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Dormant disseminated tumor cells (DTCs) remain viable for years to decades before establishing a clinically overt metastatic lesion. DTCs are known to be highly resilient and able to overcome the multiple biological hurdles imposed along the metastatic cascade. However, the specific metabolic adaptations of dormant DTCs remain to be elucidated. Here, we reveal that dormant DTCs upregulate de novo lipogenesis and favor the activation and incorporation of monounsaturated fatty acids (MUFAs) to their cellular membranes through the activation of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3). Pharmacologic inhibition of de novo lipogenesis or genetic knockdown of ACSL3 results in lipid peroxidation and non-apoptotic cell death through ferroptosis. Clinically, ACSL3 was found to be overexpressed in quiescent DTCs in the lymph nodes of breast cancer patients and to significantly correlate with shorter disease-free and overall survival. Our work provides new insights into the molecular mechanisms enabling the survival of dormant DTCs and supports the use of de novo lipogenesis inhibitors to prevent breast cancer metastasis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.-M.F. has received funding from BlackBelt Therapeutics, Gilead and Alesta Therapeutics, is in the advisory board of Alesta Therapeutics, has consulted for Fund+ and Droia Ventures and is in the advisory board of several Cell Press Journals. All other authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This study aimed to validate the classification of breast cancer (BC) patients in progression risk groups based on total tumor load (TTL) value to predict lymph node (LN) affectation after neo-adjuvant systemic therapy (NAST) obtained in the NEOVATTL study., Methods/patients: This was an observational, retrospective, international, multicenter study including patients with infiltrating BC who received NAST followed by sentinel lymph node biopsy (SLNB) analyzed with one-step nucleic acid amplification (OSNA) from nine Spanish and two Italian hospitals. Patients were classified into three groups according to the progression risk, measured as disease-free survival (DFS), based on TTL values (> 250, 250-25,000, and > 25,000 copies/μL). The previous (NEOVATTL study) Cox regression model for prognosis was validated using prognostic index (PI) and Log ratio test (LRT) analyses; the value of TTL for axillary non-SLN affectation was assessed using receiver operating characteristic (ROC) curves., Results: We included 263 patients with a mean age of 51.4 (± SD 10.5) years. Patients with TTL > 25,000 copies/μL had a shorter DFS (HR 3.561 [95% CI 1.693-7.489], p = 0.0008 vs. TTL ≤ 25,000). PI and LRT analyses showed no differences between the two cohorts (p = 0.2553 and p = 0.226, respectively). ROC analysis showed concordance between TTL and non-SLN involvement (area under the curve 0.828), with 95.7% sensitivity and 92.9% specificity at a TTL cut-off of > 15,000 copies/μL., Conclusions: In BC patients who had received NAST and underwent SLNB analysis using OSNA, a TTL value of > 25,000 copies/μL was associated with a higher progression risk and > 15,000 copies/μL was predictive of non-SLN involvement., (© 2023. The Author(s).)

Purpose: This study aimed to compare the prognosis in terms of disease-free survival (DFS) in three populations of women with breast cancer (BC) treated with neoadjuvant systemic treatment (NAST) in which axillary lymph node dissection (ALND) was performed based on different total tumor load (TTL) thresholds in the sentinel nodes., Methods: This was an observational, retrospective study carried out in three Spanish centers. Data from patients with infiltrating BC who underwent BC surgery after NAST and intraoperative sentinel lymph node biopsy (SLNB) performed by One Step Nucleic acid Amplification (OSNA) technique during 2017 and 2018 were analyzed. ALND was performed according to the protocol of each center, based on three different TTL cut-offs (TTL > 250, TTL > 5000, and TTL > 15,000 CK19-mRNA copies/μL for centers 1, 2, and 3, respectively)., Results: A total of 157 BC patients were included in the study. No significant differences in DFS were observed between centers (Hazard ratio [HR] center 2 vs 1: 0.77; p = 0.707; HR center 3 vs 1: 0.83; p = 0.799). Patients with ALND had a shorter DFS (HR 2.43; p = 0.136), albeit not statistically significant. Patients with a triple negative subtype had a worse prognosis than those with other molecular subtypes (HR 2.82; p = 0.056)., Conclusion: No significant differences in DFS were observed between three centers with different surgical approaches to ALND based on different TTL cut-offs in patients with BC after NAST. These results suggest that restricting ALND to those patients with TTL ≥ 15,000 copies/μL is a reliable approximation, avoiding unnecessary morbidities caused by ALND., (© 2023. The Author(s).)

Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature. Experimental Design: Patient survival data were determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX). Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer. Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. Clin Cancer Res; 24(22); 5697-709. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Lymphatic metastasis is regulated in multiple steps including the transit of tumor cells via the lymphatic vessels and the successful seeding in draining lymph nodes. Thus, several molecular signals and cellular changes must be involved in this complex process to facilitate tumor cell entry, colonization, and survival in the lymph node. To our knowledge, the present work explores, for the first time in the literature, the redox status (oxidative stress parameters and enzymatic and non-enzymatic antioxidant defense systems) in the sentinel lymph node (SLN) of women with breast cancer., Patients and Methods: SLNs from 75 women with breast cancer were identified using the one-step nucleic acid amplification (OSNA) method as negative (n = 43), with micrometastases (n = 13), or with macrometastases (n = 19). It will allow us to gain knowledge about the pro-oxidant/antioxidant mechanisms involved in the processes of distant metastases in breast cancer and also to assess whether these parameters may be alternative techniques for staging., Results: We found different levels of lipid peroxidation in SLNs with micrometastases (increased) and macrometastases (decreased), a decrease in carbonyl group content in SLNs with macrometastases only, and an increase in total antioxidant capacity (TAC) in SNLs with micrometastases and macrometastases. A decrease in the levels of reduced glutathione (GSH) also appears in the SLNs with macrometastases only. Finally, we show increased levels of superoxide dismutase (SOD) and catalase (CAT) activity in SLNs with micrometastases and macrometastases, and decreased levels of glutathione peroxidase (GPx) activity in SNLs with macrometastases but not with micrometastases., Conclusions: Redox status of lymph node microenvironment participates in the progression of metastatic breast cancer.

Purpose: To evaluate the pathologic complete response (pCR) rate of a combination of epirubicin (E) and cyclophosphamide (C) followed by paclitaxel (P) and gemcitabine (G) (+ trastuzumab[T]) in Her2+ patients) in a sequential and dose-dense schedule as neoadjuvant chemotherapy for stages II and III patients with breast cancer. Secondary endpoints: clinical response rate, disease free survival, safety and correlation between pCR and biologic markers., Patients and Methods: Eligible patients were treated with E (90 mg/m²) and C (600 mg/m²) for 3 cycles (first sequence) followed by P (150 mg/m²) and G (2500 mg/m²) (second sequence) for 6 cycles. All drugs were administered on day 1, every 2 weeks, with prophylactic growth factor support. Weekly T (2 mg/kg [4 mg/kg first infusion]) was administered concomitantly with P and G in Her2+ patients. A core biopsy was performed before treatment for biologic markers assessment. Patients underwent surgery, radiotherapy, and adjuvant hormonal therapy according to institutional practice., Results: Seventy-three patients were treated. A pCR was achieved in 27 (37%) patients (32.1%, Her2- and 50%, Her2+). pCR was significantly higher in tumors that were hormonal receptor negative, poorly differentiated and positive for Ki67 and p53. Breast-conserving surgery was performed in 47 patients (64.4%). Most frequent grade 3/4 hematologic and nonhematological toxicities included neutropenia (12%), nausea/vomiting (17%), and transient liver enzymes elevation (7%). One patient suffered an asymptomatic and reversible decrease in left ventricular ejection fraction., Conclusions: These results show a highly effective regimen in terms of pCR with a good toxicity profile in the neoadjuvant treatment of patients with breast cancer. The addition of trastuzumab increased pCR rate in Her2+ tumors.

Purpose: To study the role of breast cancer molecular subtypes according to hormone receptors and HER2 status as a predictive factor for pathological complete response (pCR) to neoadjuvant chemotherapy., Patients and Methods: Eligible patients received one of the two chemotherapy schedules every two weeks with prophylactic growth factor support; schedule A: epirubicin 90 mg/m2-cyclophosphamide 600 mg/m2 d1 for 3 cycles followed by a second sequence with paclitaxel (P) 150 mg/ m2-gemcitabine (G) 2500 mg/m2 d1+/-trastuzumab (T) 2 mg/kg/week according to HER2 status (n=73); schedule B: adriamycin (40 mg/m2) d1 plus P (150 mg/m2)-G (2000 mg/m2) d2 for 6 cycles (n=54). Subsequently, patients underwent surgery, radiotherapy and/or adjuvant hormonal therapy according to standard practice., Results: A total of 127 patients were evaluated. Forty-three patients (33.9%) achieved a pCR (50% in patients with HER2+tumours treated with T). Patients treated with che - motherapy alone (n=107, 18 HER2+) had a pCR of 32% (p=0.068). The pCR rate for patients with triple negative (HR and HER2-) cancers was 58.3%, 39.5% for HER2+ and 5.4% for ER/PR+ and HER2- (p<0.001). No differences in disease-free survival (DFS) were noted as a function of pCR, HER2 and HR status or treatment received (+/-T). However, statistical differences in DFS were observed as a function of whether patients had + or - axillar lymph nodes. Patients with + lymph node disease did worse (3 years DFS of 53.7% vs. 81.5%, p=0.025). Breast-conserving surgery was performed in 77 patients (60.6%)., Conclusion: Tumour molecular subtyping defines different pCR to neoadjuvant chemotherapy (NC) but has no impact over DFS in patients with LABC. Although no significant correlation between HER2 status and trastuzumab therapy with pCR was found, probably due to the small number of patients, a favourable trend was observed in the group of HER2+ tumours treated with T.

The melanomas are unusual tumours with a high mortality. The mucosal malignant melanoma type supposes loss than 1% of the total of melanoma. The initial symptoms are unspecific and the regional metastasis are rare. The surgical approach it's the most effective treatment complemented with radiotherapy and or chimiotherapy. We present the case of primary nasal mucosal malignant melanoma and review the litterature of this disease.