BACKGROUND:Poly(ADP-ribose) polymerase inhibitors (PARPis) are established maintenance therapies in epithelial ovarian cancer (EOC). Although considered relatively safe, their impact on renal function remains unclear. Increases in serum creatinine (SCr) are frequently observed during treatment, but the clinical significance of these changes is uncertain. We conducted a systematic review and meta-analysis to assess the risk of renal adverse events associated with PARPis in randomized controlled trials (RCTs). METHODS:PubMed/MEDLINE, Embase, and the Cochrane Library were searched for phase II-III, placebo-controlled RCTs published through 30 June 2025. Eligible studies enrolled patients with ovarian cancer receiving maintenance monotherapy with olaparib, niraparib, rucaparib, or fuzuloparib and reported renal adverse events. The primary endpoint was creatinine increase (all grades). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models according to heterogeneity. RESULTS:Nine high-quality RCTs comprising 2578 patients met the inclusion criteria. PARPi therapy was associated with a significantly increased risk of creatinine elevation compared with placebo (OR 5.04; 95% CI 3.51-7.24; p < 0.001). Heterogeneity was moderate (I2 = 31.7%). High-grade renal adverse events (≥grade 3) were rare (<1%) and could not be reliably pooled. No significant publication bias was detected. CONCLUSIONS:PARP inhibitors significantly increase the likelihood of SCr elevation in EOC; however, severe nephrotoxicity appears uncommon in RCTs. Observed SCr increases may partly reflect inhibition of renal tubular creatinine transport rather than true reductions in glomerular filtration. Careful renal monitoring and prospective studies incorporating direct GFR assessment are warranted.

Cisplatin-based neoadjuvant chemotherapy (NACT) followed by radical cystectomy (RC) is the standard treatment for eligible patients with muscle-invasive bladder cancer (MIBC). However, the comparative effectiveness of gemcitabine/cisplatin (GC) and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) in routine practice remains insufficiently defined, particularly in broader real-world populations that include patients with regional lymph node involvement. We conducted a multicenter retrospective real-world study of 232 patients with non-metastatic urothelial MIBC treated with cisplatin-based NACT at seven Polish reference cancer centers between 2016 and 2024. One hundred patients received ddMVAC and 132 received GC. We compared pathological response, treatment toxicity, event-free survival (EFS), and overall survival (OS). EFS was defined as the time from NACT initiation to progression during neoadjuvant treatment, failure to undergo RC due to progression or treatment-related deterioration, recurrence after RC, or death from any cause. Univariable and multivariable Cox regression analyses were performed. Cumulative cisplatin dose was assessed using a cutoff of 280 mg/m². Baseline characteristics were generally comparable, although patients treated with ddMVAC had better ECOG performance status. Median treatment duration was shorter with ddMVAC than with GC (6.3 vs. 9 weeks; p < 0.001), while cumulative cisplatin dose was higher (280 vs. 210 mg/m²; p = 0.002). Pathological complete response (pCR) was achieved more frequently with ddMVAC than with GC (39.8% vs. 13.6%; p < 0.001). Median OS was longer in the ddMVAC group (39 vs. 27 months; p = 0.0203), and median EFS was also superior (not reached vs. 20.1 months; p = 0.001). In multivariable analysis, pCR remained independently associated with both OS and EFS, while R0 resection remained independently associated with EFS. Hematologic toxicity and treatment discontinuation due to toxicity were more frequent with GC. In this real-world cohort, ddMVAC was associated with a markedly higher pCR rate than GC. pCR was the strongest independent factor associated with favorable long-term outcomes, while R0 resection was independently associated with improved EFS. These findings support treatment strategies aimed at maximizing pathological response and ensuring timely radical surgery.

