Neoadjuvant treatment of breast cancer is applied to an increasing extent, but treatment response varies and side effects pose a challenge. The vitamin E isoform delta-tocotrienol might enhance the efficacy of chemotherapy and reduce the risk of side effects. The aim of this study was to investigate the clinical effect of delta-tocotrienol combined with standard neoadjuvant treatment and the possible association between detectable circulating tumor DNA (ctDNA) during and after neoadjuvant treatment with pathological treatment response. This open-label, randomized phase II trial included 80 women with newly diagnosed, histologically verified breast cancer randomized to standard neoadjuvant treatment alone or in combination with delta-tocotrienol. There was no difference in the response rate or frequency of serious adverse events between the two arms. We developed a multiplex digital droplet polymerase chain reaction (ddPCR) assay for the detection of ctDNA in breast cancer patients that targets a combination of two methylations specific for breast tissue (LMX1B and ZNF296) and one cancer specific methylation (HOXA9). The sensitivity of the assay increased when the cancer specific marker was combined with the ones specific to breast tissue (p < 0.001). The results did not show any association between ctDNA status and pathological treatment response, neither at midterm nor before surgery.

Optimizing Ponatinib Treatment in CP-CML (OPTIC) was a randomized, phase II dose-optimization trial of ponatinib in chronic phase-chronic myeloid leukemia (CP-CML) resistant to ≥ 2 tyrosine kinase inhibitors or with T315I mutation. Patients were randomized to starting doses of 45-, 30-, or 15-mg ponatinib once daily. Patients receiving 45- or 30-mg reduced to 15-mg upon achievement of ≤ 1% BCR::ABL1IS (≥ molecular response with 2-log reduction (MR2)). The exposure-molecular response relationship was described using a four-state, discrete-time Markov model. Time-to-event models were used to characterize the relationship between exposure and arterial occlusive events (AOEs), grade ≥ 3 neutropenia, and thrombocytopenia. Increasing systemic exposures were associated with increasing probability of transitioning from no response to ≥ MR1, and from MR1 to ≥ MR1, with odds ratios of 1.63 (95% confidence interval (CI), 1.06-2.73) and 2.05 (95% CI, 1.53-2.89) for a 15-mg dose increase, respectively. Ponatinib exposure was a significant predictor of AOEs (hazard ratio (HR) 2.05, 95% CI, 1.43-2.93, for a 15-mg dose increase). In the exposure-safety models for neutropenia and thrombocytopenia, exposure was a significant predictor of grade ≥ 3 thrombocytopenia (HR 1.31, 95% CI, 1.05-1.64, for a 15-mg dose increase). Model-based simulations predicted a clinically meaningful higher rate of ≥ MR2 response at 12 months for the 45-mg starting dose (40.4%) vs. 30-mg (34%) and 15-mg (25.2%). The exposure-response analyses supported a ponatinib starting dose of 45 mg with reduction to 15 mg at response for patients with CP-CML.

In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status.

The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT.

Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients.

Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia.

Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.

In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results.

Biliary system cancers are most commonly gallbladder cancers (GBC). Elderly patients (≥ 65) were reported to suffer from an unfavorable prognosis. In this study, we analyzed the RNA-seq and clinical data of elderly GBC patients to derive the genetic characteristics and the survival-related nomograms.

In the Netherlands, patients with ovarian cancer are offered genetic testing. Pre-test preparation may help counseling patients. The aim of this study was to determine if use of a web-based intervention, leads to more effective genetic counseling of ovarian cancer patients.

Parental nutritional interventions have considerably affected gametogenesis and embryogenesis, leading to the differential susceptibility of offspring to chronic diseases such as cancer. Moreover, combinatorial bioactive diets are more efficacious in ameliorating epigenetic aberrations in tumorigenesis.

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P = .029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence ≥ 5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.

Intermediate-risk prostate cancer is a heterogeneous disease state with diverse treatment options. The 22-gene Decipher genomic classifier (GC) retrospectively has shown to improve risk stratification in these patients. We assessed the performance of the GC in men with intermediate-risk disease enrolled in NRG Oncology/RTOG 01-26 with updated follow-up.

Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms.

