The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours.

PORTEC-4a investigated molecular risk profile-based individualised adjuvant treatment for women with high-intermediate risk endometrial cancer, aiming to reduce both overtreatment and undertreatment while optimising locoregional control.

Anti-epidermal growth factor receptor (EGFR) drug rechallenge could be of therapeutic value in a subgroup of refractory metastatic colorectal cancer (mCRC).

Accurate risk stratification is essential to optimize neoadjuvant therapy for locally advanced rectal cancer (LARC) in the era of precision medicine. This study assessed the feasibility and safety of a circulating tumor DNA (ctDNA)-guided neoadjuvant strategy.

PURPOSE: Midostaurin is predominantly metabolized by cytochrome P450 (CYP) 3A4 to form two active metabolites, CGP62221 and CGP52421. The current analysis from UNIFY, a randomized, double-blind, phase 3 study, investigated the impact of genetic polymorphism of CYP3A4/CYP3A5 on the exposure of midostaurin and its active metabolites, and on treatment-related toxicity in patients with FLT3-mutation-negative acute myeloid leukemia (AML). METHODS: Based on the literature, CYP3A4/CYP3A5 polymorphic variants were selected and further interpreted as individual, combined, and clustered phenotypes. The pharmacokinetic (PK) parameters for midostaurin and the active metabolites were estimated based on concentration data collected after the first dose (full PK profile) and during the induction, consolidation, and post-consolidation phases at trough (pre-dose) and post-dose 3 h. Adverse event (AE) summaries included all treatment-emergent AEs starting on or after study day 1 and starting no later than 30 days after study treatment discontinuation. RESULTS: PK profiles and parameters of midostaurin and its metabolites after the first dose and multiple dosing, at steady state, at the different visits through different phases of the study were generally comparable across CYP3A4/CYP3A5 polymorphic variants and clustered phenotypes. The safety profile of midostaurin in this study was consistent with the known safety profile of midostaurin in FLT3-mutation-positive patients with AML. No meaningful differences were observed in the safety profile of midostaurin versus placebo in patients with CYP3A4/CYP3A5 polymorphic variants and clustered phenotype groups. CONCLUSION: Our extensive pharmacogenomic/PK/safety analysis in patients with AML does not indicate the need for dose adjustments of midostaurin based on CYP3A4/CYP3A5 polymorphic variants. CLINICALTRIALS.GOV NUMBER: NCT03512197.

PTEN hamartoma tumor syndrome (PHTS) is a rare genetic disorder caused by germline pathogenic variants in the PTEN tumor suppressor gene. Everolimus, an oral mTORC1 inhibitor, is approved for the treatment of tuberous sclerosis complex-related tumors; however, evidence for its efficacy in PHTS remains limited. A recent randomized controlled trial (RCT) reported safety and efficacy findings, but the composite primary efficacy endpoint did not reach statistical significance.

Longitudinal measuring of circulating tumor DNA (ctDNA) during systemic treatment of metastatic colorectal cancer (mCRC) is promising for disease monitoring, but it is hampered by high costs and lacks formal demonstration of clinical usefulness.

BACKGROUND: Guidelines recommend identifying individuals with a family or personal history of cancer, offering genetic testing, with the goal of managing disease risk. Yet, risk assessment (“screening”) and genetic testing remain underutilized in the primary care setting and the value of an optimal strategy for engaging individuals is unknown. Our goal is to estimate the incremental cost, incremental effectiveness, and incremental cost-effectiveness ratio (ICER) between two population-based engagement strategies in proportions of individuals risk assessed and tested, by providing these services in a primary care setting. METHODS: Data were obtained from the EDGE (Early Detection of GEnetic risk)-clinic-randomized controlled trial that evaluated two engagement strategies - an in-clinic point of care (POC) strategy and a direct participant engagement (DPE) strategy that involved (e)mailing invitations after a visit. At risk participants were offered complementary genetic testing and counseling. Using these data, we constructed a decision-analytic cohort model and compared the POC to DPE strategy. We modeled testing all clinic participants over a two-year timeframe and present results from both health-system and limited societal perspectives. Outcomes were the proportion of participants risk-assessed and tested, the costs for each strategy, and the ICERs. RESULTS: From the health-system perspective, costs for approaching 100,000 participants were $641,278 (POC) and $702,653 (DPE). The POC strategy led to 14,490 (46%) of participants completing risk assessment and the DPE strategy to 6,385 (7%) participants, thus POC dominated DPE for risk assessment completion (68% of simulations). The POC strategy led to fewer individuals completing testing than the DPE strategy [780 (73%) vs. 1,184 (77%)], revealing an ICER of $152 (health-system) and $136 (limited societal) perspectives in favor of DPE (52% and 58% of simulations). With substantial uncertainty, results suggest that the DPE strategy may provide good value for money spent on testing at a willingness-to-pay test-kit cost of $250. CONCLUSIONS AND RELEVANCE: That the incremental cost-effectiveness of risk assessment versus testing contrasts, suggests that engagement approaches play an important role in shaping outcomes of population-based risk assessments. A hybrid approach (DPE, followed by POC for those who do not respond) may be optimally cost-effective. TRIAL REGISTRATION: NCT04746794; Date: February 4, 2021.

Adding the pan-Akt serine/threonine kinase (AKT) inhibitor capivasertib to first-line paclitaxel in metastatic triple-negative breast cancer (TNBC) led to significantly longer progression-free survival (PFS) and overall survival (OS) versus placebo-paclitaxel in the phase II PAKT trial. CAPItello-290 was designed to further assess capivasertib-paclitaxel, including in patients with PIK3CA/AKT1/PTEN-altered tumours.

