We compared daunorubicin/cytarabine plus fractionated gemtuzumab ozogamicin (DAGO2) with CPX-351 (CPX; 1:2 randomization) in 439 patients with acute myeloid leukemia (AML) aged ≥60 years (median age, 68 years) without known adverse-risk cytogenetics. Median follow-up was 35 months. Patients not in measurable residual disease (MRD)-negative remission after course 1 could enter a second randomization between standard and intensified chemotherapy. Post-course 1, the overall response rate (complete remission [CR] + CR with incomplete hematological recovery) was greater after DAGO2 (60% vs 47.5%; odds ratio [OR], 0.61; P = .016). Following course 2, the overall response was not significantly different (85% for DAGO2 vs 78% for CPX; P = .095). More patients attained CR with MRD negativity after course 1 in the DAGO2 arm (47% vs 29% for CPX; OR, 0.46; P = .004). We observed better 3-year event-free survival (34% vs 27%; hazard ratio [HR], 0.73; P = .012) and overall survival (52% vs 35%; HR, 0.62; P = .001) with DAGO2. CPX did not provide a survival benefit in patients with myelodysplasia (MDS)-related mutations and was associated with poorer survival in patients with NPM1 (HR, 2.83) and FLT3 mutations (HR, 2.14). Overall, 37% of patients underwent transplantation in first remission, with no difference in transplantation frequency or survival after transplant between randomization groups. Among patients entering the course 2 randomization (n = 107), survival was equivalent between standard and intensified CPX doses (P = .565). In conclusion, in this population of older patients with AML without known adverse-risk cytogenetics, DAGO2 resulted in superior survival compared with CPX. CPX did not benefit patients with MDS-related mutations over DAGO2. This trial was registered at www.ClinicalTrials.gov as #NCT02272478.

Brain metastases reduce overall survival rates of patients with non-small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC.

Background Neoadjuvant chemotherapy (NAC) is a standard approach for treating locally advanced gastric cancer (GC), but resistance in some patients can result in treatment toxicity and surgical delays without therapeutic benefit. Identifying biomarkers predictive of NAC response is crucial for personalized treatment strategies. This study evaluated circulating microRNAs (miRNAs) as potential biomarkers for NAC response. Materials and methods Plasma samples from 39 GC patients undergoing NAC followed by gastrectomy (NCT04223401) were collected before treatment. Four miRNAs (miR-19a, miR-21, miR-27a, miR-200c) were analyzed via quantitative real-time polymerase chain reaction. NAC response was assessed in histological specimens using the Becker tumor regression grade (TRG), which classifies patients as Responders (TRG 1-2) or Non-responders (TRG 3). Results Among 39 patients, 20 (51%) were Responders, and 19 (49%) were Non-responders. miR-19a, miR-21, and miR-200c were significantly upregulated in Non-responders (p < 0.05). ROC analysis revealed miR-19a (AUC: 0.693), miR-21 (AUC: 0.700), and miR-200c (AUC: 0.772) as predictive of resistance. Univariate analysis revealed a correlation between higher levels of miR-19a, miR-21, and miR-200c and a low neutrophil count, with increased resistance risk. Multivariate analysis confirmed miR-200c as an independent predictor of resistance (OR: 20.90; 95% CI: 1.54-283.73). Conclusions This pilot study identifies circulating miR-19a, miR-21, and miR-200c as novel biomarkers for poor NAC response in GC, providing a foundation for personalized treatment strategies.

Genetic counselling (GC) for familial colorectal cancer (fCRC) has been previously shown to improve outcomes such as emotional distress and screening adherence. This is the first randomised clinical trial to evaluate the efficacy of GC for fCRC. We included individuals affected or at-risk for fCRC (Lynch syndrome, APC-associated polyposis, other risk-associated pathogenic variants and clinically defined fCRC). Participants were randomised to (1) standard care or (2) standard care and genetic counselling. Measures include empowerment, anxiety, depression, knowledge, emotional distress, perceived social support, risk perception. Eighty-two individuals participated in the study. The average age was 44.81 years old, with 52.4% women. There was a significant effect in the counselling group (42/82) on post-intervention empowerment scores compared to the control group (40/82) (p = 0.004, d = 0.71), and similarly for depression (p = 0.025, d = 0.40), anxiety (p = 0.036, d = 0.35) and knowledge (p = 0.016, d = 0.25). Exploratory analysis show that several sociodemographic, affective and cognitive variables are moderating the improvement in empowerment following genetic counselling. Our data show significant improvements for both primary endpoint (empowerment) and secondary endpoints (knowledge, depression, anxiety, emotional distress). Genetic counselling is an effective intervention for fCRC both when the diagnosis is part of a syndrome or clinically defined, and both for affected or at-risk individuals.

