A review of trials investigating ctDNA-guided adjuvant treatment of solid tumors: The importance of trial design.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for guiding adjuvant treatment decisions in solid tumors. This review systematically assembles ongoing and published trials investigating ctDNA-directed adjuvant treatment strategies. A total of 57 phase II/III trials focusing on ctDNA in minimal residual disease (MRD) detection were identified, with a notable increase in initiation over recent years. Most trials target stage II or III colon/colorectal cancer, followed by breast cancer and non-small cell lung cancer. Trial methodologies vary, with some randomizing ctDNA-positive patients between standard-of-care (SoC) treatment and intensified regimens, while others aim to de-escalate therapy in ctDNA-negative patients. Challenges in trial design include the need for randomized controlled trials to establish clinical utility for ctDNA, ensuring adherence to standard treatment in control arms, and addressing the ethical dilemma of withholding treatment in high-risk ctDNA-positive patients. Longitudinal ctDNA surveillance emerges as a strategy to improve sensitivity for recurrence, particularly in less proliferative tumor types. However, ctDNA as longitudinal marker is often not validated yet. Ultimately, designing effective ctDNA interventional trials requires careful consideration of feasibility, meaningful outcomes, and potential impact on patient care.

Comprehensive characterization of circulating tumor cells and cell-free DNA in patients with metastatic melanoma.

Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head-to-head comparison of several techniques to analyze circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in 20 patients with metastatic melanoma. In this study, we investigated whether diagnostic leukapheresis (DLA) combined with multimarker flow cytometry (FCM) increased the detection of CTCs in blood compared to the CellSearch platform. Additionally, we characterized cfDNA at the level of somatic mutations, extent of aneuploidy and genome-wide DNA methylation. Both CTCs and cfDNA measures were compared to tumor markers and extracranial tumor burden on radiological imaging. Compared to the CellSearch method applied on peripheral blood, DLA combined with FCM increased the proportion of patients with detectable CTCs from 35% to 70% (P = 0.06). However, the median percentage of cells that could be recovered by the DLA procedure was 29%. Alternatively, cfDNA mutation and methylation analysis detected tumor load in the majority of patients (90% and 93% of samples successfully analyzed, respectively). The aneuploidy score was positive in 35% of all patients. From all tumor measurements in blood, lactate dehydrogenase (LDH) levels were significantly correlated to variant allele frequency (P = 0.004). Furthermore, the presence of CTCs in DLA was associated with tumor burden (P < 0.001), whereas the presence of CTCs in peripheral blood was associated with number of lesions on radiological imaging (P < 0.001). In conclusion, DLA tended to increase the proportion of patients with detectable CTCs but was also associated with low recovery. Both cfDNA and CTCs were correlated with clinical parameters such as LDH levels and extracranial tumor burden.

Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells: a phase II trial.

PURPOSE: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. METHODS: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual. RESULTS: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1-131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51). CONCLUSION: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.

Integrative whole-genome and transcriptome analysis of HER2-amplified metastatic breast cancer.

BACKGROUND: In breast cancer, the advent of anti-HER2 therapies has made HER2+ tumors a highly relevant subgroup. However, the exact characteristics which prohibit clinical response to anti-HER2 therapies and drive disease progression are not yet fully known. Integrative whole-genome and transcriptomic sequencing data from both primary and metastatic HER2-positive breast cancer will enhance our understanding of underlying biological processes. METHODS: Here, we used WGS and RNA sequencing data of 700 metastatic breast tumors, of which 68 being HER2+, to search for specific genomic features of HER2+ disease and therapy resistance. Furthermore, we integrated results with transcriptomic data to associate tumors exhibiting a HER2+-specific gene expression profile with ERBB2 mutation status, prior therapy and relevant gene expression signatures. RESULTS: Overall genomic profiles of primary and metastatic HER2+ breast cancers were similar, and no specific acquired genomics traits connected to prior anti-HER2 treatment were observed. However, specific genomic features were predictive of progression-free survival on post-biopsy anti-HER2 treatment. Furthermore, a HER2-driven expression profile grouped HER2-amplified tumors with ERBB2-mutated cases and cases without HER2 alterations. The latter were reported as ER positive in primary disease, but the metastatic biopsy showed low ESR1 expression and upregulation of the MAPK pathway, suggesting transformation to ER independence. CONCLUSIONS: In summary, although the quantity of variants increased throughout HER2-positive breast cancer progression, the genomic composition remained largely consistent, thus yielding no new major processes beside those already operational in primary disease. Our results suggest that integrated genomic and transcriptomic analyses may be key in establishing therapeutic options.

Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling.

Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.

Combatting the rising costs of cancer drugs; interventions from a university hospital's perspective.

Rapid increase in cost continues to have negative impact on patients' accessibility to life-changing anticancer medications. Moreover, the rising cost does not equate to similar increase in medication effectiveness. We recognise our responsibility as a university hospital to tackle this imbalance and strive to provide high quality, sustainable, affordable and accessible care. An active approach in cost containment of expensive and innovative cancer drugs was adopted in our organisation to safeguard accessibility and improve quality of life for patients. In this article, we described four inverventions: 1) identify right patient and minimise overtreatment, 2) in-house medicine production for selected indications, 3) minimise medicine spillages and 4) effective procurement strategies. We call on other hospitals to take action and, favourably, to collaborate on a European level. Together, we will safeguard the current and future care of our patients.

Tumor-agnostic ctDNA levels by mFAST-SeqS in first-line HR-positive, HER2 negative metastatic breast cancer patients as a biomarker for survival.

This prospective cohort study reports aneuploidy score by mFast-SeqS as a strong prognostic marker in MBC patients. mFAST-SeqS is an affordable and easily implementable method for the assessment of total ctDNA levels and, as such, provides an alternative prognostic tool. One mixed cohort (cohort A, n = 45) starting any type of treatment in any line of therapy and one larger cohort (cohort B, n = 129) consisting of patients starting aromatase inhibitors (AI) as first-line therapy were used. mFAST-SeqS was performed using plasma of blood in which CTCs (CellSearch) were enumerated. The resulting aneuploidy score was correlated with categorized CTC count and associated with outcome. The aneuploidy score was significantly correlated with CTC count, but discordance was observed in 31.6% when applying cut-offs of 5. In both cohorts, aneuploidy score was a significant prognostic marker for both PFS and OS. In the Cox regression models, the HR for aneuploidy score for PFS was 2.52 (95% CI: 1.56-4.07), and the HR for OS was 2.37 (95% CI: 1.36-4.14). Results presented here warrant further investigations into the clinical utility of this marker in MBC patients.

Local treatment in metastatic GIST patients: A multicentre analysis from the Dutch GIST Registry.

BACKGROUND: The added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of a survey study and retrospective analyses in a clinical database. METHODS: A survey study was conducted among clinical specialists to select most relevant characteristics of metastatic GIST patients considered for local treatment, defined as elective surgery or ablation. Patients were selected from the Dutch GIST Registry. A multivariate Cox-regression model for overall survival since time of diagnosis of metastatic disease was estimated with local treatment as a time-dependent variable. An additional model was estimated to assess prognostic factors since local treatment. RESULTS: The survey's response rate was 14/16. Performance status, response to TKIs, location of active disease, number of lesions, mutation status, and time between primary diagnosis and metastases, were regarded the 6 most important characteristics. Of 457 included patients, 123 underwent local treatment, which was associated with better survival after diagnosis of metastases (HR = 0.558, 95%CI = 0.336-0.928). Progressive disease during systemic treatment (HR = 3.885, 95%CI = 1.195-12.627) and disease confined to the liver (HR = 0.269, 95%CI = 0.082-0.880) were associated with worse and better survival after local treatment, respectively. CONCLUSION: Local treatment is associated with better survival in selected patients with metastatic GIST. Locally treated patients with response to TKIs and disease confined to the liver have good clinical outcome. These results might be considered for tailoring treatment, but should be interpreted with care because only specific patients are provided with local treatment in this retrospective study.

Physical symptom burden in patients with desmoid-type fibromatosis and its impact on health-related quality of life and healthcare use.

