KRAS (Kristen rat sarcoma viral oncogene homolog) mutations occur in approximately 40–50% of metastatic colorectal cancer (CRC) cases and have long been associated with resistance to anti-epidermal growth factor receptor (EGFR) therapies and poor clinical outcomes. Historically considered “undruggable”, KRAS has recently become a viable therapeutic target following the development of allele-specific inhibitors. The approval of KRAS G12C inhibitors such as sotorasib and adagrasib represents a major milestone, demonstrating clinical activity and improved outcomes compared with standard therapies in the molecularly defined subset. However, single-agent activity remains modest in CRC due to adaptive resistance mechanisms, including compensatory activation of EGFR and downstream signalling pathways. Combination strategies, particularly co-targeting of EGFR and KRAS G12C, have shown enhanced efficacy and are redefining treatment paradigms. Beyond G12C, newer approaches aim to broaden therapeutic coverage through next-generation KRAS inhibitors, pan-RAS or RAS(ON) inhibitors, and allele-specific agents targeting KRAS G12D and KRAS G12V. Additional strategies incorporating Src homology region 2-containing protein tyrosine phosphatase-2 (SHP2), son of sevenless homolog 1 (SOS1), or mitogen-activated protein kinase (MEK) inhibition, as well as emerging immune-based therapies, hold promise in overcoming resistance and improving durability of response. This review summarises recent advances in targeting KRAS-mutant CRC, explores mechanisms of therapeutic resistance, and highlights ongoing efforts to expand precision-based strategies across diverse KRAS alterations.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and high resistance to chemotherapy. Doxorubicin is commonly used, but its efficacy is limited by variable sensitivity and resistance. Bacopaside II, a saponin compound, has shown anti-cancer potential. This study evaluates the effects of doxorubicin and bacopaside II, both individually and in combination, across TNBC subtypes to explore mechanisms of resistance and enhanced drug efficacy. Methods: The growth-inhibitory effects of doxorubicin and bacopaside II were assessed in four TNBC cell lines. IC50 values were determined using dose–response assays, and doxorubicin accumulation was measured via spectral flow cytometry. ATP-binding cassette (ABC) transporter expression (ABCB1, ABCC1, ABCC3, and ABCG2) was analyzed for correlations with drug sensitivity. In silico docking assessed the binding affinity of bacopaside II to ABC transporters. A 3D culture model simulated drug-resistant TNBC, and combination effects were evaluated with live-cell imaging. Results: Doxorubicin sensitivity varied across TNBC molecular subtypes, correlating to intracellular accumulation. Bacopaside II inhibited growth across subtypes, inducing apoptosis in sensitive cells and necrosis in resistant cells. Bacopaside II increased doxorubicin accumulation, independent of P-glycoprotein (ABCB1), possibly through interactions with other ABC transporters. In drug-resistant 3D cultures, bacopaside II maintained efficacy and enhanced doxorubicin accumulation, counteracting ABC transporter-mediated resistance. The doxorubicin and bacopaside II combination showed synergistic growth inhibition. Conclusions: Bacopaside II enhances doxorubicin efficacy in TNBC by increasing drug accumulation and overcoming ABC transporter-mediated resistance, suggesting its potential as an adjuvant in TNBC treatment. These findings support further investigation of bacopaside II, particularly for resistant TNBC subtypes.

INTRODUCTION:Neoadjuvant therapy has been proposed as a safe and effective treatment option for resectable colon cancer, providing several advantages over the current standard adjuvant protocol. AREAS COVERED:This review summarizes the recent developments in neoadjuvant strategies for resectable colon cancer, highlighting key clinical trial data, current and emerging challenges, and the role of precision medicine in guiding treatment. Sources for this review were obtained through searches of PubMed, ClinicalTrials.gov, and relevant conference abstracts. EXPERT OPINION:Neoadjuvant therapy is emerging as a promising approach for treating colon cancer, especially for dMMR/MSI-H colon cancer where neoadjuvant immunotherapy have shown exceptional complete pathologic response rates and durable responses. Ongoing trials are focused on identifying optimal treatment approaches that balance oncological efficacy with the minimization of toxicity. A reliable multimodal evaluation framework incorporating advanced staging techniques and biomarkers such as circulating tumor DNA is essential to guide treatment and improve patient selection.

