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We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D â EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.
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Hereditary cancer syndromes caused by germline mutations account for 5-10% of all cancers. The finding of a genetic mutation could have far-reaching consequences for pharmaceutical therapy, personalized prevention strategies, and cascade testing. According to the National Comprehensive Cancer Network's (NCCN) and the Italian Association of Medical Oncology (AIOM) guidelines, unaffected family members should be tested only if the affected one is unavailable. This article explores whether germline genetic testing may be offered to high-risk families for hereditary cancer even if a living affected relative is missing. A retrospective study was carried out on 103 healthy subjects tested from 2017 to 2023. We enrolled all subjects with at least two first- or second-degree relatives affected by breast, ovarian, pancreatic, gastric, prostate, or colorectal cancer. All subjects were tested by Next Generation Sequencing (NGS) multi-gene panel of 27 cancer-associated genes. In the study population, 5 (about 5%) pathogenic/likely pathogenic variants (PVs/LPVs) were found, while 40 (42%) had a Variant of Uncertain Significance (VUS). This study highlights the importance of genetic testing for individuals with a strong family history of hereditary malignancies. This approach would allow women who tested positive to receive tailored treatment and prevention strategies based on their personal mutation status.
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Pancreatic cancer (PC) has a poor prognosis and displays resistance to immunotherapy. A better understanding of tumor-derived extracellular vesicle (EV) effects on immune responses might contribute to improved immunotherapy. EVs derived from Capan-2 and BxPC-3 PC cells isolated by ultracentrifugation were characterized by atomic force microscopy, Western blot (WB), nanoparticle tracking analysis, and label-free proteomics. Fresh PBMCs from healthy donors were treated with PC- or control-derived heterologous EVs, followed by flow cytometry analysis of CD8+ and CD4+ lymphocytes. The proteomics of lymphocytes sorted from EV-treated or untreated PBMCs was performed, and the IFN-γ concentration was measured by ELISA. Notably, most of the proteins identified in Capan-2 and BxPC-3 EVs by the proteomic analysis were connected in a single functional network (p = 1 × 10-16) and were involved in the "Immune System" (FDR: 1.10 × 10-24 and 3.69 × 10-19, respectively). Interestingly, the treatment of healthy donor-derived PBMCs with Capan-2 EVs but not with BxPC-3 EVs or heterologous control EVs induced early activation of CD8+ and CD4+ lymphocytes. The proteomics of lymphocytes sorted from EV-treated PBMCs was consistent with their activation by Capan-2 EVs, indicating IFN-γ among the major upstream regulators, as confirmed by ELISA. The proteomic and functional analyses indicate that PC-EVs have pleiotropic effects, and some may activate early immune responses, which might be relevant for the development of highly needed immunotherapeutic strategies in this immune-cold tumor.
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Breast cancer treatments can elicit negative kinesiological side effects concerning both the posture and functional status of breast cancer survivors. As our body is functionally organized in myofascial meridians, physical exercise practice should favor a whole-body approach rather than a local one. The aim of the study was to investigate and compare the effects of two whole-body disciplines, i.e., adapted Nordic Walking and myofascial exercise, on the flexibility and strength performances in BCS. One hundred and sixty breast cancer survivors were trained three times per week for 12 weeks through adapted Nordic Walking or myofascial exercise. Handgrip, sit and reach, back scratch, and single leg back bridge tests and body composition were assessed at the beginning and completion of the training period. Linear mixed models showed no significant changes in body composition, whereas flexibility (p < 0.001), strength (p < 0.001), and muscle quality index (p = 0.003) changed independently from the treatment. When data modification has been analyzed according to sub-sample membership, no significant differences have been observed. Age, radiation therapy, and chemotherapy seem to have independent effects on several investigated variables. Twelve weeks of adapted myofascial exercise and Nordic Walking led to significant changes in flexibility, strength, and muscle quality in breast cancer survivors, with no apparent superiority of one approach over the other.
