months with RSD vs. 24.5 [19.8, 32.0] and 54.2 [48.8, NA] months with FSD. In this real-world MBC setting, patients ≥65 years and/or with CCI ≥ 1 had an increased probability of dose reduction and may benefit from RSD, as this yielded outcomes comparable to FSD. Younger, fitter patients may require full dosing. Future studies, ideally randomized controlled trials, should aim to confirm these findings.

Zusammenfassung Brustkrebs ist gekennzeichnet durch genetische Heterogenität, die durch erbliche und erworbene Faktoren geprägt ist. Molekulare Marker zu identifizieren, kann heutzutage individualisierte, zielgerichtete Therapien ermöglichen.Trotz wachsenden Bewusstseins für die Bedeutung hierfür werden einfach verfügbare molekulargenetische Testungen oft nicht genutzt – somit bleibt ein relevanter Teil an Therapieoptionen für Patientinnen unzugänglich.

e15565 Background: Metastatic colorectal cancer (mCRC) has a poor prognosis and is a major burden to patients and healthcare systems. In the last decades, the therapeutic landscape of mCRC has evolved, improving overall survival (OS). Conditional survival estimates prognosis among patients who already survived a defined period, which can guide individual risk assessment and treatment decisions in the course of disease. Analysis of conditional OS and progression-free survival (PFS) in a large cohort of mCRC patients receiving first-line systemic treatment is lacking. Methods: We analyzed data of mCRC patients from the safety analysis set of 12 randomized controlled trials. Patients with incomplete data, MSI-H patients and patients who received immune checkpoint inhibitors in first line treatment were excluded. OS was calculated from time of randomization or registration until death. PFS was calculated from time of randomization or registration until progression or death, whichever occurred first. Conditional survival was estimated among patients alive and/or progression-free at predefined landmarks (12, 24, and 36 months). Survival was assessed using the Kaplan-Meier method and Cox proportional hazard modeling. The Benjamini-Hochberg method was used to adjust for multiple testing. Results: 3,507 patients from the initial cohort met the inclusion criteria and were analyzed. Mean age was 61.5 years and 64.1% were male. Median follow-up was 50.7 months. Details of conditional survival estimates of patients in our cohort are summarized in table 1. Interestingly, the “remaining” OS ranged from 20-27 months, irrespective of the landmark analyzed. In patients with PFS > 24 months, only history of local or surgical treatment of metastases in the first 24 months (HR 0.31, p < 0.001) and only one organ initially involved with metastases (HR 0.54, p = 0.022) were significantly associated with ongoing conditional OS. Conclusions: Conditional OS of mCRC patients alive at predefined OS landmarks remained stable with increasing OS time. Furthermore, conditional OS and PFS improved substantially in patients with PFS > 24 months after first-line treatment. In this small, but significant fraction of patients, initial local or surgical treatment might be the key factor of long survival. OS/PFS landmark Proportion surviving (OS) [%] Proportion surviving (PFS) [%] median cOS (OS-conditioned) median cOS (PFS-conditioned) median cPFS (PFS-conditioned) 0 100.0 100.0 27.29(26.16 - 28.03) 27.29(26.16 - 28.03) 10.53(10.26 - 10.81) 12 83.2 42.4 19.68(18.77 - 21.16) 32.29(30.6 - 34.97) 6.11(5.65 - 6.71) 24 55.6 13.4 19.65(18.29 - 21.29) 81.38(47.1 - NE) 18.97(15.35 - 25.53) 36 36.2 7.9 20.97(19.19 - 23.93) 69.38(NE - NE) 32.06(31.3 - NE) cOS, conditional OS; cPFS, conditional PFS; NE, not estimable. Time is reported in months. 95% confidence intervals are indicated in brackets.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy are the preferred choice for first-line treatment of patients with HR+/HER2- locally advanced/metastatic breast cancer (aBC). The CDK4/6i ribociclib in combination with an aromatase inhibitor (AI) or fulvestrant (FUL) has demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits for pre- and postmenopausal aBC patients who were enrolled in the three pivotal MONALEESA trials. Following the initial approval of ribociclib in 2017, the non-interventional RIBANNA study was initiated to evaluate the effectiveness and safety of ribociclib plus AI/FUL therapy among patients with aBC in a real-world setting. Two additional treatment cohorts (endocrine monotherapy [ET] and chemotherapy [CT]) were included to extend the knowledge about current aBC treatments. A total of 2567 patients were enrolled in 279 study centers, of whom 1852 were treated with ribociclib+AI/FUL, 183 were treated with ET, and 139 were treated with CT, who were available for effectiveness analyses. Median PFS (mPFS) and median OS (mOS) on first-line treatment with ribociclib+AI/FUL were 35.0 and 76.0 months, respectively. Adjustment for differences in demographic and baseline characteristics resulted in a longer mPFS on ribociclib+AI/FUL (34.7 months) compared to ET (26.4 months) or CT (19.2 months). Adverse events (AEs) on ribociclib were consistent with those seen in the pivotal trials, and no new safety signals were observed. The RIBANNA study confirmed the PFS and OS benefit seen in the MONALEESA trials. Together with the safety data, this large real-world dataset supports the favorable risk/benefit profile of ribociclib in large scale patient populations.