INTRODUCTION:Resection of primary tumor and liver metastases is the gold standard for colorectal cancer with liver-only metastases (CRLM). Although treatment options have expanded to enable conversion of unresectable to resectable CRLM, about 40% of patients will have definitively unresectable disease. Major advances in surgical techniques, immunosuppressive protocols and patient selection criteria for liver transplantation have resulted in improved outcomes. AREAS COVERED:A literature search has been conducted in Pubmed for articles published between 2014 and 2024. This review paper comments on current liver-directed treatment options for CRLM: resection, percutaneous ablation, conversion-chemotherapy, TACE, SIRT, and SABR. We explore evidence for liver transplantation in patients with unresectable CRLM, comment on possible limitations for implementation in clinical practice and give an overview of the current guidelines on liver transplantation in the USA, Europe, the United Kingdom, and Australia/New Zealand. EXPERT OPINION:The recent randomized TRANSMET trial, investigating liver transplantation versus chemotherapy in unresectable CRLM, shows promising 5-year OS reaching similar values as for other accepted liver transplantation indications. Further investigations with RCTs to investigate reproducibility and feasibility in clinical practice are needed. Before liver transplantation can be implemented as a standard treatment option, reorganizations at federal, regional and hospital levels would be required.

The breast tissue microbiome has been increasingly recognized as a potential contributor to breast cancer development and progression. However, inconsistencies in microbial composition across studies have hindered the identification of definitive microbial signatures. We conducted a systematic review and meta-analysis of 11 studies using 16S rRNA sequencing to characterize the bacterial microbiome in 1260 fresh breast tissue samples, including normal, mastitis-affected, benign, cancer-adjacent, and cancerous tissues. Studies published until 31 December 2023 were included if they analyzed human breast tissue using Illumina short-read 16S rRNA sequencing with sufficient metadata, while non-human samples, non-breast tissues, non-English articles, and those lacking metadata or using alternative sequencing methods were excluded. We also incorporated microbiome data from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort to enhance our analyses. Our meta-analysis identified Proteobacteria, Firmicutes, Actinobacteriota, and Bacteroidota as the dominant phyla in breast tissue, with Staphylococcus and Corynebacterium frequently detected across studies. While microbial diversity was similar between cancer and cancer-adjacent tissues, they both exhibited a lower diversity compared to normal and mastitis-affected tissues. Variability in bacterial genera was observed across primer sets and studies, emphasizing the need for standardized methodologies in microbiome research. An analysis of TCGA-BRCA data confirmed the dominance of Staphylococcus and Corynebacterium, which was associated with breast cancer proliferation-related gene expression programs. Notably, high Staphylococcus abundance was associated with a 4.1-fold increased mortality risk. These findings underscore the potential clinical relevance of the breast microbiome in tumor progression and emphasize the importance of methodological consistency. Future studies to establish causal relationships, elucidate underlying mechanisms, and assess microbiome-targeted interventions are warranted.

Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently utilised in later-line therapy for metastatic colorectal cancer, with a unique mechanism of action and clinical activity in patients with prior FP failure. Preclinical data demonstrates synergistic activity with panitumumab or irinotecan, providing rationale for its use in earlier lines of treatment. PIT was a non-randomised, phase IB/II study determining the safety and tolerability of TT combined with panitumumab and irinotecan for first- or second-line management of RAS wildtype metastatic colorectal cancer. Methods: The part IB dose escalation study enrolled 3 patients before the MTD was determined from other published work. TT was dosed orally, BID 25 mg/m2 on days 1–5, with 6 mg/kg panitumumab and 180 mg/m2 irinotecan administered intravenously on day 1 of 14-day cycles. The phase II expansion study aimed to enrol 50 patients, with the primary endpoint modified to toxicity. Results: This study closed early due to slow recruitment, with the enrolment of 14 patients. Thirteen received PIT as first-line therapy for metastatic disease. A total of 64% experienced grade 3 toxicity (predominantly rash, electrolyte disturbances, diarrhoea, and neutropenia). One patient experienced grade 4 neutropenia, and there was one treatment-related death (neutropenic sepsis). At a median follow-up of 36 months, 12 patients had evaluable disease (PR: 58%; SD: 42%), with a 6-month PFS of 91%, a median PFS of 18.2 months, a median OS of 41.3 months, and a 12-month OS of 57%. Conclusions: The toxicity profile was notable for high rates of grade 3 rash and diarrhoea. Whilst the small patient numbers limit interpretation, there is a significant signal of activity for this combination, supporting this concept for future trials (ANZCTR number: ACTRN12617001190392, 2017 Aug 15).