BACKGROUND: Desmoid-type fibromatosis (DTF) has a highly variable clinical course with varying intensity of symptoms. The objectives of this study were to identify subgroups of DTF patients based on physical symptom burden and to compare symptom burden subgroups on health-related quality of life (HRQoL) and healthcare use (univariate and multivariate). METHODS: Desmoid-type fibromatosis patients from the United Kingdom and the Netherlands received cross-sectional questionnaires on HRQoL (EORTC QLQ-C30), DTF-specific HRQoL (DTF-QoL) and healthcare utilisation. Latent class cluster analysis was performed to identify subgroups based on patients' symptom burden using EORTC QLQ-C30 and DTF-QoL physical symptom items. Multivariate linear and logistic regression analyses were conducted to examine associations of symptom burden with HRQoL and healthcare utilisation, respectively. RESULTS: Among 235 DTF patients, four symptom burden clusters were identified, with low symptom burden (24%), intermediate symptom burden-low pain (20%), intermediate symptom burden-high pain (25%) and high symptom burden (31%). DTF patients with high symptom burden had clinically relevant lower HRQoL scores compared to patients with low and intermediate symptom burden (p < 0.001) and reported more general and DTF-related visits to their general practitioner compared to the low symptom burden cluster (p < 0.01). In the multivariate analyses, symptom burden was independently associated with both HRQoL and healthcare utilisation. CONCLUSIONS: This study identified four distinct subgroups of DTF patients based on their level of symptom burden, with a considerable number of patients being highly symptomatic. Knowledge of the level of symptom burden DTF patients experience can help to identify patients at risk of poorer outcomes and tailor supportive care to the individual needs of DTF patients.

Methylated Cell-Free DNA Sequencing (MeD-seq) of LpnPI Digested Fragments to Identify Early Progression in Metastatic Renal Cell Carcinoma Patients on Watchful Waiting.

According to the current guidelines, watchful waiting (WW) is a feasible option for patients with good or intermediate prognosis renal-cell carcinoma (RCC). However, some patients rapidly progress during WW, requiring the initiation of treatment. Here, we explore whether we can identify those patients using circulating cell-free DNA (cfDNA) methylation. We first defined a panel of RCC-specific circulating methylation markers by intersecting differentially methylated regions from a publicly available dataset with known RCC methylation markers from the literature. The resulting RCC-specific methylation marker panel of 22 markers was subsequently evaluated for an association with rapid progression by methylated DNA sequencing (MeD-seq) in serum from 10 HBDs and 34 RCC patients with a good or intermediate prognosis starting WW in the IMPACT-RCC study. Patients with an elevated RCC-specific methylation score compared to HBDs had a shorter progression-free survival (PFS, p = 0.018), but not a shorter WW-time (p = 0.15). Cox proportional hazards regression showed that only the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria were significantly associated with WW time (HR 2.01, p = 0.01), whereas only our RCC-specific methylation score (HR 4.45, p = 0.02) was significantly associated with PFS. The results of this study suggest that cfDNA methylation is predictive of PFS but not WW.

Health-related Quality of Life of Patients With Non-Intra-abdominal Desmoid-Type Fibromatosis During Active Surveillance: Results of a Prospective Observational Study.

OBJECTIVE: To examine the impact of an active surveillance (AS) approach on the health-related quality of life (HRQoL) of patients with desmoid-type fibromatosis (DTF). BACKGROUND DATA: AS is recommended as initial approach in DTF patients. AS might however negatively affect HRQoL due to physical symptoms or stress and anxiety. METHODS: In a prospective observational study, the GRAFITI trial (NTR4714), DTF patients were followed during an initial AS approach for 3 years. HRQoL was assessed by the EORTC QLQ-C30 at baseline, 6, 12 and 24-month follow-up. Patients who completed questionnaires at≥1-time point were included in this analysis of the secondary endpoint. A multivariable linear mixed-effects model with random intercept was conducted to assess trends of HRQoL scores over time and to explore the effect of treatment strategy on HRQoL. RESULTS: All 105 patients enrolled in the GRAFITI trial were eligible for the HRQoL analyses. During 24-month follow-up, 75 patients (71%) continued AS and 30 patients (29%) started an active treatment (AT). DTF patients who continued AS demonstrated relatively stable HRQoL scores during follow-up. HRQoL scores of patients who started AT worsened compared to patients who continued AS, although no significant changes in HRQoL score over time were found in the mixed-model analyses. Overall, DTF patients who started AT scored significantly worse on pain (ß=10.08, P =0.039) compared to patients who continued AS. CONCLUSIONS: An initial AS approach did not impair HRQoL of DTF patients who continued AS over time, therefore providing further support for AS as the frontline approach in DTF patients. Longitudinal assessment of HRQoL should be part of clinical follow-up to identify patients who may need a change in treatment strategy.

