Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We ...conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody-drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge.
This study explores the predictive and monitoring capabilities of clinical and multiparametric MR parameters in assessing capecitabine and temozolomide (CAPTEM) therapy response in patients with ...neuroendocrine tumors (NET).
This retrospective study (n = 44) assessed CAPTEM therapy response in neuroendocrine liver metastases (NELM) patients. Among 33 monitored patients, as a subgroup of the overall study cohort, pretherapeutic and follow-up MRI data (size, apparent diffusion coefficient ADC values, and signal intensities), along with clinical parameters (chromogranin A CgA and Ki-67%), were analyzed. Progression-free survival (PFS) served as the reference. Responders were defined as those with PFS ≥ 6 months.
Most patients were male (75%) and had G2 tumors (76%) with a pancreatic origin (84%). Median PFS was 5.7 months; Overall Survival (OS) was 25 months. Non-responders (NR) had higher Ki-67 in primary tumors (16.5
. 10%, p = 0.01) and increased hepatic burden (20%
. 5%, p = 0.007). NR showed elevated CgA post-treatment, while responders (R) exhibited a mild decrease. ADC changes differed significantly between groups, with NR having decreased ADCmin (-23%) and liver-adjusted ADCmean/ADCmean liver (-16%), compared to R's increases of ADCmin (50%) and ADCmean/ADCmean liver (30%). Receiver operating characteristic (ROC) analysis identified the highest area under the curve (AUC) (0.76) for a single parameter for ∆ ADC mean/liver ADCmean, with a cut-off of < 6.9 (76% sensitivity, 75% specificity). Combining ∆ Size NELM and ∆ ADCmin achieved the best balance (88% sensitivity, 60% specificity) outperforming ∆ Size NELM alone (69% sensitivity, 65% specificity). Kaplan-Meier analysis indicated significantly longer PFS for ∆ ADCmean/ADCmean liver < 6.9 (p = 0.024) and ∆ Size NELM > 0% + ∆ ADCmin < -2.9% (p = 0.021).
Survival analysis emphasizes the need for adapted response criteria, involving combined evaluation of CgA, ADC values, and tumor size for monitoring CAPTEM response in hepatic metastasized NETs.
The enzymatic release of a model drug from a polymer carrier inside a tumor using multispectral optical imaging in vivo in nude mice bearing colorectal carcinomas HT‐29 and DLD‐1 is demonstrated. ...Much higher release rate in vivo from a linear (30 kDa) (N‐2‐hydroxypropyl)methacrylamide‐based polymer compared with a high molecular weight branched (170 kDa) polymer conjugate is observed, probably due to steric hindrance of the cleavable spacer of the latter polymer to proteolytic enzymes. There is no significant difference in the relative biodistribution of the two polymers, but the branched polymer circulates much longer. Both polymers are labeled with two different fluorophores. Dyomics‐676 as a drug model is attached to the polymer via an enzymatically cleavable Gly‐Phe‐Leu‐Gly spacer; Dyomics 782 is bound to the same polymer via a nondegradable amide bond, enabling the tracking of the polymer carrier after i.v. application to mice.
Simultaneous biodistribution of N‐2‐hydroxypropyl)methacrylamide‐based polymer carrier and a lysosomotropic drug model in tumor bearing nude mice using multispectral optical imaging in vivo is demonstrated. The enzymatic release of a model drug inside the tumor is clearly shown. The significant influence of the molecular weight of the polymer to tumor accumulation and to the rate of drug release is confirmed.