To investigate the performance of the Xpert® Breast Cancer STRAT4 (CE-IVD∗) Assay (STRAT4) in the neoadjuvant, randomized Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 34.

SOLACE2 (ACTRN12618000686202) investigates whether 12-weeks of olaparib, or cyclophosphamide-olaparib priming, improves subsequent durvalumab-olaparib progression-free survival (PFS), and is superior to olaparib monotherapy without any priming, in platinum-sensitive recurrent ovarian cancer (n = 114). We also evaluate the utility of CUP-CC assay, an immune signature of C-C chemokine receptor type 4 up-regulation, chemokines, and cytokines. Priming with olaparib, or cyclophosphamide-olaparib, followed by durvalumab-olaparib, are both associated with longer PFS compared to olaparib monotherapy, but do not reach the pre-specified primary endpoint of 36-week trial threshold (PFS36). PFS36 rates are 47.4% (95% CI, 31.0-62.1; olaparib priming then olaparib-durvalumab), 48.7% (32.5-63.2; olaparib-cyclophosphamide then olaparib-durvalumab) and 35.1% (20.4-50.3; olaparib monotherapy). PFS is significantly longer for the homologous recombination deficient (N = 71) as compared to the proficient (HRP) (N = 29) subgroups (Hazard Ratio (HR) 0.55, 0.35-0.87). CUP-CC+ subgroup (N = 58) has a significantly longer PFS (HR 0.31, 0.19-0.49) than CUP-CC- (N = 46). Future studies should investigate whether CUP-CC has the potential to personalize poly (ADP-ribose) polymerase inhibitor therapies for patients who are BRCA wild-type, including HRP patients.

Older adults with HER2-positive early breast cancer are underrepresented in clinical trials, and the benefit of chemotherapy in this population remains uncertain. We evaluated the HER2DX genomic assay within the randomized RESPECT trial (NCT01104935), which compared adjuvant trastuzumab with or without chemotherapy in patients aged 70-80 years. In this prespecified translational analysis (Trans-RESPECT), HER2DX scores were available for 154 patients. The HER2DX risk score classified 74.0% as low risk and 26.0% as high risk. Ten-year relapse-free and overall survival were higher in the low-risk group. HER2DX remained independently associated with overall survival in multivariable analysis. The HER2DX immune, luminal, and proliferation signatures that compose the risk score were also prognostic. While the HER2DX pCR score was not prognostic overall, exploratory subgroup analyses suggested a potential survival benefit from chemotherapy in the pCR-high group. HER2DX offers prognostic value and may guide chemotherapy use in older patients with HER2-positive early breast cancer. Clinical Trial Information NCT01104935.

BACKGROUNDPredictive biomarkers to guide chemotherapy decisions for metastatic castration-resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance.METHODSThe CARD trial randomized individuals with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a preplanned biomarker analysis, CTCs were isolated from blood samples obtained at baseline, cycle 2, and the end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression-free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA50 response rate were assessed. RESULTSHigh baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs. 8.9 months; univariate HR, 2.16; 95% CI, 1.52-3.06; P < 0.001; multivariate HR, 1.56; 95% CI, 1.01-2.43; P = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel with ARPI. CONCLUSIONThis preplanned analysis of biomarker data from the CARD trial confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested.TRIAL REGISTRATIONClinicalTrials.gov number NCT02485691.FUNDINGFunded by Sanofi and Epic Sciences.

In the PAPILLON study, first-line amivantamab-chemotherapy in epidermal growth factor receptor (EGFR) exon 20 insertion-mutated non-small cell lung cancer demonstrated significantly prolonged progression-free survival and favorable overall survival over chemotherapy; a consistent benefit was also observed across some secondary endpoints. However, the complete clinical benefit of first-line amivantamab-chemotherapy is not fully understood, nor is the survival advantage in the presence of per-protocol crossover from chemotherapy to amivantamab after progression.