Borderline breast lesions (B3 lesions, also termed lesions of uncertain malignant potential or high-risk lesions) represent a heterogeneous group of entities associated with variable risks of malignancy. While the management of screen-detected B3 lesions has become increasingly standardised, no dedicated international recommendations exist for symptomatic B3 lesions, despite them posing a distinct clinical challenge. Symptomatic lesions differ from screen-detected lesions in their mode of presentation, lesion characteristics, biopsy techniques, and diagnostic objectives; consequently, management strategies derived from screening populations may not be directly applicable. This review summarises the current evidence and proposes a pragmatic management framework for B3 lesions encountered in the symptomatic setting (defined as those presenting with breast symptoms outside population-based screening programmes). This is particularly relevant for patients under 50 years of age, where the primary objective is to exclude malignancy at the index site rather than solely to stratify long-term cancer risk. Clinical-radiological-pathological concordance and multidisciplinary assessment are central to management decisions. Lesions presenting as palpable abnormalities (which are typically larger) or those demonstrating radiological-pathological discordance warrant a lower threshold for additional sampling or excision. Conversely, selected concordant lesions without atypia may be managed conservatively following adequate sampling. The long-term cancer risk associated with epithelial atypia should also be considered with subsequent risk-based surveillance implemented where appropriate. Overall, management requires a risk-adapted, multidisciplinary approach integrating pathological, radiological, and clinical factors alongside patient symptoms and quality-of-life considerations. Given the limited evidence, current recommendations rely on expert consensus and a proposed practical framework. They underscore the need for large-scale, high-quality studies with long-term follow-up to establish formal clinical guidelines.

Not all patients with advanced pancreatic cancer (PC) profit from 2nd-line chemotherapy. We evaluated predictive factors that are routinely collected during clinical care with the aim to support an informed and shared decision. In a prospective study across 35 German sites, 151 patients with PC previously treated with gemcitabine/nab-paclitaxel were enrolled and 146 patients received biweekly nanoliposomal irinotecan/5-fluorouracil/FA. We investigated whether time-to-treatment-failure of 1st-line (TTF1) predicts 2nd-line treatment outcome. Patients were stratified into three equal cohorts based on TTF1. Primary endpoint was TTF2, with secondary endpoints including overall survival (OS) and growth modulation index (GMI). Median TTF2 was 3.71 months (95

3543 Background: BRAF V600E mutation in metastatic colorectal cancer (mCRC) is associated with poor prognosis. Registrational approval of anti-EGFR antibodies does not exclude their use in BRAF V600E mutated (mut) mCRC, while current guidelines explicitly advise against the use of anti-EGFR-directed therapy and recommend the use of chemotherapy plus anti-VEGF antibodies. The present analysis of single-patient data evaluates the therapeutic benefit from anti-EGFR- vs. anti-VEGF-directed therapy in BRAF V600E mut mCRC. Methods: We conducted a pooled analysis of eight first-line AIO-studies (FIRE-1, FIRE-3, FIRE-4, FIRE-4.5, CIOX, XELAVIRI, PANAMA, VOLFI) including 251 evaluable pts with BRAF V600E mut and RAS wild-type mCRC. Right-sided primary tumors (RSPT) included tumors from the caecum to the colon transversum, while left-sided tumors (LSPT) included the splenic flexure to the rectum. Results: Of 251 BRAF V600E mut pts, exact primary tumor location was available in 230 pts. In this cohort, 117 were male (50.9%) and 113 female (49.1%). LSPT was observed in 106 (46.1%) pts compared to 124 (53.9%) with RSPT. In the entire cohort, median OS (mOS) of LSPT vs. RSPT did not differ significantly (15.2 months vs. 13.4 months; HR 0.96; 95% CI, 0.70–1.29; P=0.77). Pts with LSPT showed a numerical survival benefit with anti-EGFR therapy compared to anti-VEGF therapy (17.8 months vs. 11.8 months; HR 0.71; 95% CI, 0.45–1.14; P=0.16). This effect was observed independent of sex. In contrast, pts with RSPT showed a trend towards inferior outcome with anti-EGFR vs. anti-VEGF therapy (11.6 months vs. 17.1 months; HR 1.31; 95% CI, 0.84–2.05; P=0.23). This effect was primarily driven by females, who experienced a significant survival disadvantage with anti-EGFR therapy (10.2 months vs. 17.1 months; HR 1.85; 95% CI, 1.05–3.25; P=0.031). For males, however, both anti-VEGF and anti-EGFR antibodies were associated with comparable outcome. Conclusions: The present analysis performed in the first-line treatment of BRAF V600E mut mCRC suggests a survival benefit from anti-EGFR antibodies in pts with LSPT, independent of gender. Male pts with RSPT appear to derive comparable benefit from anti-EGFR and anti-VEGF antibodies, while female pts exhibit a survival disadvantage from anti-EGFR antibodies. Clinical trial information: NCT00433927 (FIRE-3), NCT02934529 (FIRE-4), NCT04034459 (FIRE-4.5), NCT01249638 (ML22011), NCT00254137 (CIOX), NCT01991873 (PANAMA), NCT01328171 (VOLFI). [clinicaltrials.gov].