IJMS is retracting the article titled “Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)” [...]

We performed a pilot study in which Illumina (ILMN) and nanopore (ONT) whole genome sequencing (WGS) was generated for samples obtained from a 37-year-old patient with locally advanced rectal cancer who did not respond to neoadjuvant chemoradiotherapy (nCRT). Pre-treatment and post-treatment tumour biopsy, adjacent normal tissue, and matched pre-treatment blood samples were sequenced to identify somatic alterations. We used DNA methylation from ONT WGS to detect changes in the tumour epigenomes compared to adjacent normal tissue. We employed established pipelines for the identification of somatic alterations to assess the concordance of SNV, short indel, copy number and structural variation from the short-read and long-read tumour genome data. Overall, 69.4% and 30.1% of SNVs were concordant between technologies in the pre-and post-treatment tumours, respectively. A multinomial logistic regression was performed to further understand discordant SNV calls, highlighting tumour purity, presence in a repetitive region, strand bias, and germline variant allele frequency as factors contributing to discordance. Indel concordance was poor (26.8% and 9.2% in the pre-and post-treatment tumour, respectively). Copy number alteration profiles were highly similar while minimal concordance was reported for structural variants (2.4% and 0.3% for pre-and post-treatment tumours, respectively). Finally, we used the ONT data to detect DNA modifications (5-methylcytosine and 5-hydroxymethylcytosine) between tumour and matched adjacent normal tissue. Based on genome-wide average CpG modification rates, global hypomethylation was observed in tumours compared to adjacent normal tissues. Biologically relevant epigenomic changes related to epithelial-mesenchymal transition were detected in the post-treatment tumour, as well as potential radiation-induced changes in the post-treatment adjacent normal tissue.

Pancreatic cancer (PDAC) often responds poorly to chemotherapy, represents an unmet clinical need and new therapeutic approaches are urgently required. Desmoplasia is a hallmark of PDAC. Multiple preclinical studies suggest cancer associated fibroblasts (CAF) support cancer growth, and attention has recently turned towards inclusion of anti-stromal agents into chemotherapy trials. Our objective was to evaluate safety and tolerability of oral paricalcitol in combination with systemic chemotherapy in patients with advanced PDAC. This was a phase II, single-arm study in patients with advanced PDAC who had received no prior systemic chemotherapy. Gemcitabine and NAB-paclitaxel were administered weekly for 3 of every 4 weeks (days 1, 8 and 15) and paricalcitol administered orally every day of a 28-day cycle. Patients were treated until disease progression with an interim analysis. The primary efficacy endpoint was progression free survival (PFS). Secondary efficacy endpoints were evaluation of overall survival (OS), time to treatment failure (TTF) and tumour response rate (TRR). Fifteen patients were enrolled. Median PFS was 14.6 weeks with 95

Small Cell Carcinoma of the Ovary (SCCO) is an extremely rare form of ovarian cancer characterised by bi-allelic mutations in the SMARCA4 gene, a member of the SWI/SNF chromatin remodelling complex. Most previous analyses have characterised SCCO using whole exome sequencing; we present the treatment plans of two SCCO patients with post-treatment analysis of whole genome sequencing and tumour RNA sequencing which include structural variant and mutational signature analysis not previously reported in the literature for this cancer type. Both patients underwent salpingo-oophorectomy followed by BEP chemotherapy and pelvic radiotherapy leading to 34 month remission in one case though one patient died 12 months post-diagnosis. Consistent with known aetiology, we identified complete SMARCA4 loss of function and probable SMARCA2 expression loss in both patients. Beyond this, both tumours present remarkably low tumour mutational burdens and were microsatellite stable though one sample also showed chromosomal instability with high levels of inversions and a ploidy level of 2.8 which has not been well characterised in SCCO patients. This report contributes towards the small number of cases of SCCO that are currently documented and have their genome characterised in the literature.