BACKGROUND:With an ongoing debate concerning the optimal timing of advanced ovarian cancer surgical treatment, primary debulking surgery (PDS) versus neoadjuvant chemotherapy followed by interval debulking surgery (IDS), this study aimed to compare survival outcomes between PDS and IDS populations and evaluate prognostic factors in a real-world cohort of patients treated with first-line chemotherapy and bevacizumab. METHODS:A retrospective multi-center study was conducted involving 369 patients with newly diagnosed advanced ovarian cancer. Patient data included demographics, histology, treatment details, chemotherapy response, and survival outcomes. Kaplan-Meier estimates with log-rank tests were used for univariate analyses, as well as Cox proportional hazard models for multivariate analyses. RESULTS:Patients undergoing IDS were older (62.5 vs. 60.0 years), had higher pretreatment CA-125 (1846 vs. 395.6 IU/mL), an increased proportion were at with stage IV (36.25% vs. 21.10%), and they received fewer bevacizumab cycles (12 vs. 18) compared to those undergoing PDS. Median progression-free survival (PFS) was 18.6 months (95% CI: 17.3-20.2) and overall survival (OS) was 45.4 months (95% CI: 41.1-52.1). Multivariate analysis confirmed poor chemotherapy response (HR 1.80, 95% CI: 1.36-2.37; p < 0.0001) and IDS (HR 1.65, 95% CI: 1.37-2.39; p < 0.0001) as independent predictors of shorter PFS. For OS, independent risk factors were age > 70 (HR 1.62; p = 0.0202), poor response (HR 2.03; p < 0.0001), and IDS (HR 1.75; p = 0.0006). CONCLUSIONS:In this real-world cohort treated with first-line chemotherapy and bevacizumab, interval debulking surgery was associated with inferior progression-free and overall survival compared with primary debulking surgery. However, these findings reflect a high-risk population and are strongly influenced by patient selection and treatment pathways, underscoring the need for cautious interpretation.

BACKGROUND:Ovarian cancer is the second deadliest gynecologic malignancy globally. The current standard of care first-line therapy for newly diagnosed advanced epithelial ovarian cancer is surgery and platinum-based chemotherapy (±bevacizumab), followed by maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor, bevacizumab, or a combination of the two. Although anti-programmed cell death (PD) protein 1 and anti-PD ligand 1 antibodies (PD-[L]1 inhibitors) have shown benefit in several solid tumors, their effect in ovarian cancer remains uncertain. Several trials are evaluating PD-(L)1 inhibitors in combination with first-line platinum-based chemotherapy and PARP inhibitor maintenance treatment. Here, we review trial designs to understand key similarities and differences for future assessments of the results. MATERIALS AND METHODS:The clinical trials registry "ClinicalTrials.gov" was searched using keywords, including ovarian cancer and niraparib, olaparib, or rucaparib. Search results were then filtered for phase 3 and manually reviewed to identify trials evaluating combinations of PARP inhibitors and PD-(L)1 inhibitors in the first-line setting. RESULTS:Four trials, ENGOT-OV44/FIRST (NCT03602859), ENGOT-OV46/AGO-OVAR 23/GOG-3025/DUO-O (NCT03737643), ENGOT-OV43/GOG-3036/KEYLYNK-001 (NCT03740165), and ENGOT-OV45/GOG-3020/ATHENA (NCT03522246), were identified. Of these, FIRST, DUO-O, and KEYLYNK-001 are evaluating both first-line use in combination with chemotherapy and maintenance, whereas ATHENA focuses on maintenance after a response to chemotherapy; however, DUO-O and KEYLYNK-001 do not include a PARP inhibitor in the comparator arm, limiting the ability to compare the added benefit of immunotherapy over the current standard of care. CONCLUSIONS:Results of these trials will determine whether PARP inhibitor and PD-(L)1 inhibitor combination with or without bevacizumab can improve patient outcomes.