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BACKGROUND: Several hereditary-familial syndromes associated with various types of tumors have been identified to date, evidencing that hereditary cancers caused by germline mutations account for 5-10% of all tumors. Advances in genetic technology and the implementation of Next-Generation Sequencing (NGS) have accelerated the discovery of several susceptibility cancer genes, allowing for the detection of cancer-predisposing mutations in a larger number of cases. The aim of this study is to highlight how the application of an NGS-multigene panel to a group of oncological patients subsequently leads to improvement in the identification of carriers of healthy pathogenic variants/likely pathogenic variants (PVs/LPVs) and prevention of the disease in these cases. METHODS: Starting from a total of 110 cancer patients carrying PVs/LPVs in genes involved in cancer susceptibility detected via a customized NGS panel of 27 cancer-associated genes, we enrolled 250 healthy collateral family members from January 2020 to July 2022. The specific PVs/LPVs identified in each proband were tested in healthy collateral family members via Sanger sequencing. RESULTS: A total of 131 out of the 250 cases (52%) were not carriers of the mutation detected in the affected relative, while 119 were carriers. Of these, 81/250 patients carried PVs/LPVs on BRCA1/2 (33%), 35/250 harbored PVs/LPVs on other genes beyond BRCA1 and BRCA2 (14%), and 3/250 (1%) were PVs/LPVs carriers both on BRCA1/2 and on another susceptibility gene. CONCLUSION: Our results show that the analysis of BRCA1/2 genes would have only resulted in a missed diagnosis in a number of cases and in the lack of prevention of the disease in a considerable percentage of healthy carriers with a genetic mutation (14%).
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Sex might influence prognosis in patients affected by colorectal cancer. We retrospectively studied a cohort of patients affected by metastatic colon cancer (mCC) stratified by sex and primary tumor location. RAS mutational status was also included in the analysis. Overall, 616 patients met the eligibility criteria, 261 women and 355 men. Neither gender, nor RAS mutational status influenced overall survival (OS) in the entire population. As expected, patients with right-sided colon cancer (RCC) had a significant shorter OS compared to those with left-sided colon cancer (LCC) (21.3 vs 33.1 months, p= 0.002). When the analysis was performed stratifying for gender, RCC retained worse prognosis among men (OS 20.5 vs 33.9 months, p= 0.008), but not among women (p= 0.132). Similarly, the presence of RAS mutations had no prognostic effect in women, but was significantly associate with shorter survival in men (OS 29.5 vs 33.7 months, p= 0.046). In addition, when comparing clinical outcome of women or men according to sidedness and RAS mutational status, RCC was associated with dismal prognosis only in men with RAS mutated tumor (OS 17.2 vs 32.3 months, p= 0.008). Our study highlights the importance of gender in the outcome of patients with mCC.
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Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.
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Advances in the management of gastric cancer have improved patient survival in the last decade. Nonetheless, the number of patients relapsing and dying after a diagnosis of localized gastric cancer is still too high, even in early stages (10% in stage I). Adjuvant systemic chemotherapy has been proven to significantly improve outcomes. In the present article we have critically reviewed the clinical trials that guide the current clinical practice in the adjuvant treatment of patients affected by resectable gastric cancer, focusing on the different approaches worldwide, i.e., adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy. We also delineate the clinical-pathological characteristics that are commonly taken into account to identify patients at a higher risk of recurrence and requiring adjuvant chemotherapy, and also describe novel biomarkers and therapeutic agents that might allow personalization of the treatment.
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Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide. Identification of novel tumor biomarkers is highly advocated in PC to optimize personalized treatment algorithms. Blood-circulating extracellular vesicles hold promise for liquid biopsy application in cancer. We used an optimized flow cytometry protocol to study leukocyte-derived EVs (CD45+) and PD-L1+ EVs in blood from 56 pancreatic cancer patients and 48 healthy controls (HCs). Our results show that PC patients presented higher blood levels of total EVs (p = 0.0003), leukocyte-derived EVs (LEVs) (p = 0.001) and PD-L1+ EVs (p = 0.01), as compared with HCs. Interestingly, a blood concentration of LEVs at baseline was independently associated with improved overall survival in patients with borderline resectable or primary unresectable PC (HR = 0.17; 95% CI 0.04-0.79; p = 0.02). Additionally, increased blood-based LEVs were independently correlated with prolonged progression-free survival (HR = 0.10; 95% CI 0.01-0.82; p = 0.03) and significantly associated with higher disease control rate (p = 0.02) in patients with advanced PC receiving standard chemotherapy. Notably, a strong correlation between a decrease in blood LEVs concentration during chemotherapy and disease control was observed (p = 0.005). These intriguing findings point to the potential of LEVs as novel blood-based EV biomarkers for improved personalized medicine in patients affected by PC.