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors.

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.

A Nationwide Prospective Clinical Trial on Active Surveillance in Patients With Non-intraabdominal Desmoid-type Fibromatosis: The GRAFITI Trial.

OBJECTIVE: To assess tumor behavior and the efficacy of active surveillance (AS) in patients with desmoid-type fibromatosis (DTF). SUMMARY OF BACKGROUND DATA: AS is recommended as initial management for DTF patients. Prospective data regarding the results of AS are lacking. METHODS: In this multicenter prospective cohort study (NTR4714), adult patients with non-intraabdominal DTF were followed during an initial AS approach for 3 years. Tumor behavior was evaluated according to Response Evaluation Criteria in Solid Tumors. Cumulative incidence of the start of an active treatment and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Factors predictive for start of active treatment were assessed by Cox regression analyses. RESULTS: A total of 105 patients started with AS. Median tumor size at baseline was 4.1cm (interquartile range 3.0-6.6). Fifty-seven patients had a T41A CTNNB1 mutation; 14 patients a S45F CTNNB1 mutation. At 3 years, cumulative incidence of the start of active treatment was 30% (95% confidence interval [CI] 21-39) and PFS was 58% (95% CI 49-69). Median time to start active treatment and PFS were not reached at a median follow-up of 33.7 months. During AS, 32% of patients had stable disease, 28% regressed, and 40% demonstrated initial progression. Larger tumor size (≥5 cm; hazard ratio = 2.38 [95% CI 1.15-4.90]) and S45F mutation (hazard ratio = 6.24 [95% CI 1.92-20.30]) were associated with the start of active treatment. CONCLUSIONS: The majority DTF patients undergoing AS do not need an active treatment and experience stable or regressive disease, even after initial progression. Knowledge about the natural behavior of DTF will help to tailor the follow-up schedule to the individual patient.

Risk of metachronous contralateral breast cancer in patients with primary invasive lobular breast cancer: Results from a nationwide cohort.

Lobular primary breast cancer (PBC) histology has been proposed as a risk factor for contralateral breast cancer (CBC), but results have been inconsistent. We investigated CBC risk and the impact of systemic therapy in lobular versus ductal PBC. Further, CBC characteristics following these histologic subtypes were explored. We selected 74,373 women diagnosed between 2003 and 2010 with stage I-III invasive PBC from the nationwide Netherlands Cancer Registry. We assessed absolute risk of CBC taking into account competing risks among those with lobular (n = 8903), lobular mixed with other types (n = 3512), versus ductal (n = 62,230) histology. Hazard ratios (HR) for CBC were estimated in a cause-specific Cox model, adjusting for age at PBC diagnosis, radiotherapy, chemotherapy and/or endocrine therapy. Multivariable HRs for CBC were 1.18 (95% CI: 1.04-1.33) for lobular and 1.37 (95% CI: 1.16-1.63) for lobular mixed versus ductal PBC. Ten-year cumulative CBC incidences in patients with lobular, lobular mixed versus ductal PBC were 3.2%, 3.6% versus 2.8% when treated with systemic therapy and 6.6%, 7.7% versus 5.6% in patients without systemic therapy, respectively. Metachronous CBCs were diagnosed in a less favourable stage in 19%, 26% and 23% and less favourable differentiation grade in 22%, 33% and 27% than the PBCs of patients with lobular, lobular mixed and ductal PBC, respectively. In conclusion, lobular and lobular mixed PBC histology are associated with modestly increased CBC risk. Personalised CBC risk assessment needs to consider PBC histology, including systemic treatment administration. The impact on prognosis of CBCs with unfavourable characteristics warrants further evaluation.

Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab.

Immune checkpoint inhibitors have revolutionised cancer treatment by offering durable responses to many patients with solid and haematological cancers. The high prices and increasing use of immune checkpoint inhibitors put considerable strain on health-care budgets globally. This financial strain could jeopardise patients' access to these anti-cancer therapies. However, substantial evidence suggests that immune checkpoint inhibitors are being administered at doses that exceed the minimum dose required for maximum anti-tumour efficacy. Therefore, investigating and implementing the most cost-effective dosing strategies for immune checkpoint inhibitors are urgently necessary. This Personal View provides an overview of existing data on immune checkpoint inhibitor pharmacology and (novel) dosing strategies for anti-PD-1 therapy with nivolumab and pembrolizumab, with a special focus on cost-effectiveness and saving potential. Furthermore, specific recommendations to guide health-care professionals are provided, through the process of prescribing, rounding, preparing, and administering nivolumab and pembrolizumab in the most practical and cost-effective way possible.

CABA-V7: a prospective biomarker selected trial of cabazitaxel treatment in AR-V7 positive prostate cancer patients.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) patients with positive AR-V7 expression in their circulating tumour cells (CTCs) rarely derive benefit from abiraterone and enzalutamide. DESIGN: We performed a prospective, multicenter, single arm phase II clinical trial (CABA-V7) in mCRPC patients previously treated with docetaxel and androgen deprivation therapy. OBJECTIVE: In this trial, we investigated whether cabazitaxel treatment resulted in clinically meaningful PSA response rates in patients with positive CTC-based AR-V7 expression and collected liquid biopsies for genomic profiling. RESULTS: Cabazitaxel was found to be modestly effective, with only 12% of these patients obtaining a PSA response. Genomic profiling revealed that CTC-based AR-V7 expression was not associated with other known mCRPC-associated alterations. CTC-based AR-V7 status and dichotomised CTC counts were observed as independent prognostic markers at baseline. CONCLUSIONS: AR-V7 positivity predicted poor overall survival (OS). However, cabazitaxel-treated AR-V7 positive patients and those lacking AR-V7 positivity, who received cabazitaxel as standard of care, appeared to have similar OS. Therefore, despite the low response rate, cabazitaxel may still be an effective treatment in this poor prognosis, AR-V7 positive patient population.

Intratumoral Niches of B Cells and Follicular Helper T Cells, and the Absence of Regulatory T Cells, Associate with Longer Survival in Early-Stage Oral Tongue Cancer Patients.

In early oral squamous cell carcinoma (OSCC), the occurrence of clusters between CD20 B cells and CD4 T cells in the invasive margin (IM) can be captured by using the CD20 cluster score, and is positively associated with patient survival. However, the exact contribution of different CD4 T cell subsets, as well as B cell subsets toward patient prognosis is largely unknown. To this end, we studied regulatory T cells ((Treg cells) FOXP3 and CD4), T helper-type 1 cells ((Th1 cells) Tbet and CD4), follicular helper T cells ((Tfh cells) Bcl6 and CD4), B cells (CD20), germinal center B cells ((GC B cells) BCL6 and CD20), and follicular dendritic cells ((fDCs) CD21) for their density, location, and interspacing using multiplex in situ immunofluorescence of 75 treatment-naïve, primary OSCC patients. We observed that Treg, Th1-, Tfh-, and GC B cells, but not fDCs, were abundantly present in the stroma as compared with the tumor, and in the IM as compared with in the center of the tumor. Patients with high CD20 cluster scores had a high density of all three CD4 T cell subsets and GC B cells in the stromal IM as compared with patients with low CD20 cluster scores. Notably, enriched abundance of Tfh cells (HR 0.20, p = 0.04), and diminished abundance of Treg cells (HR 0.10, p = 0.03), together with an overall short distance between Tfh and B cells (HR:0.08, p < 0.01), but not between Treg and B cells (HR 0.43, p = 0.28), were significantly associated with overall survival of patients with OSCC. Our study identified the prognostic value of clusters between CD20 B cells and Tfh cells in the stromal IM of OSCC patients, and enabled an improved understanding of the clinical value of a high CD20 cluster score, which requires validation in larger clinical cohorts.