Introduction. Olaparib, the first approved poly(ADP)-ribose polymerase (PARP) inhibitor (PARPi), is a cornerstone of targeted therapy in patients with homologous recombination deficiency (HRD), in particular with pathogenic (P) or likely pathogenic (LP) variants in the BRCA1/2 genes. Growing evidence also indicates its efficacy in combination therapies, regardless of the presence of classical HRD markers. Material and methods. A narrative literature review was conducted, including the results of clinical trials with olaparib in monotherapy and combination therapies, preclinical data, current guidelines of scientific societies (ESMO, NCCN, PTOK, PTGO) and the role of molecular diagnostics, including the presence of P/LP variants, both germline and somatic, in the qualification for therapy in ovarian, endometrial and prostate cancer. Results. Combination therapy with olaparib and bevacizumab shows high efficacy in patients with ovarian cancer and HRD. The DUO-E study confirmed the clinical benefit of olaparib in combination with durvalumab in patients with endometrial cancer and proficientmismatch repair (pMMR), usually poorlyresponding to immunotherapy. Olaparib also shows efficacy in patients with prostate cancer and P/LP variants in BRCA1/2 genes, both as monotherapy and in combination with new hormonal agents, regardless of HRD status. Conclusions. Olaparib in monotherapy is effective in patients with P/LP variants in the BRCA1/2 genes, while its use in combination therapies allows for the extension of indications for targeted treatment. Comprehensive molecular diagnostics and further research on the mechanisms of resistance and new strategies for personalizing oncological treatment are of key importance.

Introduction:Discrepancies between preclinical tests and clinical results raise serious concerns about the appropriateness of the current methodologies. In particular, cell biology approaches neglect fundamental physical parameters despite their relevance to in vivo conditions. Oxygen availability is critical for cell reactions; thus, the lack of consideration of hypoxia as the main regulator of the tumor microenvironment (TME) leads to misinterpreted data with consequences for translational applications. In this study, we show that mitomycin C (MMC), an antineoplastic antibiotic, is rarely used in ovarian cancer (OC) treatment despite its potential efficacy; we use MMC as an example of a treatment that warrants reevaluation under microenvironmental conditions, particularly during in vitro testing. Methods:To evaluate the effects of MMC and oxygen tension (pO2) on OC cells (SKOV3), HTA 2.0 microarrays were used, which demonstrated that hypoxia and MMC induced transcriptomic changes in OC cells. Their combination particularly emphasized the effect of pO2 modification on MMC activity. The most significant findings were verified in three other OC cell lines, namely, TOV112D, ES-2, and A2780. Results:Under normoxic conditions, MMC mostly affected several pathways associated with ribosome-related processes, whereas under hypoxic conditions, it induced modifications in the extracellular matrix (ECM). The most significantly upregulated gene in response to hypoxia-MMC treatment was MMP1, regulated by both MMC and hypoxia. Low pO2 levels during MMC treatment allowed the identification of important regulators, such as SPP1, and the corresponding processes, including cholesterol biosynthesis. Conclusion:Hypoxia modulated the effects of MMC on OC cells and identified genes that may serve as promising targets to enhance the effectiveness of MMC treatment.

BACKGROUND:Relacorilant, a first-in-class selective glucocorticoid receptor antagonist, increases a tumour's sensitivity to chemotherapy by reducing cortisol signalling. This study aimed to show whether the addition of relacorilant to nab-paclitaxel improves progression-free and overall survival in females with platinum-resistant ovarian cancer. METHODS:This randomised, controlled, open-label phase 3 trial (ROSELLA [GOG-3073/ENGOT-ov72]) was done at 117 hospitals and community oncology treatment centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Patients had to be aged 18 years or older and had to have a confirmed diagnosis of platinum-resistant, epithelial (ie, high-grade serous, endometrioid, or carcinosarcoma with a ≥30% epithelial component) ovarian, primary peritoneal, or fallopian tube cancer; up to three previous lines of anticancer therapy and previous bevacizumab and disease progression or intolerance to the most recent therapy; measurable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1); an Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate organ function. Patients were assigned (1:1) to relacorilant (150 mg orally the day before, of, and after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). The dual primary endpoints were progression-free survival assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours (version 1.1) and overall survival, and were assessed in all randomly assigned patients by intention to treat. The safety population included all randomly assigned patients who received at least one dose of the assigned treatment. This trial was registered at ClinicalTrials.gov, NCT05257408, and is ongoing. FINDINGS:Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the combination group (n=188) or to the nab-paclitaxel monotherapy group (n=193). Patients receiving relacorilant plus nab-paclitaxel had a statistically significant improvement in progression-free survival assessed by blinded independent central review compared with those receiving nab-paclitaxel monotherapy (hazard ratio 0·70 [95% CI 0·54-0·91]; median 6·54 months [95% CI 5·55-7·43] vs 5·52 months [3·94-5·88]; stratified log-rank p=0·0076). At the planned interim analysis, there was a clinically meaningful difference in overall survival with the addition of relacorilant to nab-paclitaxel (0·69 [95% CI 0·52-0·92]; 15·97 months [95% CI 13·47-not reached] vs 11·50 months [10·02-13·57]; log-rank p=0·0121). Adverse events were similar across study groups when adjusted for nab-paclitaxel exposure; no new safety signals were observed. INTERPRETATION:The addition of relacorilant to nab-paclitaxel prolonged progression-free survival and interim results also showed an improvement in overall survival. Together, the results position the combination of relacorilant and nab-paclitaxel as a potential new standard treatment for patients with platinum-resistant ovarian cancer. FUNDING:Corcept Therapeutics.