Purpose To assess the eligibility of patients with advanced or recurrent solid malignancies presented to a molecular tumor board (MTB) at a large precision oncology center for inclusion in trials ...with the endpoints objective response rate (ORR) or duration of response (DOR) based on Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Methods Prospective patients with available imaging at the time of presentation in the MTB were included. Imaging data was reviewed for objectifiable measurable disease (MD) according to RECIST v1.1. Additionally, we evaluated the patients with MD for representativeness of the identified measurable lesion(s) in relation to the overall tumor burden. Results 262 patients with different solid malignancies were included. 177 patients (68%) had MD and 85 (32%) had non-measurable disease (NMD) at the time point of MTB presentation in accordance with RECIST v1.1. MD was not representative of the overall tumor burden in eleven patients (6%). The main reasons for NMD were lesions with longest diameter shorter than 10 mm (22%) and non-measurable peritoneal carcinomatosis (18%). Colorectal cancer and malignant melanoma displayed the highest rates of MD (> 75%). In contrast, gastric cancer, head and neck malignancies, and ovarian carcinoma had the lowest rates of MD (< 55%). In case of MD, the measurable lesions were representative of the overall tumor burden in the vast majority of cases (94%). Conclusion Approximately one third of cancer patients with advanced solid malignancies are not eligible for treatment response assessment in trials with endpoints ORR or DOR at the time of MTB presentation. The rate of patients eligible for trials with imaging endpoints differs significantly based on the underlying malignancy and should be taken under consideration during the planning of new precision oncology trials. Keywords: RECIST, Response assessment, MTB, Precision oncology
Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III ...histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized. Thus, we have investigated the endothelial effects of decreased endogenous SIRT1 in hypercholesterolemic ApoE-/- mice. We observed no difference in endothelial relaxation and eNOS (Ser1177) phosphorylation between 20-week old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice. However, SIRT1 prevented endothelial superoxide production, inhibited NF-kappaB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-kappaB signaling led to a more pronounced endothelial expression of ICAM-1 and VCAM-1 as compared to ApoE-/- SIRT1+/+ mice. In conclusion, endogenous SIRT1 diminishes endothelial activation in ApoE-/- mice, but does not affect endothelium-dependent vasodilatation.
The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with ...microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.
Background
Precision oncology, using comprehensive biomarker testing (cBT) to inform individual cancer diagnosis, prognosis and treatment, includes increasingly complex technology and clinical data ...sets. People impacted by cancer (patients and caregivers) and healthcare professionals (HCPs) face distinct challenges in navigating the cBT and personalized treatment landscape. This review summarizes evidence regarding cBT‐related communication between people impacted by cancer and HCPs and identifies important avenues for future research in precision oncology.
Methods
A scoping review was conducted using records published in PubMed during January 2017–August 2022, focusing on the breadth of topics on patient‐HCP communication and knowledge resources used by HCPs as guidance in cBT‐related communication. Data were extracted from records meeting inclusion criteria, and findings were summarized according to main topics.
Results
The search identified 287 unique records and data were extracted from 42 records, including nine from expert input. Most records originated from the United States included patients with different types of cancer, and oncologists were the main HCPs. Patients' motivation for undergoing cBT and receiving results was generally high in different settings. However, patients' understanding of cBT‐related concepts was limited, and their knowledge and information preferences changed based on cBT implications and significance to family members. HCPs were valued by patients as a trusted source of information. Limited evidence was available on HCPs' information‐seeking behavior and factors influencing cBT‐related knowledge and confidence, often self‐reported as insufficient.
Conclusions
Patient education by knowledgeable and confident HCPs, information management and a caring patient‐HCP relationship communicating continuity of care regardless of cBT results are crucial to empower patients and shared decision‐making in precision oncology. More data on the process and structure of cBT‐related communication, distinction between and characterization of different timepoints of patient‐HCP interactions are needed.
Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic ...colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial.
DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex.
In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%;
= 0.001) and significantly greater DpR (-40.0% vs. -24.7%;
< 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in
/
wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS:
< 0.001; OS:
= 0.012) and molecular subgroup (PFS:
< 0.001; OS:
< 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS:
< 0.001, HR 0.532; OS:
< 0.001, HR 0.574 vs. PFS:
= 0.107; OS:
= 0.965).
Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.
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