Physicians' Perspectives on Ethical Issues Regarding Expensive Anti-Cancer Treatments: A Qualitative Study.

BACKGROUND: When anti-cancer treatments have been given market authorization, but are not (yet) reimbursed within a healthcare system, physicians are confronted with ethical dilemmas. Arranging access through other channels, e.g., hospital budgets or out-of-pocket payments by patients, may benefit patients, but leads to unequal access. Until now, little is known about the perspectives of physicians on access to non-reimbursed treatments. This interview study maps the experiences and moral views of Dutch oncologists and hematologists. METHODS: A diverse sample of oncologists and hematologists (n = 22) were interviewed. Interviews were analyzed thematically using Nvivo 12 qualitative data software. RESULTS: This study reveals stark differences between physicians' experiences and moral views on access to anti-cancer treatments that are not (yet) reimbursed: some physicians try to arrange other ways of access and some physicians do not. Some physicians inform patients about anti-cancer treatments that are not yet reimbursed, while others wait for reimbursement. Some physicians have principled moral objections to out-of-pocket payment, while others do not. CONCLUSION: Oncologists and hematologists in the Netherlands differ greatly in their perspectives on access to expensive anti-cancer treatments that are not (yet) reimbursed. As a result, they may act differently when confronted with dilemmas in the consultation room. Physicians working in different healthcare systems may face similar dilemmas.

Unraveling Desmoid-Type Fibromatosis-Specific Health-Related Quality of Life: Who Is at Risk for Poor Outcomes.

Desmoid-type fibromatosis (DTF) is a rare, soft-tissue tumour. These tumours do not metastasize, but their local aggressive tumour growth and unpredictable behaviour can have a significant impact on health-related quality of life (HRQoL). Little is known about which DTF patients are particularly affected by an impaired HRQoL. The objectives of this study were to assess HRQoL among different groups of DTF patients and to investigate which socio-demographic and clinical characteristics were associated with DTF-specific HRQoL. A cross-sectional study was conducted among DTF patients from the United Kingdom and the Netherlands. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), accompanied by the DTF-QoL to assess DTF-specific HRQoL. The scores were compared amongst subgroups, based on the socio-demographic and clinical characteristics of DTF patients. Multiple linear regression analyses with a backward elimination were conducted to identify the factors associated with DTF-specific HRQoL. A total of 235 DTF patients completed the questionnaires. Female patients, patients with more than two comorbidities, or patients who received treatment other than only active surveillance (AS) or surgery scored significantly worse on the subscales of both the EORTC QLQ-C30 and DTF-QoL. Patients that were ≥ 40 years scored significantly worse on the physical functioning scale of the EORTC QLQ-C30, while younger patients (18-39 years) scored significantly worse on several DTF-QoL subscales. Differences in the DTF-QoL subscales were found for tumour location, time since diagnosis and the presence of recurrent disease. Furthermore, treatments other than AS or surgery only, female sex, younger age and the presence of comorbidities were most frequently associated with worse scores on the DTF-QoL subscales. This study showed that (DTF-specific) HRQoL differs between groups of DTF patients. Awareness of these HRQoL differences could help to provide better, personalised care that is tailored to the needs of a specific subgroup.

ESR1 Methylation Measured in Cell-Free DNA to Evaluate Endocrine Resistance in Metastatic Breast Cancer Patients.

ESR1 methylation was proposed as mechanism for endocrine resistance in metastatic breast cancer patients. To evaluate its potential as a minimally invasive biomarker, we investigated the feasibility of measuring ESR1 methylation in cell-free DNA (cfDNA) and its association with endocrine resistance. First, we provided evidence that demethylation in vitro restores ER expression. Subsequently, we found that ESR1 methylation in cfDNA was not enriched in endocrine-resistant versus endocrine-sensitive patients. Interestingly, we found a correlation between ESR1 methylation and age. Publicly available data confirm an age-related increase in ESR1 methylation in leukocytes, confounding the determination of the ESR1 methylation status of tumors using cfDNA.