Secreted Frizzled-Related Protein 5 (SFRP5) modulates Wnt signalling pathways, affecting diverse biological processes. We assessed the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC). Plasma cSFRP5 concentrations were measured using ELISA in healthy donors (n=133), individuals diagnosed with CRC (n=449), colorectal polyps (n=85), and medical conditions in other organs including cancer, inflammation, and benign states (n=64). Patients with CRC, polyps, and other conditions showed higher cSFRP5 levels than healthy individuals (p<0.0001). Receiver operating characteristic curves comparing healthy donors with medical conditions, polyps, and CRC were 0.814 (p<0.0001), 0.763 (p<0.0001), and 0.762 (p<0.0001), respectively. In CRC, cSFRP5 correlated with patient age (p<0.0001), tumour stage (p<0.0001), and histological differentiation (p=0.0273). Levels peaked in stage II versus I (p<0.0001), III (p=0.0007), or IV (p<0.0001), and were higher in stage III versus I (p=0.0007) and IV (p=0.0054), with no difference between I and IV. Elevated cSFRP5 levels predicted longer overall survival in stage II-III CRC (univariate: HR 1.82, 95% CI 1.02-3.26, p=0.024; multivariable: HR 2.34, 95% CI 1.12-4.88, p=0.015). This study confirms elevated cSFRP5 levels in CRC and reveals a correlation between elevated cSFRP5 and overall survival in stage II-III disease. Novelty and Impact Our study unveils the clinical significance of circulating Secreted Frizzled-Related Protein 5 (cSFRP5) as a potential diagnostic and prognostic marker in colorectal cancer (CRC). Analysing plasma from 731 participants, we provide novel insights into cSFRP5, observing elevated levels in CRC compared to healthy controls, with the highest concentrations in stage II. Importantly, elevated cSFRP5 levels correlate with prolonged survival in stage II-III patients, suggesting a promising avenue for improving outcomes and reducing recurrence. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by AusHealth (Grant number RES-SFRP-01). Author Runhao Li has received an International PhD scholarship from The University of Adelaide. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Human Research Ethics Committee of Central Adelaide Local Health Network gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon reasonable request. * (AUROC) : area under the receiver operating characteristic (cSFRP5) : circulating SFRP5 (CRC) : colorectal cancer (CRD) : cysteine-rich domain (ELISA) : enzyme-linked immunosorbent assay (dMMR) : mismatch repair deficiency (pMMR) : mismatch repair proficient (NTR) : netrin-like domain (SFRP5) : secreted frizzled-related protein 5

Background: Secreted Frizzled-Related Protein 5 (SFRP5) modulates Wnt signalling pathways, affecting diverse biological processes. We assessed the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC) Methods: Plasma cSFRP5 concentrations were measured using enzyme-linked immunosorbent assay (ELISA) in healthy donors (n = 133), individuals diagnosed with CRC (n = 449), colorectal polyps (n = 85), and medical conditions in other organs including cancer, inflammation, and benign states (n = 64). Results: Patients with CRC, polyps, and other conditions showed higher cSFRP5 levels than healthy individuals (p < 0.0001). Receiver operating characteristic curves comparing healthy donors with medical conditions, polyps and CRC were 0.814 (p < 0.0001), 0.763 (p < 0.0001) and 0.762 (p < 0.0001), respectively. In CRC, cSFRP5 correlated with patient age (p < 0.0001), tumour stage (p < 0.0001), and histological differentiation (p = 0.0273). Levels, adjusted for patient age, sex, plasma age and collection institution, peaked in stage II versus I (p < 0.0001), III (p = 0.0002) and IV (p < 0.0001), were lowest in stage I versus III (p = 0.0002) and IV (p = 0.0413), with no difference between stage III and IV. Elevated cSFRP5 levels predicted longer overall survival in stages II-III CRC (univariate: HR 1.82, 95% CI: 1.02-3.26, p = 0.024; multivariable: HR 2.34, 95% CI: 1.12-4.88, p = 0.015). Conclusion: This study confirms cSFRP5 levels are elevated in CRC compared to healthy control and reveals a correlation between elevated cSFRP5 and overall survival in stages II-III disease.