In a phase 3 trial, vorasidenib, an oral brain-penetrant inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), resulted in improved progression-free survival (primary endpoint) and time to next intervention (key secondary endpoint) at second interim analysis, resulting in study unblinding. We report 6 months of additional double-blind data, from second interim analysis (Sept 6, 2022) to unblinding (March 7, 2023), and the effect of vorasidenib on volumetric tumour growth rate, health-related quality of life (HRQOL), neurocognitive function, and seizure control.

This retrospective study was designed to demonstrate the clinical utility of two diagnostic tests, the FoundationOneCDx (F1CDx) and Exact Sciences Resolution homologous recombination deficiency (HRD; Resolution HRD assay) as clinical trial-enrollment assays to identify patients with metastatic castration-resistant prostate cancer harboring homologous recombination repair (HRR) gene alterations. Tumor tissue and plasma collected from patients with metastatic castration-resistant prostate cancer in the phase 3 MAGNITUDE study were tested using the F1CDx tissue assay and/or the Resolution HRD plasma assay. Patients with HRR alterations were randomized (1:1) to receive niraparib (NIRA) and abiraterone acetate (AA) + prednisone (NIRA + AAP) or placebo and AAP (PBO + AAP; NCT03748641). Efficacy was based on radiographic progression-free survival (primary end point), time tosymptomatic progression, time to cytotoxic chemotherapy, and overall survival as secondary end points (interim analysis 1). Of 423 HRR patients, 291 (68.8%) were HRR positive (HRR+) by F1CDx [BRCA+: 162 (38.2%)], and 38 (8.9%) were HRR negative by F1CDx but HRR+ by Resolution HRD assay. Also, 277 of 423 (65.5%) were HRR+ by Resolution HRD assay [BRCA+: 150 (35.5%)], and 124 (29.3%) were HRR negative by Resolution HRD assay but HRR+ by F1CDx assay. Clinically meaningful benefits for all end points were comparable for BRCA+ and HRR+ patients detected by either tissue or plasma assays. These results demonstrated the clinical utility of both tissue and plasma assays in identifying patients for NIRA + AAP treatment.

The paradigm of molecular negative hyperselection, beyond RAS and BRAF, identifies metastatic colorectal cancer (mCRC) patients with the greatest benefit from anti-epidermal growth factor receptor (anti-EGFR) agents. We hypothesize that applying this model to stage III colon cancer (CC) might identify a subgroup deriving benefit from anti-EGFRs in the adjuvant setting.

The firstMIND trial (NCT04134936) evaluated the safety and efficacy of adding lenalidomide to R-CHOP+tafasitamab in the first-line treatment settings of patients with diffuse large B-cell lymphoma. To address response dynamics and the impact of measurable residual disease (MRD), we analyzed prospectively collected plasma samples from 56 study patients using the EuroClonality immunoglobulin gene (IG)-NGS assay. At baseline, disease-related clonotypes were identified in 50/56 (89%) patients by IG-NGS in cell-free (cf)DNA and/or FFPE samples. MRD markers were successfully identified in 49/52 (94%) cfDNA samples and 35/41 (85%) FFPE samples. Baseline cfDNA and circulating tumor (ct)DNA levels correlated with preclinical risk factors, and high cfDNA levels ≥3.35 log10hGE/ml plasma were significantly associated with poor progression-free survival (PFS) (hazard ratio (HR): 3.1). ctDNA clearance was rapid with 52% of patients MRD-negative at C2D1, 83% patients at C4D1, and 82% patients after finishing six 21-day cycles (end of treatment (EOT)) and a sustained treatment response (93% MRD negative) six months after EOT. ctDNA detection was associated with worse PFS outcomes at C2D1 (p = 0.039, HR:4.51, 95%Cl:0.93-21.74), C4D1 (p = 0.07, HR:3.34, 95%Cl:0.83-13.48) and EOT (p = 0.01, HR:6.38, 95%Cl:1.27-32.01) and inferior overall survival at these time points. In PET-positive patients, ctDNA-MRD had a higher specificity rendering PET/CT more precisely.