Congenital lipomatous overgrowth, vascular epidermal nevi, and skeletal abnormalities (CLOVES) syndrome is a rare genetic disorder caused by somatic activating mutations in the PIK3CA gene that arise during embryonic development. Mutations in the PI3K-AKT-mTOR pathway have been linked to various benign overgrowth disorders, including syndromes within the PIK3CA-related overgrowth spectrum. Somatic PIK3CA mutations also occur frequently across many cancer types; however, evidence linking CLOVES syndrome to increased cancer risk is not conclusive. Here, we describe a whole-genome sequencing (WGS) study of a primary pT3 high-grade urothelial carcinoma in a 62-year-old male patient diagnosed with CLOVES syndrome. A left laparoscopic nephroureterectomy was completed. Tumour tissue and a matched blood sample were collected for whole-genome sequencing, and somatic variant detection was performed. The somatic alterations were consistent with previous reports of urothelial carcinoma, including homozygous deletions of CDKN2A and CDKN2B. In this case, we could not detect somatic PIK3CA alterations in this patient's urothelial carcinoma and suggest that it is unrelated to CLOVES syndrome.

Tight junction (TJ) proteins, such as Junctional Adhesion Molecule-A (JAM-A), claudins, and occludin, play increasingly recognized roles in cancer biology beyond their structural functions, influencing tumour proliferation, invasion, metastasis and therapy resistance. Understanding how these proteins modulate tumour progression in vivo requires models that are both physiologically relevant and ethically viable. The chick chorioallantoic membrane (CAM) xenograft model has emerged as a powerful and cost-effective in vivo system that aligns with the 3Rs (replacement, reduction, and refinement), offering unique advantages such as vascular accessibility, rapid tumour growth kinetics and immunotolerance. This review explores how the CAM model can be leveraged to study the mechanistic role of TJ proteins in tumour-stroma interactions, angiogenesis, extracellular matrix (ECM) remodelling and mechanotransduction, including the YAP/TAZ pathway. While limitations remain, particularly with respect to immune modelling and long-term studies, recent advances in imaging, genetic manipulation and integration of patient-derived xenografts (PDXs) are expanding the model's translational relevance. Standardizing methodologies and embracing new molecular tools will further elevate the utility of this approach as a complementary platform to traditional rodent models, with significant promise for TJ-focused cancer research and therapeutic innovation.

1542 Background: For patients with advanced non-small cell lung cancer, tumour genotyping identifies actionable variants that inform targeted therapeutic choices, that improve outcomes. Liquid biopsy genotyping (LBG) is a non-invasive approach to tissue biopsy genotyping (TBG) that reduces turnaround, avoids repeat tissue biopsy, and can identify additional actionable variants. However, despite these benefits, patient access to LBG is not universal in a range of healthcare systems. While others have developed models evaluating the cost-effectiveness of LBG, these have are limited by assumptions regarding frequency of oncogenic variants and treatment utilisation. We utilised a micro-costing model (MCM) to quantify the cost/resources of LBG and TBG in a prospective trial ( PLAN; ClinicalTrials.gov Identifier: NCT05542485) aimed at investigating the feasibility of LBG in a tertiary cancer centre. Methods: A deterministic MCM was developed to enumerate the cost to generate a genomics report for both LBG and TBG in NSCLC. Capital costs were calculated based on up-front investment and annual depreciation/maintenance. Costs of consumables and staff time associated with each procedure was sourced from relevant hospital departments (e.g. Medical Physics) and evaluated for accuracy by a health economist and medical oncologist. We calculated the cost of sample acquisition (endobronchial ultrasound-guided biopsy or phlebotomy), processing, and genotyping for both LBG and TBG, from patients enrolled on the PLAN study (n = 100) between 08/2023-07/2024. Finally, we performed an exploratory analysis investigating potential reduction in staff time associated with automated library preparation, using currently available technology. Results: We identified that TBG requires more staff time (€534 vs €330), capital investment (€326 vs €16), and consumables (€1544 vs €788), resulting in an overall increased cost, compared with LBG (€2404 vs €1135). Automation of library preparation would reduce staff time required for LBG (Reduced to €191; 33% reduction) with less of an impact on TBG (Reduced to €485; 10% reduction). This difference was due to the increased wet-lab time with LBG and greater staff time for sample acquisition in TBG vs LBG (€298 vs €8). Finally, in the PLAN study, LBG resulted in cancellation of 12 repeat tissue biopsies, resulting in further savings. Conclusions: LBG is a cheaper alternative to TBG. Our data indicates LBG saves cost in the areas of healthcare staffing and capital infrastructure with further savings made through avoidance of repeat tissue biopsies. Thus, the resources required for LBG and TBG are different and should be considered in service planning for tumour types such as NSCLC in which genotyping is standard-of-care. Clinical trial information: NCT05542485 .