e15532 Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently used in later line therapy. Preclinical data have demonstrated synergistic activity when panitumumab (Pmab) or irinotecan (Ir) are combined with TT supporting use in combination schedules in early line protocols. PIT was a phase IB/II study determining the maximum tolerated dose (MTD), safety and tolerability of substituting FP with TT, combined with Pmab and Ir in RAS wild-type mCRC. Methods: Phase IB 3+3 design dose escalation study (Dose level 1: TT 20mg/m2 oral BD, Ir 150mg/m2 IV, Pmab 6mg/m2). Primary objective was MTD of the combination in RAS WT mCRC patients, either 1 st or 2nd line. Treatment was administered in 14-day cycles. Pmab and Ir were administered intravenously on day 1 with TT dosed orally, bid, days 1-5. Once MTD was established the phase II expansion study was to enrol 50 previously untreated mCRC patients. Primary endpoint was modified to toxicity. Results: The study closed due to slow recruitment. 14 patients were enrolled from 6/18 to 10/21. Med follow up 23 months. Med age 59 yrs (range 37-74yrs). 60% were male. One patient each was BRAF MT and right sided. ECOG 0/1 50%/50%. Thirteen patients had PIT as first line, 57% had prior adjuvant therapy. There was one DLT in first 3 patients however based on additional toxicity data (Clin Cancer Res. 2020 Apr 1:1555) a decision was made to not dose escalate beyond level 1 and commence phase II. Overall Gd 3 toxicity: Acne/rash 46%, Diarrhoea 31%, Fatigue 8%, neutropenia 15%, hypomagnesaemia 23%. One patient had Gd 4 neutropenia and there was one treatment related death (neutropenic sepsis). 12 patients had evaluable disease, 58% PR, 42% SD. Survival: Med PFS 14.1 mths, Med OS 40.6mths and 12 mth OS 64%. Conclusions: The MTD was deemed TT 20mg/m2, irinotecan 150mg/m2 and panitumumab 6mg/kg. Toxicity was manageable however significant grade 3 diarrhoea and rash was seen. There was one toxic death contributed to therapy. Small numbers do make interpretation difficult however there is a signal of activity. The slow recruitment illustrates difficulty in exploring novel combinations in early lines and potentially the reluctance to consider first line anti-EGFR therapy. Clinical trial information: ACTRN12617001190392.

IntroductionThe outcome of patients with metastatic colorectal cancer (mCRC) has improved significantly in the last few decades. Metastatic colorectal cancer is a highly heterogenous cancer. Beyond second line chemotherapy, treatment decisions are often based on molecular testing.MethodIn this narrative review, we provide a comprehensive summary of data from key clinical trials and discuss how to integrate these agents into the current treatment landscape of metastatic colorectal cancer.Expert OpinionIn the era of precision medicine, molecular testing plays an increasingly important role in the management of mCRC. Efforts need to be made to target treatment based on molecular test results.

BACKGROUND:Colorectal cancer with synchronous liver-only metastasis is managed with a multimodal approach, however, optimal sequencing of modalities remains unclear.METHODS:A retrospective review of all consecutive rectal or colon cancer cases with synchronous liver-only metastasis was conducted from the South Australian Colorectal Cancer Registry from 2006 to 2021. This study aimed to investigate how order and type of treatment modality affects overall survival.RESULTS:Data of over 5000 cases were analysed (n = 5244), 1420 cases had liver-only metastasis. There were a greater number of colon than rectal primaries (N = 1056 versus 364). Colonic resection was the preferred initial treatment for the colon cohort (60%). In the rectal cohort, 30% had upfront resection followed by 27% that had chemo-radiotherapy as 1st line therapy. For the colon cohort, there was an improved 5-year survival with surgical resection as initial treatment compared to chemotherapy (25% versus 9%, P < 0.001). In the rectal cohort, chemo-radiotherapy as the initial treatment was associated with an improved 5-year survival compared to surgery or chemotherapy (40% versus 26% versus 19%, P = 0.0015). Patients who were able to have liver resection had improved survival, with 50% surviving over 5 years compared to 12 months in the non-resected group (P < 0.001). Primary rectal KRAS wildtype patients who underwent liver resection and received Cetuximab had significantly worse outcomes compared to KRAS wildtype patients who did not (P = 0.0007).CONCLUSIONS:Where surgery is possible, resection of liver metastasis and primary tumour improved overall survival. Further research is required on the use of targeted treatments in patients undergoing liver resection.

