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Active surveillance versus treatment in low-risk DCIS: Women’s preferences in the LORD-trial

Background

Ductal carcinoma in situ (DCIS) can progress to invasive breast cancer (IBC), but most DCIS lesions remain indolent. However, guidelines recommend surgery, often supplemented by radiotherapy. This implies overtreatment of indolent DCIS. The non-randomised patient preference LORD-trial tests whether active surveillance (AS) for low-risk DCIS is safe, by giving women with low-risk DCIS a choice between AS and conventional treatment (CT). Here, we aim to describe how participants are distributed among both trial arms, identify their motives for their preference, and assess factors associated with their choice.

Methods

Data were extracted from baseline questionnaires. Descriptive statistics were used to assess the distribution and characteristics of participants; thematic analyses to extract self-reported reasons for the choice of trial arm, and multivariable logistic regression analyses to investigate associations between patient characteristics and chosen trial arm.

Results

Of 377 women included, 76% chose AS and 24% CT. Most frequently cited reasons for AS were “treatment is not (yet) necessary” (59%) and trust in the AS-plan (39%). Reasons for CT were cancer worry (51%) and perceived certainty (29%). Women opting for AS more often had lower educational levels (OR 0.45; 95% confidence interval [CI], 0.22–0.93) and more often reported experiencing shared decision making (OR 2.71; 95% CI, 1.37–5.37) than women choosing CT.

Conclusion

The LORD-trial is the first to offer women with low-risk DCIS a choice between CT and AS. Most women opted for AS and reported high levels of trust in the safety of AS. Their preferences highlight the necessity to establish the safety of AS for low-risk DCIS.

Team PRECISION
Journal European Journal of Cancer
Authors Renée S.J.M. Schmitz et al
DATE 03 August 2023
Inverse relationship between Fusobacterium nucleatum amount and tumor CD274 (PD-L1) expression in colorectal carcinoma

Objectives


The CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence also supports an immunosuppressive effect of Fusobacterium nucleatum. We hypothesised that tumor CD274 overexpression might be inversely associated with abundance of F. nucleatum in colorectal carcinoma.

 

Methods


We assessed tumor CD274 expression by immunohistochemistry and F. nucleatum DNA within tumor tissue by quantitative PCR in 812 cases among 4465 incident rectal and colon cancer cases that had occurred in two prospective cohort studies. Multivariable logistic regression analyses with inverse probability weighting were used to adjust for selection bias because of tissue data availability and potential confounders including microsatellite instability status, CpG island methylator phenotype, LINE-1 methylation level and KRAS, BRAF and PIK3CA mutations.

 

Results


Fusobacterium nucleatum DNA was detected in tumor tissue in 109 (13%) cases. Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue (P = 0.0077). For one category-unit increase in three ordinal F. nucleatum categories (negative vs. low vs. high), multivariable-adjusted odds ratios (with 95% confidence interval) of the low, intermediate and high CD274 categories (vs. negative) were 0.78 (0.41–1.51), 0.64 (0.32–1.28) and 0.50 (0.25–0.99), respectively (Ptrend = 0.032).

 

Conclusions


Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting that different immunosuppressive mechanisms (i.e. PDCD1 immune checkpoint activation and tumor F. nucleatum enrichment) tend to be used by different tumor subgroups.

Team OPTIMISTICC
Journal Clinical & Translational Immunology
Authors Tomotaka Ugai et al
DATE 02 August 2023
FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy

Highlights

 

  • FOXC2 is upregulated in vasculogenic mimicry (VM)-proficient tumor cells
  • FOXC2 regulates endothelial genes in tumor cells
  • Severe hypoxia promotes quasi-endothelial differentiation of tumor cells
  • FOXC2-driven VM promotes resistance to anti-angiogenic therapy

Summary

 

Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood vessels, and their presence is generally associated with poor patient prognosis. Here we show that the transcription factor, Foxc2, promotes VM in diverse solid tumor types by driving ectopic expression of endothelial genes in tumor cells, a process that is stimulated by hypoxia. VM-proficient tumors are resistant to anti-angiogenic therapy, and suppression of Foxc2 augments response. This work establishes co-option of an embryonic endothelial transcription factor by tumor cells as a key mechanism driving VM proclivity and motivates the search for VM-inhibitory agents that could form the basis of combination therapies with anti-angiogenics.

Team IMAXT
Journal Cell Reports
Authors Ian G. Cannell et al
DATE 26 July 2023
Holtiella tumoricola gen. nov. sp. nov., isolated from a human clinical sample

The diversity of bacteria associated with biopsy material obtained from patients with colorectal cancer was investigated using culture techniques. A novel bacterium, strain CC70AT, was isolated by diluting a sample of homogenized tissue in anaerobic medium, and then plating to yield a pure culture. Strain CC70AT was a Gram-positive, strictly anaerobic, motile, rod-shaped bacterium. Formate, but not acetate, was a fermentative end-product from growth in peptone–yeast extract and peptone–yeast–glucose broth. The G+C content of DNA from strain CC70AT was 34.9 mol%. 16S rRNA gene sequence analysis revealed that the isolate was part of the phylum Bacillota. The closest described relatives of strain CC70AT were Cellulosilyticum lentocellum (93.3 %) and Cellulosilyticum ruminicola (93.3 and 91.9% sequence similarity across 16S rRNA gene, respectively). According to the data obtained in this work, strain CC70AT represents a novel bacterium belonging to a new genus for which the name Holtiella tumoricola gen. nov., sp. nov. is proposed. The type strain for our described novel species is CC70AT (=DSM 27931T= JCM 30568T).

Team OPTIMISTICC
Journal International Journal of Systematic and Evolutionary Microbiology
Authors Emma Allen-Vercoe et al
DATE 12 July 2023
Strain specificity in fusobacterial co-aggregation with colorectal cancer-relevant species

Objectives

The purpose of the present study was to characterize co-aggregation interactions between isolates of Fusobacterium nucleatum subsp. Animalis and other colorectal cancer (CRC)-relevant species.

Methods

Co-aggregation interactions were assessed by comparing optical density values following 2-h stationary strain co-incubations to strain optical density values when incubated alone. Co-aggregation was characterized between strains from a previously isolated, CRC biopsy-derived community and F. nucleatum subsp. Animalis, a species linked to CRC and known to be highly aggregative. Interactions were also investigated between the fusobacterial isolates and strains sourced from alternate human gastrointestinal samples whose closest species match aligned with species in the CRC biopsy-derived community.

Results

Co-aggregation interactions were observed to be strain-specific, varying between both F. nucleatum subsp. Animalis strains and different strains of the same co-aggregation partner species. F. nucleatum subsp. Animalis strains were observed to co-aggregate strongly with several taxa linked to CRC: Campylobacter concisusGemella spp., Hungatella hathewayi, and Parvimonas micra.

Conclusions

Co-aggregation interactions suggest the ability to encourage the formation of biofilms, and colonic biofilms, in turn, have been linked to promotion and/or progression of CRC. Co-aggregation between F. nucleatum subsp. Animalis and CRC-linked species such as C. concisusGemella spp., H. hathewayi, and P. micra may contribute to both biofilm formation along CRC lesions and to disease progression.

Team OPTIMISTICC
Journal Anaerobe
Authors Avery V. Robinson, Emma Allen-Vercoe
DATE 08 July 2023