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Nell’ambito delle neoplasie mammarie, il carcinoma della mammella triplo negativo (TNBC) continua a essere il sottotipo molecolare a maggiore aggressività e dunque rappresenta una sfida per l’identificazione della relativa gestione terapeutica ottimale. A causa della mancanza di target molecolari “tradizionali”, per decenni, il trattamento sistemico è stato caratterizzato dall’uso dei classici farmaci citotossici. Negli ultimi anni, è stato dimostrato come il TNBC non sia costituito da una singola patologia priva di caratteristiche specifiche, ma da diverse entità con distinte alterazioni genetiche, istologiche e cliniche. Tale consapevolezza ha consentito, pertanto, di ottimizzare e migliorare il trattamento della malattia, con l’approvazione di molteplici agenti anti-tumorali, tra i quali gli anticorpi farmaco coniugati (ADC). Il caso clinico che presentiamo illustra il “viaggio” di una paziente affetta da TNBC in fase metastatica, delle scelte terapeutiche effettuate tra le opzioni disponibili negli anni, ovvero tra le possibilità standard e le strategie innovative.

PurposeTriple negative breast cancer (TNBC), an aggressive subtype of breast cancer, lacks the three major receptors for predicting outcome or targeting therapy. Hence, our aim was to evaluate the potential of estrogen receptor beta (ERβ) as a possible endocrine therapy target in TNBC.MethodsThe expression and prognostic effect of ERβ isoforms were analyzed using TCGA breast tumor data, and the expression of ERβ isoform mRNA and protein in TNBC cell lines was assayed. Endogenous ERβ2 and ERβ5 were knocked down with siRNA, and ERβ2, ERβ5, and ERβ1 were upregulated using a doxycycline-inducible lentiviral system. Cell proliferation, migration and invasion, and specific gene expressions were evaluated.ResultsERβ2 and ERβ5 were the predominant endogenous forms of ERβ in TNBC tumors and cell lines. High ERβ2 predicted worse clinical outcome. Knockdown of endogenous ERβ2/ERβ5 in cell lines suppressed proliferation, migration and invasion, and downregulated proto-oncogene survivin expression. ERβ2/ERβ5 upregulation did the reverse, increasing survivin and these cell activities. ERβ1 was barely detectable in TNBC cell lines, but its upregulation reduced survivin, increased tumor suppressor expression (E-cadherin and cystatins), and suppressed proliferation, migration and invasion in both ligand-independent and dependent manners, suggesting the possible translational benefit of ERβ ligands.ConclusionsERβ2/ERβ5 and ERβ1 exhibit sharply contrasting activities in TNBC cells. Our findings imply that delineating the absolute amounts and relative ratios of the different ERβ isoforms might have prognostic and therapeutic relevance, and could enable better selection of optimal approaches for treatment of this often aggressive form of breast cancer.

Background Different breast cancer subtypes show distinct tropisms for sites of metastasis. Notably, the lung is the most common site for the first distant recurrence in triple-negative breast cancer (TNBC). The identification of novel biomarkers for lung metastasis is of great importance to improving the outcome of TNBC. In this study, we sought to identify a microRNA (miRNA)-based biomarker and therapeutic target for lung metastasis of TNBC. Methods A total of 669 patients without de novo stage IV TNBC were recruited for this study. miRNA profiling was conducted in the discovery cohort. Diagnostic accuracy and prognostic values of candidate miRNAs were evaluated in the training and validation cohorts, respectively. The biological functions of candidate miRNAs, as well as potential targets, were further evaluated through bioinformatic analysis as well as by performing in vitro and in vivo assays. Results In the discovery set, we found that miR-629-3p was specifically upregulated in both metastatic foci (fold change 144.16, P  < 0.0001) and primary tumors (fold change 74.37, P  = 0.004) in patients with lung metastases. In the training set, the ROC curve showed that miR-629-3p yielded high diagnostic accuracy in discriminating patients with lung metastasis from patients without recurrence (AUC 0.865, 95% CI 0.800–0.930, P  < 0.0001). Although miR-629-3p predicted poor overall survival and disease-free survival in the validation set, it failed to show significance after multivariate analysis. Notably, logistic regression analyses confirmed that miR-629-3p was an independent risk factor for lung metastasis (OR 4.1, 95% CI 2.5–6.6, P  < 0.001). Inhibition of miR-629-3p drastically attenuated the viability and migration of TNBC cells, and it markedly suppressed lung metastasis in vivo. Furthermore, we identified the leukemia inhibitory factor receptor ( LIFR ), a well-known metastatic suppressive gene, to be a direct target of miR-629-3p. Conclusions miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of TNBC mediated via LIFR.

La malattia triplo negativa, ovvero l’assenza di espressione dei recettori ormonali e di HER2, resta a oggi il sottotipo a peggiore prognosi nell’ambito dei tumori mammari, e soprattutto in fase metastatica rimane un bisogno clinico irrisolto. Tuttavia anche in questo setting possiamo avvalerci di nuovi farmaci quali l’immunoterapia e gli anticorpi coniugati per poter ottenere un miglioramento della prognosi. In particolare, sacituzumab govitecan è il primo Ab coniugato che ha dimostrato un vantaggio in termini di sopravvivenza globale e libera da progressione in pazienti affette da carcinoma mammario triplo negativo metastatico pretrattate con 2-3 linee di terapia precedenti.

Higher body mass index (BMI) and diabetes are associated with worse breast cancer prognosis. However, few studies have focused on triple-negative breast cancer (TNBC). The goal of this study is to examine this association in a cohort of patients with TNBC. We retrospectively reviewed 501 consecutive patients with TNBC seen at the Washington University Breast Oncology Clinic. Cox proportional hazard models were used to determine the relationship between BMI and diabetes at diagnosis with overall survival (OS) and disease free survival (DFS). Four hundred and forty-eight patients had BMI recorded and 71 patients had diabetes. The median age at diagnosis was 53 (23–98) years and follow-up was 40.1 months (IQR 25.2–62.9). Baseline BMI and diabetes were not associated with OS or DFS. OS hazard ratios (HRs) for patients who were overweight (BMI 25.0–29.99), with class I obesity (BMI 30–34.99), or BMI ≥35 were 1.22 (CI 0.78–1.91), 0.92 (CI 0.59–1.43), and 1.16 (CI 0.70–1.90), respectively. The HRs for DFS in patients who were overweight, with class I obesity, or BMI ≥35 were 1.01 (CI 0.65–1.56), 0.94 (CI 0.60–1.47), and 0.99 (CI 0.63–1.57), respectively. Similarly, the HRs for diabetics were 1.27 (CI 0.82–1.96) for OS and 0.98 (CI 0.64–1.51) for DFS. Obesity and diabetes did not significantly affect survival for patients with TNBC in this study.