Kaplan-Meier Survival Curves for Biomarker Substudy (n=33)

e15577 Background: Treatment of mCRC has changed dramatically over the last decade with therapy guided by clinical and molecular features which include side of primary, RAS, BRAF and MMR status. For left sided RAS WT mCRC survival is optimized by using first line anti-EGFR anti-bodies combined with chemotherapy. This is reflected in modern guidelines. Methods: We aim to assess the uptake of first line anti-EGFR/chemotherapy combinations in patients with mCRC and assess for difference between cetuximab (C) and panitumumab (P) use from the SAmCRCR. The real word registry has collected data from all patients diagnosed with mCRC in SA prospectively since 2/2006. We compared RAS WT patients treated with chemo/bevacizumab (CB). Survival was analysed using the Kaplan Meier method. Results: Of the 5537 patients currently entered onto the registry, only 97 had RAS status recorded and had received first line anti-EGFR/chemotherapy (FaEC). 102 patients were RAS WT and received CB. Table summarises patient characteristics and median OS for FaEC (C or P) and CB. There was no statistical difference in survival for C v P (p = 0.055). Conclusions: When comparing C & P choice in first line therapy, C was more often combined with irinotecan/chemo. C patients had higher rate of left sided primary. There were lower rates of liver resection in patients treated with C which may explain the numerically lower median overall survival. An updated cohort analysis will be included to assess changes in practice over time.[Table: see text]

Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. We correlated cetuximab plasma concentrations after 4 weeks of treatment with survival and toxicity. Plasma cetuximab concentration was associated with OS (HR 0.66, 95% CI: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea. The standard cetuximab dosing regimen may not be optimal for all patients.Background: Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity.Methods: The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m(2) intravenously followed by weekly maintenance of 250 mg/m(2), plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables.Results: Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea.Conclusion: The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS.

BACKGROUND:Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals.AIMS:To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia (SA).METHODS:Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio-Economic Advantage and Disadvantage were analysed.RESULTS:A total of 3470 patients' data was analysed during February 2006-January 2015. The majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for Index of Relative Socio-Economic Advantage and Disadvantage score were more likely to receive treatment at a private hospital (41.2% vs 21.56%) compared to <50%. Public patients had higher burden of disease (10.49% vs 7.41%, P = 0.005). Public patients received less treatment compared to the private patients (odds ratio = 0.48 (0.38-0.61), P = 0.01) and rates of surgical resections were lower in public patients. After adjusting for the covariates, public patients survive 1.33 months (P = 0.025) shorter than private patients with follow-up time of 5 years. Patients receiving metastasectomy and more than three lines of treatment were shown to have the greatest survival benefit.CONCLUSION:Public patients have a higher burden of disease and in comparison are less likely to receive systemic therapy and have lower survival than patients treated in private hospitals.

Background Effective targeting of RAS mutations has proven elusive until recently. Novel agents directly targeting KRAS G12C have shown promise in early-phase clinical trials that included patients with metastatic colorectal cancer. Prior reports have suggested that G12C mutation may be predictive of poor outcome. Objective Assessment of the specific characteristics and prognostic implications of individual RAS mutation subtypes in patients with metastatic colorectal cancer. Patients and methods Retrospective review of individual RAS mutation types from the South Australian Metastatic Colorectal Registry between 2006 and 2020. Results Of the 5165 patients entered onto the registry, 2305 (45%) had RAS mutation results available. 772 (33%) had a RAS mutation. The nature of the RAS mutation was available in 668 (87% of those with RAS mutation). Rare mutations (outside codons 12 and 13) made up 12.6% of the total. There were numerical differences in survival between the specific RAS mutation subgroups, with the longest median overall survival (30 months) observed in those with G12S mutations. However, there was no statistical difference in survival when comparing the various RAS mutations, including the comparison of G12C to G12S ( p = 0.38). Patients with cancer harbouring rare RAS mutations had a median survival of 30 months. Conclusions Whilst the G12S mutation was associated with the longest survival numerically, the observed survival for patients with the most common RAS mutations (G12C, G12V, G12A, G12D and G13D) did not significantly differ.