Cervical cancer, a prevalent female malignancy, is treated with surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapy. Yet, prognosis remains influenced by multiple factors. Epithelial-mesenchymal transformation (EMT) is an important link in the malignant progression of tumor cells and has an important impact on the progression and prognosis of cervical cancer. This study aimed to analyze effect of Baofukang suppository on the related indexes of EMT of tumor cells in cervical cancer patients. Eighty patients with cervical cancer received in The First Affiliated Hospital of Anhui Medical University from March 2020 to March 2022 were randomized into a control group (chemotherapy alone, n=40) and a study group (chemotherapy + Baofukang, n=40). Post-treatment, the study group showed significantly lower mRNA levels of EMT markers Vimentin and N-cadherin, and higher E-cadherin and β-catenin (p<0.05). Additionally, interleukin-6 (IL-6) decreased while interleukin-2 (IL-2) and interferon-γ (INF-γ) increased (p<0.05). Immune function improved, with higher CD3+, CD4+ and CD4+/CD8+ ratios, and lower CD8+ (p<0.05). The adverse reactions between two groups were not unconspicuous (p>0.05). The adjuvant therapy of Baofukang Suppository can effectively regulate the relevant indexes of tumor cell EMT, delay or prevent the EMT of tumor cells.

COMPEL (NCT04765059) was a global, randomized, double-blind study that evaluated osimertinib plus chemotherapy versus placebo plus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) following non-central nervous system (CNS) progression on first-line osimertinib.

To report the rates of proven, probable and possible invasive fungal disease (IFD) in patients receiving antifungal prophylaxis during initial induction and consolidation treatment of acute myeloid leukaemia (AML) plus either sorafenib or placebo.

In SERENA-6, switching from aromatase inhibitor (AI) to camizestrant with continuation of CDK4/6 inhibitor (CDK4/6i) guided by emergence of ESR1 mutations (ESR1-mut) during first-line AI-CDK4/6i in patients with hormone receptor (HR)-positive advanced breast cancer (ABC) resulted in statistically significant and clinically meaningful improvement in progression-free survival compared with AI-CDK4/6i and reduction in the risk of deterioration in global health status (GHS)/quality of life (QoL) (hazard ratio 0.54). Here we report additional data from patient-reported outcomes (PROs).

Sacituzumab tirumotecan (sac-TMT) is an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 that has shown significant survival benefits in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) that has progressed after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy.

Patients with muscle-invasive bladder cancer have varied outcomes after cystectomy. Circulating tumor DNA (ctDNA)-based detection of molecular residual disease may identify patients at high risk for recurrence after cystectomy who can benefit from adjuvant immunotherapy, thus sparing patients at lower risk from unnecessary treatment burden.

The randomized phase II MA.38 trial estimated the relative progression-free survival (PFS) associated with second-line endocrine therapy plus palbociclib administered on a 100 mg continuous daily dosing (CDD) schedule compared with the standard dose schedule (SDS) of 125 mg (days 1-21 of a 28-day cycle). A total of 180 patients were allocated 1:1 to protocol therapy. Molecular profiling was performed on the archival tissue and cell-free DNA (cfDNA) at enrollment, 3 months, and 6 months. The primary analysis for PFS demonstrated a similar outcome for the CDD versus SDS treatment strategy: HR = 0.93 (90% confidence interval, 0.66-1.30). Secondary efficacy measures for CDD versus SDS included the following: overall survival, HR = 1.07 (90% confidence interval, 0.67-1.69); response rate, 16.1% versus 18.0% (P = 0.66); median duration of response, 4.2 months (range, 2.8-13.9 months) versus 5.6 months (range, 2.4-13.9 months; P = 0.86); and clinical benefit rate, 53.2% versus 57.3% (P = 0.89). cfDNA profiling of the baseline enrollment sample prior to palbociclib commencement showed low tumor fraction (HR = 2.28; P = 9.9 × 10-6); higher short/long fragment length ratios (HR = 1.19; P = 0.049) and cfDNA variants in FGFR4 (HR = 3.65; P = 0.012) were prognostic and associated with inferior PFS. Variants in TP53 (HR = 2.48; P = 0.006) and ESR1 (HR = 3.42; P = 0.005) detected at 12 weeks on treatment were also associated with poor PFS. CDD palbociclib 100 mg dosing was not associated with improved efficacy compared with the standard intermittent 125 mg dosing schedule. Additionally, we identified prognostic biomarkers in alignment with prior research and demonstrated the value of cfDNA dynamics, including fragment length ratios and tumor fraction as a measure of treatment response.