The identification of lung squamous cell carcinoma (LUSC) patients who may benefit from first-line chemo-immunotherapy (CIT) remains a challenge. This study aimed to develop a pathomics model to predict the T cell-inflamed gene-expression profile (GEP) status and validate its utility in identifying patients who derive survival benefit from CIT.

We aimed to describe the association between molecular sub-groups and outcomes in patients with advanced/metastatic endometrial carcinoma amenable to maintenance/active surveillance after carboplatin-based chemotherapy.

CDK2 is a principal mediator of CDK4/6 resistance. Concurrent CDK2/4/6 blockade may be effective in treating HR-positive, HER2-negative advanced breast cancer (ABC). This randomized, double-blind, parallel-controlled, phase 3 trial (ClinicalTrials.gov, NCT05375461) assessed the efficacy of culmerciclib, a CDK2/4/6 inhibitor, plus fulvestrant in ABC. Patients with HR-positive, HER2-negative, locally recurrent or metastatic breast cancer were randomized (2:1) to receive culmerciclib plus fulvestrant or matching placebo plus fulvestrant. Between March 18, 2022 and March 3, 2023, 293 pretreated patients (median age 53.0 years; pre- or perimenopausal 42.3%; bone metastasis 65.2%) were randomized to assigned treatments. At this prespecified interim analysis, culmerciclib plus fulvestrant extended the median investigator-assessed progression-free survival (PFS) significantly, the primary endpoint, as compared with placebo plus fulvestrant (16.6 months, 95% CI 13.8 to not evaluable versus 7.5 months, 95% CI 5.3 to 11.0; hazard ratio 0.36, 95% CI 0.26-0.51; stratified log rank test P < 0.001). Consistent effects were observed across diverse subgroups of patients. At a median follow-up duration of 13.8 months, overall survival was immature. The investigators-assessed objective response rate was 40.2% (95% CI, 33.3-47.5) for culmerciclib compared to 12.1% (95% CI 6.4-20.2) for placebo (stratified Mantel-Haenszel χ2 test P < 0.001). Diarrhea (87.1%) and neutropenia (80.4%) were the most common toxicities with culmerciclib plus fulvestrant. In conclusion, this randomized clinical trial met its primary outcome. Culmerciclib plus fulvestrant is well tolerated and leads to a significant gain in PFS of pretreated HR-positive HER2-negative ABC patients.

Cell-free DNA (cfDNA) is an emerging technology to predict and monitor response to cancer treatment, including immune checkpoint blockade (ICB). However, data on cfDNA dynamics during ICB in metastatic triple negative breast cancer (mTNBC) are limited. While most applications of cfDNA involve assays that focus on mutation detection, mTNBC and multiple other cancer types are driven by copy-number alterations (CNAs). We evaluate cfDNA-based copy-number profile abnormality (CPA) score as a potential biomarker for monitoring ICB response in mTNBC, analyzing data from 87 patients enrolled in stage 1 and stage 2 of the TONIC trial. We find significant concordance between cfDNA-based and tissue-based CNA profiles. Additionally, responders show a decrease in CPA scores upon ICB at week 6 (three cycles of nivolumab). These findings underscore the potential of cfDNA-based CNA dynamics as a non-invasive biomarker for ICB early response assessment in patients with mTNBC. The TONIC trial is registered at ClinicalTrial.gov (NCT02499367).

Treatment decisions in patients with unresectable colorectal liver metastases (CRLM) are largely guided by radiological response to induction systemic therapy. However, radiological assessment alone provides an imprecise estimate of underlying tumour biology or treatment response. Circulating tumour DNA (ctDNA) is an emerging biomarker that can support clinical decision-making. This study evaluated the independent prognostic value of radiological tumour burden and DELFI-TF, a tumour tissue- and mutation-independent cell-free DNA (cfDNA) fragmentome-based ctDNA assay.

Pembrolizumab plus olaparib versus pembrolizumab plus chemotherapy was evaluated as postinduction therapy for patients with PD-L1-unselected locally recurrent inoperable/metastatic triple-negative breast cancer (TNBC) who derived clinical benefit from first-line pembrolizumab plus platinum-based chemotherapy induction therapy.

At the primary progression-free survival (PFS) analysis, the phase III EMBER-3 trial in endocrine therapy-pretreated patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) demonstrated significant PFS benefit with imlunestrant versus standard of care (SOC: fulvestrant or exemestane) in patients with ESR1 mutations (ESR1m) and with imlunestrant-abemaciclib versus imlunestrant in all patients, regardless of ESR1m. In this article, we report updated efficacy from a prespecified interim overall survival (OS) analysis.

Evidence that a healthcare intervention is clinically effective and cost-effective, and subsequently funded, does not guarantee adoption into routine clinical practice. Implementation science can improve adoption, although it also involves valuable resources. This study assessed the cost-effectiveness of a theory-based implementation approach compared with an intuition-based one, using genetic testing for Lynch syndrome as a case study.

The prevalence of pathogenic or likely pathogenic variants (PVs) in breast cancer susceptibility genes in the US population-regardless of family history risk factors-remains largely unknown because population-based genetic screening is not routinely performed.

Neoadjuvant chemotherapy is standard for high-risk hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. This study evaluates whether 12 months of letrozole plus abemaciclib could be an alternative.

Individual breast cancer risk can guide screening initiation, frequency, use of supplemental imaging, and preventive measures to improve breast cancer screening by shifting resources from low-risk women to high-risk women.