TPS5600 Background: KIF18A is a mitotic kinesin motor protein that regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. TP53 mutant unstable aneuploid cancer cells with chromosomal instability (CIN) features are dependent on KIF18A motor activity to prevent lethal multipolar cell division. Preclinical data demonstrate that treatment with AMG 650; an oral, first in class, selective small molecule inhibitor of KIF18A may be safe and tolerable. We are conducting a first-in-human phase 1 study with AMG 650 in adult subjects with locally advanced or metastatic solid tumors with TP53MUT, triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC) or serous like endometrial cancers and other solid tumors. Methods: In this phase 1, multicentric, dose escalation and dose expansion study we evaluate the safety and tolerability of AMG 650 monotherapy in patients with advanced/metastatic solid tumors (NCT04293094). The main objective is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) based on emerging safety, efficacy, and pharmacodynamics (PD) data prior to reaching the MTD. Key inclusion criteria include the presence of measurable disease and diagnosis of advanced/metastatic triple negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC), serous-like endometrial cancer or other solid tumors with documented TP53 mutations. In the dose expansion phase, participants with locally advanced or metastatic TNBC or HGSOC will be treated with the preliminary RP2D identified from the dose exploration part of the study. Primary endpoints include the incidence of Dose Limiting Toxicities (DLTs),Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment-related Adverse Events and the evaluation of the number of participants who experience a clinically significant change from baseline in vital signs, electrocardiogram and laboratory tests parameters. Secondary endpoints include Objective Response Rate, Duration of Response, Progression-free Survival, Clinical Benefit Rate, Time to Response, Time to Progression, Overall Survival (OS), Maximum Plasma Concentration (Cmax) of AMG 650, Time to Maximum Plasma Concentration (Tmax) of AMG 650 as well as Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval for AMG 650. Continuous monitoring of toxicity is conducted. The study began enrolling pts in March 2020 and is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com Clinical trial information: NCT04293094.

Colorectal cancer (CRC) incidence in young adults is rising. Identifying genetic risk factors is fundamental for the clinical management of patients and their families. This study aimed to identify clinically significant germline variants among young adults with CRC. Whole‐exome sequencing data of blood‐derived DNA from 133 unrelated young CRC patients (<55 years of age) underwent a comprehensive analysis of 133 cancer‐predisposition/implicated genes. All patient tumors were evaluated for mismatch repair deficiency (dMMR). Among 133 patients (aged 16–54 years), 15% (20/133) had clinically actionable pathogenic or likely pathogenic (P/LP) variants in at least 1 well established cancer‐predisposing gene: dMMR genes (6), MUTYH [bi‐allelic (2), mono‐allelic (3)], RNF43 (1), BMPR1A (1), BRCA2 (4), ATM (1), RAD51C (1), and BRIP1 (1). Five patients (4%) had variants in genes implicated in cancer but where the significance of germline variants in CRC risk is uncertain: GATA2 (1), ERCC2 (mono‐allelic) (1), ERCC4 (mono‐allelic) (1), CFTR (2). Fourteen (11%) had dMMR tumors. Eighteen (14%) reported a first‐degree relative with CRC, but only three of these carried P/LP variants. Three patients with variants in polyposis‐associated genes showed no polyposis (one each in MUTYH [bi‐allelic], RNF43, and BMPR1A). Approximately one in five young adults in our series carried at least one P/LP variant in a cancer‐predisposing/implicated gene; 80% of these variants are currently considered clinically actionable in a familial cancer setting. Family history and phenotype have limitations for genetic risk prediction; therefore multigene panel testing and genetic counseling are warranted for all young adults with CRC regardless of those two factors.

We previously showed how triterpene saponin bacopaside (bac) II, purified from the medicinal herb Bacopa monnieri, induced cell death in colorectal cancer cell lines and reduced endothelial cell migration and tube formation, and further demonstrated a synergistic effect of a combination of bac I and bac II on the inhibition of breast cancer cell line growth. Here, we assessed the effects of bac I and II on the colorectal cancer HT-29 cell line, and mouse (2H-11) and human umbilical vein endothelial cell (HUVEC) lines, measuring outcomes including cell viability, proliferation, migration, tube formation, apoptosis, cytosolic Ca2+ levels and plasma membrane integrity. Combined bac I and II, each applied at concentrations below IC50 values, caused a synergistic reduction of the viability and proliferation of HT-29 and endothelial cells, and impaired the migration of HT-29 and tube formation of endothelial cells. A significant enhancement of apoptosis was induced only in HUVEC, although an increase in cytosolic Ca2+ was detected in all three cell lines. Plasma membrane integrity was compromised in 2H-11 and HUVEC, as determined by an increase in propidium iodide staining, which was preceded by Ca2+ flux. These in vitro findings support further research into the mechanisms of action of the combined compounds for potential clinical use.