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The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies.
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PURPOSE: Axillary management remains unclear when sentinel lymph node (SLN) results are positive in cN0 patients with breast cancer (BC). The trial ACOSOG Z0011 represented a revolution with axillary lymph node dissection (ALND) omission in SLN+ patients, despite critiques regarding non-uniformity of radiation fields. We conducted an observational study (LISEN) where whole breast radiotherapy (WBRT) was planned with tangential fields without nodal irradiation in patients eligible for the Z0011 trial. METHODS: Inclusion criteria were female patients with histologically proven BC, cT1-2cN0, planned conservative surgery, no neoadjuvant therapy. Patients were stratified into two groups: micrometastatic (pN1mic, group 1) and macrometastatic (pN1a, group 2) lymph nodes. Tangential field WBRT was mandatory. Clinical outcomes were analysed, measured from surgery until the first event. RESULTS: In all, 199 patients underwent conservative surgery and SLN biopsy; 133 patients meeting criteria were analysed: 41 patients (30.8%) pN1mic and 92 (69.2%) pN1a. The 5year disease-free survival (DFS) was 95.0% (85.9-100%) in group 1 and 93.0% (86.3-100.0%) in group 2 (pâ¯= 0.78). Overall survival (OS) was 100% (100-100%) in group 1 and 97.4% (92.4-100%) in group 2 (pâ¯= 0.74). For the whole cohort DFS and OS were 93.6% (88.2-99.4%) and 96.9% (91.5-100.0%), respectively. For groups 1 and 2, the 5year outcomes were 5.0% (0.0-14.4%) and 2.3% (0.0-6.1%) for local recurrence (pâ¯= 0.51), and 6.2% (0.0-17.4%) and 7.0% (0.0-13.7%) for distant metastasis (pâ¯= 0.61), respectively. In group 1, regional recurrence (RR) and local regional recurrence (LRR) were 5.0% (0.0-14.1%; pâ¯= 0.13). In group 2, RR and LRR were 0.0% (0.0-0.0%). CONCLUSION: Our results showed good regional control in patients who met the Z0011 trial criteria. WBRT, without nodal surgery or RT, avoiding axillary morbidity, seems to be a good choice.
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Neoplasias de la Mama , Ganglio Linfático Centinela , Axila/patología , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Femenino , Humanos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Metástasis Linfática/radioterapia , Masculino , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela/métodosRESUMEN
Background: Osimertinib is an irreversible tyrosine kinase inhibitor approved for the treatment of metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). In clinical trials, osimertinib has exhibited excellent activity and less toxicity compared to gefitinib, erlotinib and standard chemotherapy. Case Presentation: Herein, we describe the case of a 69-year-old man who received first-line osimertinib for metastatic EGFR-mutated NSCLC. Suspected osimertinib-induced pancytopenia together with a partial treatment response was assessed after 10 days of therapy. Osimertinib was resumed at 40 mg daily a month later while the patient exhibited durable stable disease. No other adverse events occurred. Conclusion: In the current case, first-line treatment with osimertinib at 80 mg daily in a patient with EGFR-mutated NSCLC resulted in severe pancytopenia and a rapid treatment response. Dose reduction to 40 mg daily resulted in excellent activity without any further adverse events. Osimertinib could be safely resumed at a reduced dose even after pancytopenia.
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Colorectal cancer (CRC) is one of the most incident and lethal malignancies worldwide. Recent treatment advances prolonged survival in patients with metastatic colorectal cancer (mCRC). However, there are still few biomarkers to guide clinical management and treatment selection in mCRC. In this study, we applied an optimized flow cytometry protocol for EV identification, enumeration, and subtyping in blood samples of 54 patients with mCRC and 48 age and sex-matched healthy controls (HCs). The overall survival (OS) and overall response rate (ORR) were evaluated in mCRC patients enrolled and treated with a first line fluoropyrimidine-based regimen. Our findings show that patients with mCRC presented considerably higher blood concentrations of total EVs, as well as CD133+ and EPCAM+ EVs compared to HCs. Overall survival analysis revealed that increased blood concentrations of total EVs and CD133+ EVs before treatment were significantly associated with shorter OS in mCRC patients (p = 0.001; and p = 0.0001, respectively). In addition, we observed a correlation between high blood levels of CD133+ EVs at baseline and reduced ORR to first-line systemic therapy (p = 0.045). These findings may open exciting perspectives into the application of novel blood-based EV biomarkers for improved risk stratification and optimized treatment strategies in mCRC.