BACKGROUND:Aminopeptidase N (APN) is a membrane-bound, zinc-dependent enzyme implicated in multiple physiological and pathological processes, including cancer progression. This study aimed to evaluate the inhibitory effects of selected cytostatic agents-paclitaxel, cisplatin, and carboplatin-on APN activity and to assess the potential influence of commonly used analgesics on this enzymatic function. METHODS:APN activity was measured using the chromogenic substrate L-leucine-p-nitroanilide. Reactions were monitored spectrophotometrically at 405 nm to quantify the formation of p-nitroaniline. Inhibition studies were conducted at varying concentrations of the cytostatics. Kinetic parameters and inhibition constants (Ki) were determined via Lineweaver-Burk and Dixon analyses. Additionally, the modulatory effects of acetylsalicylic acid, acetaminophen, and diclofenac on paclitaxel-induced APN inhibition were examined. RESULTS:Of the agents tested, paclitaxel showed the inhibition of APN activity, reducing enzymatic activity by approximately 65 %, with a Ki value of (140 ± 25 μM), consistent with mixed competitive inhibition. Cisplatin and carboplatin had negligible effects, retaining 90 % and 99 % enzymatic activity, respectively. Moreover, none of the analgesics tested altered the inhibitory effect of paclitaxel on APN. CONCLUSIONS:Paclitaxel acts as a potent mixed competitive inhibitor of APN, in contrast to cisplatin and carboplatin. The lack of interaction between paclitaxel and common analgesics suggests their compatibility in combined therapeutic regimens. These findings support the further exploration of APN- targeted strategies to enhance chemotherapy efficacy.

In 2023, the Polish Society of Gynecologic Oncology (PSGO) published clinical recommendations for the diagnosis, treatment, and care of women with endometrial cancer (EC), developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation) tool. A 2025 update was initiated in response to new evidence, particularly regarding systemic therapies for metastatic, advanced, or recurrent EC, and the introduction of an updated FIGO classification. A targeted literature review identified relevant phase III clinical trials and systematic reviews, including RUBY, GY-018, AtTend, and DUO-E. These trials were critically assessed by an Expert Panel in accordance with the AGREE II methodology. Updated recommendations were formulated based on this evidence, with a comparative analysis of the old and new FIGO staging systems and visual updates to treatment pathways. Key changes include the addition of immunotherapy (I/O) plus chemotherapy (CHTH) as first-line treatment for all molecular subtypes of high-grade endometrioid and non-endometrioid carcinomas, replacing chemotherapy alone. For MMRp-positive cases, the 2025 version introduces the use of Olaparib alongside Durvalumab and CHTH. HER2-positive MMRp serous carcinoma remains eligible for trastuzumab in combination with CHTH. Second-line treatment guidance remains unchanged for patients who did not receive I/O plus CHTH initially. However, options for those previously treated with this combination are still under evaluation. This update ensures alignment with the latest international standards and reinforces evidence-based, personalized care for EC patients.

