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Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from limited targeted treatment options. Following recent reports correlating Fibroblast growth factor-inducible 14 (Fn14) receptor overexpression in Estrogen Receptor (ER)-negative breast cancers with metastatic events, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of Nicotinamide phosphoribosyltransferase (NAMPT), which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients., (© 2024. The Author(s).)

Background: Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied., Methods: Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal-Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC., Results: There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (T EMRA ) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response., Conclusions: Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + T EMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer., Trial Registration: NCT02022202 . Registered 20 December 2013., (© 2024. The Author(s).)

Background: We have recently described circumferential nerve involvement of neuromuscular choristoma associated with desmoid-type fibromatosis (NMC-DTF) in cases involving the sciatic nerve, supporting a nerve-derived mechanism for the DTF. We wondered whether a similar growth pattern occurs in cases involving the brachial plexus (BP)., Methods: We reviewed all available magnetic resonance (MR) imaging in patients diagnosed at our institution with NMC or NMC-DTF of the BP. We also performed a literature search of patients with NMC or NMC-DTF of the BP., Results: In our clinical records, four patients with NMC of the BP were identified, and three developed NMC-DTF. All three patients had MR imaging evidence of circumferential encasement of the BP. In the literature, we identified 15 cases of NMC of the BP, of which 12 had identified NMC-DTF. Four published cases included MR images, and only two were of sufficient quality for review. The single provided image in both cases demonstrated a similar pattern of circumferential encasement of the BP by the NMC-DTF. One additional case report was published without MR images but described circumferential involvement in the surgical findings. One unpublished case of NMC-DTF of the BP from an international radiology meeting also had this circumferential pattern pattern on MRI., Conclusions: The MRI findings of circumferential nerve involvement in patients with NMC-DTF of the BP are similar to our previously reported data in patients with NMC-DTF of the sciatic nerve, providing further imaging-based support of a nerve-driven mechanism. Clinical implications are presented based on the proposed pathogenetic mechanism., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear., Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy., Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy., Exposure: TIL abundance in breast tissue from resected primary tumors., Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center., Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6)., Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p < 0.0001). For every 10-point increase in AMSH counts, there was a 16% increase in the risk of an RFS event (HR 1.16, 95% CI 1.08-1.25), and a 7% increase in the risk of death (HR 1.07, 95% CI 1.00-1.14). We corroborated these findings in a separate cohort of systemically untreated TNBC patients from Radboud UMC in the Netherlands. Our findings suggest that AMSH counts offer valuable prognostic information in patients with early-stage TNBC who did not receive systemic therapy, independent of tumor size, nodal status, and TILs. If further validated, AMSH counts could help inform future systemic therapy de-escalation strategies., (© 2024. The Author(s).)

In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression., (© 2024. The Author(s).)

Importance: Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD., Objectives: To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy., Design, Setting, and Participants: In this retrospective cohort study, BBD biopsy specimens collected from January 1, 2002, to December 31, 2013, from patients with BBD at Mayo Clinic in Rochester, Minnesota, were reviewed by 2 pathologists masked to outcomes. Women were followed up from 6 months after biopsy until censoring, BC diagnosis, or December 31, 2021., Exposure: Benign breast disease classification and multiplicity by pathology panel review., Main Outcomes: The main outcome was diagnosis of BC overall and stratified as ductal carcinoma in situ (DCIS) or invasive BC. Risk for presence vs absence of BBD lesions was assessed by Cox proportional hazards regression. Risk in patients with BBD compared with female breast cancer incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) program were estimated., Results: Among 4819 female participants, median age was 51 years (IQR, 43-62 years). Median follow-up was 10.9 years (IQR, 7.7-14.2 years) for control individuals without BC vs 6.6 years (IQR, 3.7-10.1 years) for patients with BC. Risk was higher in the cohort with BBD than in SEER data: BC overall (standard incidence ratio [SIR], 1.95; 95% CI, 1.76-2.17), invasive BC (SIR, 1.56; 95% CI, 1.37-1.78), and DCIS (SIR, 3.10; 95% CI, 2.54-3.77). The SIRs increased with increasing BBD severity (1.42 [95% CI, 1.19-1.71] for NP, 2.19 [95% CI, 1.88-2.54] for PDWA, and 3.91 [95% CI, 2.97-5.14] for AH), comparable to surgical cohorts with BBD. Risk also increased with increasing lesion multiplicity (SIR: 2.40 [95% CI, 2.06-2.79] for ≥3 foci of NP, 3.72 [95% CI, 2.31-5.99] for ≥3 foci of PDWA, and 5.29 [95% CI, 3.37-8.29] for ≥3 foci of AH). Ten-year BC cumulative incidence was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH vs an expected population cumulative incidence of 2.9%., Conclusions and Relevance: In this contemporary cohort study of women diagnosed with BBD in the percutaneous biopsy era, overall risk of BC was increased vs the general population (DCIS and invasive cancer combined), similar to that in historical BBD cohorts. Development and validation of pathologic classifications including both BBD severity and multiplicity may enable improved BC risk stratification.

Background: Lipomatosis of nerve (LN) is a rare disorder characterized by the massive enlargement of peripheral nerves, frequently accompanied by generalized fibroadipose proliferation and skeletal overgrowth., Observations: The authors have been routinely following a 20-year-old male for lipomatosis of median nerve at the wrist noted shortly after birth. He had undergone resection of the lesion accompanied by sural nerve grafting at another institution. Clinically, although his neurological loss of function has been stable, he has had continued soft tissue growth. Serial magnetic resonance imaging has revealed persistent LN proximal to the repair sites with evidence of fatty proliferation in the sural grafts and continued LN and fatty proliferation distally. There has been a progressive circumferential pattern of fibrosis around the proximal and distal suture lines, which has a similar radiological pattern to desmoid type fibromatosis (a pattern recently described in neuromuscular choristoma [NMC] desmoid-type fibromatosis)., Lessons: Considering the similar reaction of nerve in both LN and NMC despite differing genetic cascades, the authors believe a unifying process occurs in both lesions. The pattern of circumferential fibroproliferation would be most consistent with neuron-mediated growth from unspecified trophic factors, supporting a previously reported a nerve-derived "inside-out mechanism." The clinical consequences of this unifying process are presented.