Metastatic meningioma is rare, occurring in less than 1% of patients, and very few case studies have been reported, in particular for those that have spread to the lungs. Here we describe a rare case of metastatic meningioma to the lungs. Following a discussion at a medical oncology multi-disciplinary team meeting, whole genome sequencing was requested in November 2021 and discussed at a neurosurgical molecular tumor board in June 2022. Sequencing was performed on matched longitudinal collected samples of the primary tumor resection, the re-excised recurrent tumor after adjuvant radiation therapy, the lung metastases before treatment with sunitinib, and one paired blood sample for tumor-normal analysis. Whole genome characterization and clonal evolution analysis confirmed neurofibromatosis 2 (NF2) gene loss as the main driver of this cancer. In the same cancer clone as NF2, we identified a BRCA2 (p.E51K) mutation was present in all tumors, which may represent a potential driver event, though evidence supporting this is currently limited. Although this mutation is predicted to potentially influence homologous recombination, its clinical relevance as a biomarker for PARP inhibition remains speculative and requires further investigation. We also noted a SETD2 (p.S1885N) mutation that was present only in the recurrent tumor which was identified as a predicted biomarker of response to WEE1 inhibition. There was a stepwise increase in tumor mutational burden (TMB) from the primary meningioma to lung metastases, suggesting this patient may have been a candidate for immunotherapy.

KMT2C and KMT2D are paralogous lysine-methyltransferases that primarily monomethylate lysine residues at enhancer regions promoting an active transcriptional state. KMT2C and KMT2D are frequently mutated in multiple cancer types and in breast cancers mutations collectively occur at frequencies of 10-20%. However, the specificity and unique functions of the paralogues in breast cancer development are unclear. Using a combination of mutation, transcriptome, ChIP-seq, chromatin accessibility, and cell proliferation data from breast cancer patient and cell line samples we have investigated the roles of these proteins in tumour development. We identified a dependency of oestrogen receptor (ER) positive breast cancer cell lines on wildtype KMT2D. KMT2D ChIP-seq peaks show greater enrichment and interaction with ER and its binding partners FOXA1 and GATA3 compared to KMT2C in MCF-7 cells and uniquely bind enhancers of a set of genes enriched for oestrogen response pathways. Both KMT2C and KMT2D mutant luminal patient samples show significant downregulation of oestrogen response pathways compared to wildtype which, for KMT2C mutants, correlates with reduced chromatin accessibility around enhancers. Our results suggest that KMT2C and KMT2D have contrasting and subtype-specific roles in breast cancers and reveals KMT2D in particular as a potential target in ER + subtypes.

BACKGROUND:We report a pilot clinical trial investigating the feasibility of liquid biopsy genotyping (LBG) at the time of radiological suspicion of advanced NSCLC, incorporating a micro-cost model (MCM). (PLAsma Genomic Testing in Advanced NSCLC; The PLAN trial, ClinicalTrials.gov Identifier: NCT05542485). METHODS:Patients with a radiologic suspicion of stage III-IV lung cancer were recruited from four cancer centres in Ireland between August 2023 and July 2024. LBG was performed using the Archer LiquidplexTM NGS assay. The MCM considered staff time, consumables and capital costs and savings from avoidance of repeat tissue biopsy genotyping (TBG) or inappropriate systemic therapy such as immunotherapy for EGFR + NSCLC. RESULTS:A total of 138 patients were enrolled in the study with 38 excluded from the primary analysis (Squamous=16; SCLC = 22). Of patients that were eligible, LBG was completed in 100 % (100/100). TBG was completed in 68 % (68/100; insufficient tissue 20 %; 20/100; declining ECOG PS 12 %; 12/100). Repeat tissue biopsies were avoided in 12 % (12/100) of patients due to available LBG reports. The median calendar days from LBG to receipt of genomic report was 21 days shorter for LBG (z = -6.8, p < 0.01) versus TBG, as a median (range: 1-104 days). For evaluable paired cases with both TBG and LBG available (n = 68), concordance was 90 % (61/68). LBG resulted in detection of 5 actionable variants. LBG (€1135) was less than half the cost of TBG (€2404). LBG also resulted in overall cost savings of €20,288 (reduced TBG; use of immunotherapy). CONCLUSIONS:LBG reduces the time to genomic diagnosis in patients with newly diagnosed NSCLC compared to tissue genotyping, identifies actionable variants not reported in tissue, and results in overall cost savings.