Treatment of solid tumors remains challenging and therapeutic strategies require continuous development. Tumor-infiltrating macrophages play a pivotal role in tumor dynamics. Here, we present a Macrophage-Drug Conjugate (MDC) platform technology that enables loading macrophages with ferritin-drug complexes. We first show that macrophages actively take up human heavy chain ferritin (HFt) in vitro via macrophage scavenger receptor 1 (MSR1). We further manifest that drug-loaded macrophages transfer ferritin to adjacent cancer cells through a process termed 'TRAnsfer of Iron-binding protein' (TRAIN). The TRAIN process requires direct cell-to-cell contact and an immune synapse-like structure. At last, MDCs with various anti-cancer drugs are formulated with their safety and anti-tumor efficacy validated in multiple syngeneic mice and orthotopic human tumor models via different routes of administration. Importantly, MDCs can be prepared in advance and used as thawed products, supporting their clinical applicability. This MDC approach thus represents a promising advancement in the therapeutic landscape for solid tumors.

e16579 Background: Neoadjuvant chemotherapy (NACT) in patients (pts) with muscle-invasive bladder cancer (MIBC) significantly improves treatment outcomes. Widely used NACT regimen based on 3-4 cycles of gemcitabine and cisplatin (GC) before radical cystectomy (RC) remained the standard of care until the complete results of the VESPER trial, which demonstrated the superiority of 6 cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) in terms of progression-free survival (PFS), complete pathological responses (pCR) and overall survival (OS). In most clinical trials, pts with clinically positive lymph nodes (N+ according to TMN) were underrepresented. The aim of the study is to compare the effectiveness and safety of the mentioned NACT regimens in real medical practice. Methods: Pts from 7 urooncology hospitals in Poland with MIBC stage ≥T2, cM0 treated with NACT GC or ddMVAC (11/2016-09/2024) were included. Pts from clinical trials were excluded. Complete clinical data were collected. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square or Fisher's tests were used for comparison between groups. Data cut-off was 31/12/2024. Results: Of the 261 pts treated with NACT, 232 were included in the analysis: 132 (57%) received GC, 100 (43%) ddMVAC). There were 55 (24%) women in the study groups, the median age was 67, cT2N0: 90 (39%), N+: 61 (27%), baseline anemia of any grade: 107 (48%). In the GC group, there were significantly more ECOG performance status (PS) 2 pts, p=0.0076, other variables did not differ significantly. Median total dose of cisplatin (MTDC) was significantly higher in ddMVAC group than in GC group (280 vs 210 mg/m2), p=0.0024. Median chemotherapy period was significantly longer in GC pts: 9 vs 6.3 weeks for ddMVAC, p=0.0007. RC was not performed in 35 (15%) of pts due to adverse events (AEs), progression, or withdrawal of consent. More objective pathological responses were achieved in the ddMVAC vs GC pts, 42 vs 14%, p<0,0001, however, there were no differences in clinical response. Significant difference in mOS between GP and ddMVAC group was observed: 27 vs 39m, p=0.0203. In univariate analysis, a significant advantage was also observed for MTDC ≥250mg/m2, p=0.0093; ECOG PS 0, p=0.0018; RC, p=0.01; R0 resection, p=0.001; and pCR, p<0.0001 in terms of OS. OS did not differ significantly between cT2N0 or >cT2N0 pts, p=0.3. Multivariate analysis confirmed a statistically significant OS benefit for ECOG PS 0, higher MDTC and pCR. More hematological AEs occured in the GC vs ddMVAC group: 98% vs 84%, p=0.0007. Conclusions: The use of NACT with the ddMVAC in MIBC pts showed a statistically significant improvement of OS compared to GC with favorable toxicity. The study indicates that the best prognosis is for pts with ECOG PS 0 who received a higher MTDC (preferably in the ddMVAC regimen), responded to NACT and underwent radical surgery regardless of the primary clinical stage of T and N.