Gastric cancer is one of the most common malignancies. Although some patients benefit from immunotherapy, the majority of patients have unsatisfactory immunotherapy outcomes, and the clinical significance of immune-related genes in gastric cancer remains unknown. We used the single-sample gene set enrichment analysis (ssGSEA) method to evaluate the immune cell content of gastric cancer patients from TCGA and clustered patients based on immune cell scores. The Weighted Correlation Network Analysis (WGCNA) algorithm was used to identify immune subtype-related genes. The patients in TCGA were randomly divided into test 1 and test 2 in a 1:1 ratio, and a machine learning integration process was used to determine the best prognostic signatures in the total cohort. The signatures were then validated in the test 1 and the test 2 cohort. Based on a literature search, we selected 93 previously published prognostic signatures for gastric cancer and compared them with our prognostic signatures. At the single-cell level, the algorithms "Seurat," "SCEVAN", "scissor", and "Cellchat" were used to demonstrate the cell communication disturbance of high-risk cells. WGCNA and univariate Cox regression analysis identified 52 prognosis-related genes, which were subjected to 98 machine-learning integration processes. A prognostic signature consisting of 24 genes was identified using the StepCox[backward] and Enet[alpha = 0.7] machine learning algorithms. This signature demonstrated the best prognostic performance in the overall, test1 and test2 cohort, and outperformed 93 previously published prognostic signatures. Interaction perturbations in cellular communication of high-risk T cells were identified at the single-cell level, which may promote disease progression in patients with gastric cancer. We developed an immune-related prognostic signature with reliable validity and high accuracy for clinical use for predicting the prognosis of patients with gastric cancer.

Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3 have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18-75 years.

Early detection of ESR1 mutations is a key element for better personalization of the management of patients with HR+/HER2- Metastatic Breast Cancer (MBC). Analysis of circulating tumor DNA from liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of such patients.

Asciminib is a novel tyrosine kinase inhibitor (TKI) that specifically targets the myristoyl pocket. It has increased selectivity and potent activity against BCR-ABL1 and the mutants that most frequently prevent the activity of the ATPbinding competitive inhibitors. Results for clinical trials in patients with chronic myeloid leukemia that have received two or more TKI (randomized against bosutinib) or who have a T315I mutation (single arm study) have shown high levels of activity and a favorable toxicity profile. Its approval has offered new options for patients with these disease features. There are, however, a number of unanswered questions that remain to be defined, including the optimal dose, understanding the mechanisms of resistance, and, importantly, how it compares to ponatinib in these patient populations for whom we now have these two options available. Ultimately, a randomized trial is needed to answer questions to which we currently offer speculative informed guesses. The novelty of its mechanism of action and the exciting early data offer the potential for asciminib to address some of the remaining needs in the management of patients with chronic myeloid leukemia, including second-line therapy after resistance to a front-line second-generation TKI and improving successful treatment-free remission. Multiple studies are ongoing in these areas, and one can only hope that the desired randomized trial comparing asciminib to ponatinib will be conducted soon.

Consensus Panel 1 (CP1) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with updating guidelines for the management of symptomatic, treatment-naïve patients with WM. The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function. For first-line treatment, chemoimmunotherapy (CIT) regimens such as dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine, rituximab (Benda-R) continue to play a central role in managing WM, as they are effective, of fixed duration, generally well-tolerated, and affordable. Covalent BTK inhibitors (cBTKi) offer a continuous, generally well-tolerated alternative for the primary treatment of WM patients, particularly those unsuitable for CIT. In a Phase III randomized trial updated at IWWM-11, the second-generation cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper remissions, thus categorizing zanubrutinib as a suitable treatment option in WM. While the overall findings of a prospective, randomized trial updated at IWWM-11 did not show superiority of fixed duration rituximab maintenance over observation following attainment of a major response to Benda-R induction, a subset analysis showed benefit in patients >65 years and those with a high IPPSWM score. Whenever possible, the mutational status of MYD88 and CXCR4 should be determined before treatment initiation, as alterations in these 2 genes predict sensitivity towards cBTKi activity. Treatment approaches for WM-associated cryoglobulins, cold agglutinins, AL amyloidosis, Bing-Neel syndrome (BNS), peripheral neuropathy, and hyperviscosity syndrome follow the common principle of reducing tumor and abnormal protein burden rapidly and deeply to improve symptoms. In BNS, ibrutinib can be highly active and produce durable responses. In contrast, cBTKi are not recommended for treating AL amyloidosis. The panel emphasized that continuous improvement of treatment options for symptomatic, treatment-naïve WM patients critically depends on the participation of patients in clinical trials, whenever possible.

The identification of biomarker-adjusted treatments has revolutionized the treatment landscape of metastatic lung cancer and improved survival for a relevant share of patients with actionable genomic alterations and those benefiting from checkpoint inhibitors (CPI). Given a clear correlation between the expression of "programmed death ligand 1" (PD-L1) and treatment efficacy of CPI, immunochemotherapy is used in patients with a PD-L1 expression <50%. The lower the PD-L1 expression, the more important is the chemotherapy backbone. For lung adenocarcinoma, there is currently a choice between pemetrexed- and taxane-based regimens. Retrospective data suggested superior survival using taxane-based treatment for patients negative for "thyroid transcription factor 1". A prospective randomized clinical trial is underway to verify this hypothesis.