Lung cancer is the leading cause of cancer-related mortality worldwide, with nonsmall cell lung cancer (NSCLC) accounting for the majority of cases. Despite advancements in therapeutics, outcomes remain poor due to late-stage diagnoses and the molecular complexity of the disease. Liquid biopsy, a minimally invasive diagnostic approach, has emerged as a potentially transformative tool in lung cancer. The detection of tumour-derived biomarkers, such as circulating-tumour DNA, circulating tumour cells and exosomes, can be analysed for molecular profiling, early detection and monitoring of disease progression. There have been significant advancements of liquid biopsy technologies, such as next-generation sequencing and droplet digital PCR, that identify actionable mutations, detect resistance mechanisms and improve therapeutic outcomes. While there are still challenges like detecting early-stage disease and the risk of false positives, the combination of multi-omics data and artificial intelligence has the potential for more personalised and precise cancer treatments. Liquid biopsy represents a paradigm shift in the early detection and personalised treatment of lung cancer, offering significant potential to improve patient outcomes.

TPS849 Background: The diversity of the GM is defined as the number and relative abundance distribution of distinct types of microorganisms colonizing within the gut. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and impacts response to immunomodulating therapies. The influence of the GM diversity on the pathological response after neoadjuvant chemotherapy and radiotherapy is unclear. Some studies have suggested that the GM may offer predictive biomarkers for response to chemoradiation in rectal cancer. Other studies in early-stage rectal cancer patients indicated an association between GM diversity and pathological outcomes following neo-adjuvant therapy (NAT). We hypothesize that a more diverse GM constitution at baseline leads to an improved pathological response at the time of definitive surgery. Methods: We designed a cross-institutional translational study investigating the impact of the GM diversity on the efficacy of NAT in GI cancers by assessing its association with pathological response. The study population includes patients with early-stage rectal or esophageal cancer due to commence NAT (including chemotherapy and chemoradiation) who are planned for definitive surgery. Exclusion criteria includes prior allogenic tissue/solid organ transplantation and prior receipt of anti-cancer therapy. The study assessments include fecal sampling of the GM prior to NAT, upon completion and again six months post completion of therapy. Fecal samples are analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. Exploratory analysis will include the assessment of the association between cf-DNA and the GM diversity as well as an assessment of the association between cf-DNA at baseline and pCR. Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index will be used to calculate beta diversity. Following planned study recruitment, classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. Logistic regression analysis adjusting for potential confounding factors will be employed to assess the primary endpoint of the association between GM and complete pCR in the final statistical analysis. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. This trial accrued 11 patients between May 2023 and Sept 2024. Out of the 11 patients enrolled, 9 patients have undergone their planned surgery. We are expecting to have 30 patients accrued prior to Jan 2025.

Purpose: Adjuvant trastuzumab therapy has improved outcomes in HER2-positive breast cancer, but the impact of the timing of its initiation remains unclear. This study evaluates the effect of time to adjuvant trastuzumab-based therapy (TTAT) after surgery on survival in HER2-positive breast cancer. Methods: In this retrospective study, HER2-positive breast cancer patients treated with surgery followed by adjuvant trastuzumab without prior neoadjuvant therapy were analyzed. Patients were grouped by TTAT ≤ 42 days or >42 days post-surgery. Key endpoints included overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS), evaluated through Kaplan-Meier and Cox regression analyses. Results: Patients with TTAT greater than 42 days had significantly worse OS, DFS, and DMFS (p = 0.036, p = 0.045, and p = 0.048, respectively, log-rank test) than those initiating trastuzumab within 42 days. On multivariate analysis, delays beyond 42 days were associated with a significantly increased risk of recurrence and mortality, showing reduced DFS (HR 2.52; p = 0.027) and OS (HR 4.48; p = 0.004). These findings indicate that even moderate delays in trastuzumab initiation can adversely affect survival. Conclusions: Delaying trastuzumab initiation beyond 42 days post-surgery negatively impacts survival in HER2-positive breast cancer, emphasizing the need for timely treatment. These results support clinical guidelines advocating prompt initiation of adjuvant therapy to improve long-term outcomes for HER2-positive patients.