5512 Background: DUO-E (NCT04269200) showed statistically significant and clinically meaningful progression-free survival (PFS) with carboplatin/paclitaxel (CP) plus durvalumab (D) followed by D (CP+D) ± maintenance olaparib (O) vs CP in endometrial cancer (intent-to-treat [ITT] population; primary endpoints). The greatest benefit for CP+D was in mismatch repair deficient (dMMR) patients (pts); addition of O (CP+D+O) further enhanced PFS in MMR proficient (pMMR) pts (prespecified exploratory analyses). We present exploratory longitudinal circulating tumor (ct)DNA analyses. Methods: Pts were randomized 1:1:1 to CP (CP alone), CP+D, or CP+D+O arms. ctDNA was analyzed in plasma at baseline (BL; Cycle 1 Day 1 [C1D1]), during the chemotherapy phase (C3D1), prior to maintenance initiation (C7D1), and during the maintenance phase (C9D1) using the methylation-based Guardant Infinity assay (Guardant Health, Palo Alto, CA). Results: Of 718 pts randomized, the biomarker-evaluable population (BEP) comprised 347, 349, 350, and 349 pts at BL, C3D1, C7D1, and C9D1, respectively. Pt characteristics were similar to the ITT population but fewer pts had Eastern Cooperative Oncology Group status 1. ctDNA was detectable in 80% (278/347) of C1D1 samples, and presence of BL ctDNA was associated with shorter PFS across treatment arms. In both dMMR and pMMR pts, CP+D treatment during the chemotherapy phase led to numerically greater reductions in detectable ctDNA vs CP at C3D1; continued treatment with D led to lower ctDNA detection at C9D1 (Table) due to a lower proportion of pts switching from no detectable ctDNA to detectable (re-emergence) ctDNA between C7D1 and C9D1. The addition of maintenance O to CP+D had limited effect on ctDNA levels in dMMR pts; however, in pMMR pts, the ctDNA detection rate was lower at C9D1 vs CP or CP+D due to increased ctDNA clearance from C7D1 to C9D1 (CP+D+O vs CP+D: 48% vs 17%). Conclusions: In this post hoc exploratory analysis, BL ctDNA was associated with shorter PFS. The addition of D was associated with rapid reductions in ctDNA detection during chemotherapy and less re-emergence of ctDNA during maintenance. The addition of maintenance O was associated with further reduction of detectable ctDNA and increased ctDNA clearance in pMMR pts, reflecting an additional activity of the combination. Clinical trial information: NCT04269200 . ctDNA detection rates (% [n/N]). Population Treatment arm C1D1 C3D1 C7D1 C9D1 BEP CP 80 (94/118) 44 (51/117) 35 (41/117) 50 (58/117) CP+D 86 (96/112) 26 (29/112) 27 (30/112) 33 (37/112) CP+D+O 75 (88/117) 31 (37/120) 21 (26/121) 25 (30/120) dMMR CP 79 (11/14) 57 (8/14) 21 (3/14) 43 (6/14) CP+D 91 (21/23) 23 (5/22) 32 (7/22) 22 (5/23) CP+D+O 85 (22/26) 41 (11/27) 18 (5/28) 22 (6/27) pMMR CP 80 (83/104) 42 (43/103) 37 (38/103) 50 (52/103) CP+D 84 (75/89) 27 (24/90) 26 (23/90) 36 (32/89) CP+D+O 73 (66/91) 28 (26/93) 23 (21/93) 26 (24/93)

This research paper presents a novel approach to identifying biomarkers that can be used to prognosticate patients with triple-negative breast cancer (TNBC) eligible for neoadjuvant therapy. The study utilized survival and RNA sequencing data from a cohort of TNBC patients and identified 276 genes whose expression was related to survival in such patients. The gene expression data were then used to classify patients into two major groups based on the presence or absence of Wingless/Integrated-pathway (Wnt-pathway) and mesenchymal (Mes) markers (Wnt/Mes). Patients with a low expression of Wnt/Mes-related genes had a favorable outcome, with no deaths observed during follow-up, while patients with a high expression of Wnt/Mes genes had a higher mortality rate of 50% within 19 months. The identified gene list could be validated and potentially used to shape treatment options for TNBC patients eligible for neoadjuvant therapy providing valuable insights into the development of more effective treatments for TNBC. Our data also showed significant variation in gene expression profiles before and after chemotherapy, with most tumors switching to a more mesenchymal/stem cell-like profile. To verify this observation, we performed an in silico analysis to classify breast cancer tumors in Prediction Analysis of Microarray 50 (PAM50) molecular classes before treatment and after treatment using gene expression data. Our findings demonstrate that following drug intervention and metastasis, certain tumors undergo a transition to alternative subtypes, resulting in diminished therapeutic efficacy. This underscores the necessity for reevaluation of patients who have experienced relapse or metastasis post-chemotherapy, with a focus on molecular subtyping. Tailoring treatment strategies based on these refined subtypes is imperative to optimize therapeutic outcomes for affected individuals.

Background: Recent publications underscore the need for updated recommendations addressing less radical surgery for <2 cm tumors, induction chemotherapy, or immunotherapy for locally advanced stages of cervical cancer, as well as for the systemic therapy for recurrent or metastatic cervical cancer. Aim: To summarize the current evidence for the diagnosis, treatment, and follow-up of cervical cancer and provide evidence-based clinical practice recommendations. Methods: Developed according to AGREE II standards, the guidelines classify scientific evidence based on the Agency for Health Technology Assessment and Tariff System criteria. Recommendations are graded by evidence strength and consensus level from the development group. Key Results: (1) Early-Stage Cancer: Stromal invasion and lymphovascular space involvement (LVSI) from pretreatment biopsy identify candidates for surgery, particularly for simple hysterectomy. (2) Surgical Approach: Minimally invasive surgery is not recommended, except for T1A, LVSI-negative tumors, due to a reduction in life expectancy. (3) Locally Advanced Cancer: concurrent chemoradiation (CCRT) followed by brachytherapy (BRT) is the cornerstone treatment. Low-risk patients (fewer than two metastatic nodes or FIGO IB2-II) may consider induction chemotherapy (ICT) followed by CCRT and BRT after 7 days. High-risk patients (two or more metastatic nodes or FIGO IIIA, IIIB, and IVA) benefit from pembrolizumab with CCRT and maintenance therapy. (4) Metastatic, Persistent, and Recurrent Cancer: A PD-L1 status from pretreatment biopsy identifies candidates for Pembrolizumab with available systemic treatment, while triplet therapy (Atezolizumab/Bevacizumab/chemotherapy) becomes a PD-L1-independent option. Conclusions: These evidence-based guidelines aim to improve clinical outcomes through precise treatment strategies based on individual risk factors, predictors, and disease stages.

In advanced-stage colorectal cancer (CRC), a strategy based on a sequence of systemic therapies brings survival benefits in most patients. Trifluridine and tipiracil hydrochloride (TT) is a chemotherapy drug effective in patients in the third- or later line setting. No highly specific biomarkers have been established for TT therapy so far. However, a systemic immune-inflammation index (SII), which is based on platelet, neutrophil and lymphocyte counts is applied to predict prognosis. In this retrospective, multicenter study, clinical data on 179 metastatic CRC patients treated with TT were collected. To evaluate factors predicting TT therapy response and overall survival, univariate logistic regression analysis was conducted. Subsequently, factors with p < 0.05 in univariate analysis were included in multivariate analysis. In the multivariate analysis of progression-free survival (PFS), three favorable parameters were significant: good to moderate histological differentiation (p = 0.0038), carcinoembryonic antigen (CEA) < 5 ng/L (p = 0.0316) and SII ≤ 550 (p = 0.007). Favorable prognostic factors revealed in the multivariate analysis of overall survival (OS) were: <3 prior lines of treatment (p = 0.02), good to moderate histological differentiation (p = 0.0003), CEA < 5 ng/L (p = 0.0227) and SII ≤ 550 (p = 0.0001). Our study indicated that pre-treatment SII may be clinically useful for selecting likely responder patients and assessing the prognosis for mCRC patients treated with TT.

Background: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. Methods: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. Results: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade >= 3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. Conclusions: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. Trial registration: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. Research support: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.