PURPOSE:Receptor conversion following neoadjuvant therapy in breast cancer may influence prognosis and adjuvant treatment decisions. This systematic review and meta-analysis evaluated the prognostic significance of changes in hormone receptor (HR) and HER2 status after neoadjuvant therapy. METHODS:This study was performed in accordance with PRISMA guidelines. A systematic search of the literature was conducted to identify studies assessing the prognostic effect of receptor conversion after neoadjuvant treatment in breast cancer. Studies reporting receptor status before and after neoadjuvant therapy, with associated survival outcomes, were included. Pooled hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS) were calculated using random-effects models. RESULTS:Twenty-two studies (n = 5370) were included in this meta-analysis. HR gain demonstrated significantly improved DFS (HR 0.49, 95 % CI 0.25-0.97; p = 0.04), but no OS benefit. HR loss was associated with both significantly worse DFS (HR 3.42, 95 % CI 1.93-6.08; p < 0.001) and OS (HR 1.99, 95 % CI 1.04-3.84; p = 0.04). HER2 gain had a negative impact on DFS (HR 1.89, 95 % CI 1.00-3.58; p = 0.05), with no significant effect on OS. HER2 loss was associated with significantly poorer DFS (HR 1.92, 95 % CI 1.51-2.43; p < 0.001) and OS (HR 2.20, 95 % CI 1.44-3.38; p < 0.001). CONCLUSION:This systematic review and meta-analysis demonstrates that receptor conversion following neoadjuvant therapy in breast cancer significantly impacts survival outcomes. Specifically, gaining HR positivity is associated with improved DFS, while losing HR positivity correlates with worse DFS and OS. With regards to HER2, gaining positivity is associated with worse DFS, and losing positivity is associated with worse DFS and OS, compared to patients who maintain their initial status. These findings underscore the potential importance of reassessing receptor status after neoadjuvant therapy to tailor subsequent treatment decisions accurately.

Introduction Low-dose chest CT (LDCT) has demonstrated the ability to detect early-stage lung cancer (LC) and improve disease-specific mortality in high-risk individuals. Use of LC risk scores such as the Prostate, Lung, Colorectal, Ovarian Model Score (PLCOM2012) improves the sensitivity, specificity and positive predictive value for LC screening. Screening programmes have identified that primary care participation, patient engagement and improved accessibility may enhance the success of LC screening. Currently, there is no LC screening programme in Ireland. This first pilot study of LC screening will investigate (1) the feasibility, including uptake, of LC screening in a community setting, based on primary care-based participant invitation with mobile CT scanning and (2) novel blood/breath biomarkers in high-risk individuals who participate in the LC screening trial, to identify biologic parameters that may supplement existing risk scores, to maximise LC early detection.Methods and analysis In a pilot feasibility clinical trial, approximately 30 000 adults aged between 55 and 74 from participating general practitioner (GP) practices will be invited to a ‘lung health check (LHC)’ prescreening, involving a telephone assessment of eligibility and risk status, based on the PLCOM2012/Liverpool Score V.2. High-risk individuals will be invited to the LHC, which will take place in a mobile unit strategically located in the community and include a respiratory disease assessment, baseline spirometry, smoking cessation advice, an LDCT and in a selected cohort, blood/breath/sputum biospecimen collection. Two rounds of screening will take place at an interval of 12 months.Ethics, dissemination and registration details In this pilot feasibility trial, the uptake of LC screening using a community-based strategy among high-risk participants will be investigated. The study has been approved by Beaumont Hospital Research Ethics Committee and is registered with clinicaltrials.gov (NCT07099027). Novel features of our design include directly calling participants and our translational arm of the study, which will focus on blood/breath/sputum biomarkers associated with LC.

Responses to neoadjuvant chemoradiotherapy for locally advanced rectal cancer are not uniform. The phosphatidylinositol-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are involved in tumorigenesis and treatment resistance in many cancers; therefore, targeting these pathways could enhance response to chemoradiotherapy.A panel of colorectal cancer (CRC) cell lines (n = 10) with varying PI3K and MAPK mutational backgrounds were treated with combinations of 5-Flourouracil (5-FU), radiation, the PI3K inhibitor copanlisib, and/or the MEK inhibitor refametinib, and their effects on proliferation in vitro were measured. BALB/c SCID mice were implanted with CRC cell lines representative of each mutational background, treated with copanlisib and/or chemoradiotherapy, and monitored for tumor growth.In vitro, PIK3CA mutated cell lines were most sensitive to copanlisib (IC50=28 nM) and KRAS mutated cell lines were most sensitive to refametinib (IC50 = 36 nM), while the combination of copanlisib and refametinib was synergistic in 9/10 cell lines tested. The addition of copanlisib to 5-FU chemoradiotherapy inhibited cell growth compared to 5-FU chemoradiotherapy alone, an effect that was most notable in LS-1034 (KRAS mutated) and Caco-2 (PIK3CA/KRAS wild-type) cell lines. In vivo copanlisib and 5-FU chemoradiotherapy reduced tumor growth in all xenograft models and increased overall survival in LS-1034 and Caco-2 xenografts.Our results suggest that activation of the kinase signalling pathway may modulate PI3K/MEK inhibitor responsiveness in colorectal cancer. Furthermore, the addition of copanlisib to 5-FU chemoradiotherapy resulted in an enhanced anti-proliferative cytotoxic effect compared to 5-FU chemoradiotherapy alone, regardless of the background mutational status, and supports further clinical development of this regimen.

Background The current standard of care in the neoadjuvant setting for high-risk HER2-positive (HER2 +) breast cancer is to combine systemic chemotherapy with dual HER2 blockade, trastuzumab and pertuzumab. Targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer. To improve treatment-associated toxicity, chemotherapy-sparing approaches are currently being investigated. Trastuzumab deruxtecan (T-DXd) is an HER2-directed antibody–drug-conjugate (ADC) with promising results in the metastatic setting for HER2-positive breast cancer. The SHAMROCK study investigates neoadjuvant T-DXd in early stage HER2-positive breast cancer, using pathological complete response (pCR) rate as the primary endpoint. Methods This is a phase II open-label, single arm, adaptive multi-centre trial of T-DXd in the neoadjuvant setting in stage 2–3 HER2-positive breast cancer. Eligible patients will receive 5.4 mg/kg of T-DXd intravenously every 3 weeks for up to 6 cycles. A repeat biopsy will performed after 2 cycles for the RNA disruption index (RDI) score assessment. According to their likelihood of pCR, as determined by the RDI score, patients will either undergo 4 or 6 cycles of T-DXd prior to imaging. Patients with imaging complete response (iCR) after either 4 or 6 cycles will proceed to surgery. Patients who do not achieve iCR will either undergo further systemic therapy or proceed to surgery. Discussion The SHAMROCK study is a chemotherapy-sparing approach to curative intent treatment, investigating neoadjuvant T-DXd. We hypothesise that neoadjuvant T-DXd will have a high pCR rate and be associated low toxicity in early stage HER2-positive breast cancer. Trial registration EudraCT Number: 2022–002485-32; ClinicalTrials.gov identifier: NCT05710666; Cancer Trials Ireland study number: CTRIAL-IE 22–01.

Background: Systemic inflammatory response markers have been found to have a prognostic role in several cancers, but their value in predicting response to neoadjuvant chemotherapy is uncertain. A systematic review and meta-analysis of the literature was carried out to investigate this.

BACKGROUND:Systemic inflammatory response markers have been found to have a prognostic role in several cancers, but their value in predicting the response to neoadjuvant chemotherapy in breast cancer is uncertain. A systematic review and meta-analysis of the literature was carried out to investigate this. METHODS:A systematic search of electronic databases was conducted to identify studies that explored the predictive value of circulating systemic inflammatory response markers in patients with breast cancer before commencing neoadjuvant therapy. A meta-analysis was undertaken for each inflammatory marker where three or more studies reported pCR rates in relation to the inflammatory marker. Outcome data are reported as ORs and 95% confidence intervals. RESULTS:A total of 49 studies were included, of which 42 were suitable for meta-analysis. A lower pretreatment neutrophil-to-lymphocyte ratio was associated with an increased pCR rate (pooled OR 1.66 (95% c.i. 1.32 to 2.09); P < 0.001). A lower white cell count (OR 1.96 (95% c.i. 1.29 to 2.97); P = 0.002) and a lower monocyte count (OR 3.20 (95% c.i. 1.71 to 5.97); P < 0.001) were also associated with a pCR. A higher lymphocyte count was associated with an increased pCR rate (OR 0.44 (95% c.i. 0.30 to 0.64); P < 0.001). CONCLUSION:The present study found the pretreatment neutrophil-to-lymphocyte ratio, white cell count, lymphocyte count, and monocyte count of value in the prediction of a pCR in the neoadjuvant treatment of breast cancer. Further research is required to determine their value in specific breast cancer subtypes and to establish optimal cut-off values, before their adoption in clinical practice.