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In breast cancer survivors (BCS), the contemporaneous increase of sedentary time and reduction of physical activity (PA) requires early attention because it has negative consequences for their health. Aims of the study were to investigate: a) the correlations between PA, sedentarism, and health-related measures; b) the association between different patterns of daily activity and health-related outcomes. Two hundred and nineteen BCS (50.98 ± 6.28) were selected for this study. Psychological, anthropometric, endocrine, sleeping, and both daily sedentary time and PA variables were considered. Sedentarism and PA have opposite correlations with anthropometric variables, anxiety, depression, morning salivary cortisol, and sleeping characteristics. The first favors pathological values and the latter favors normal values. Regression tree analysis showed the impact of different daily sedentary time and PA combinations on the investigated variables and allowed the individualization of their optimal combination for health. Our results could be useful to healthcare providers and BCS.
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Neoplasias de la Mama , Supervivientes de Cáncer , Neoplasias de la Mama/psicología , Neoplasias de la Mama/terapia , Ejercicio Físico/psicología , Femenino , Estado de Salud , Humanos , Encuestas y CuestionariosRESUMEN
The aim of the study was to compare the effects of weekly personal feedback, based on objectively measured physical activity, on daily sleep in breast cancer survivors (BCS) with those of an intervention that also included online supervised physical exercise sessions (OSPES). BCS benefiting from both personal feedback and OSPES (n = 24), from pre-lockdown (T0) to the first month (T1) of the national lockdown, experienced an increase in both total (p ≤ 0.001) and restorative (p ≤ 0.001) sleep time, inverting their trend from the first month of lockdown to its end (total sleeping time T1 vs. T2 0.01 ≤ p < .001, T1 vs. T3 p ≤ 0.001; restorative sleeping time T1 vs. T2 0.05 ≤ p < .01, T1 vs. T3 p ≤ 0.001). Supportive technology, together with the reception of weekly tailored advice and OSPES seems to improve both quality and quantity of sleep.
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Neoplasias de la Mama , COVID-19 , Supervivientes de Cáncer , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/terapia , Control de Enfermedades Transmisibles , Consejo , Ejercicio Físico , Femenino , Monitores de Ejercicio , Humanos , Italia , SueñoRESUMEN
In previous studies we have demonstrated that the expression of the Major Histocompatibility Complex (MHC) class I gene in thyrocytes is controlled by several hormones, growth factors, and drugs. These substances mainly act on two regions of the MHC class I promoter a "tissue-specific" region (-800 to -676 bp) and a "hormone/cytokines-sensitive" region (-500 to -68 bp). In a previous study, we have shown that the role of the "tissue-specific" region in the MHC class I gene expression is dominant compared to that of the "hormone/cytokines-sensitive" region. In the present report we further investigate the dominant role of the "tissue-specific" region evaluating the effect of thyroid stimulating hormone (TSH), methimazole (MMI), phenylmethimazole (C10), glucose and thymosin-α1. By performing experiments of electrophoretic mobility shift assays (EMSAs) we show that TSH, MMI and C10, which inhibit MHC class I expression, act on the "tissue-specific" region increasing the formation of a silencer complex. Glucose and thymosin-α1, which stimulate MHC class I expression, act decreasing the formation of this complex. We further show that the silencer complex is formed by two distinct members of the transcription factors families activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), c-jun and p65, respectively. These observations are important in order to understand the regulation of MHC class I gene expression in thyroid cells and its involvement in the development of thyroid autoimmunity.
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Genes MHC Clase I/genética , Hormonas/fisiología , Glándula Tiroides/fisiología , Animales , Antitiroideos/farmacología , Línea Celular , Ensayo de Cambio de Movilidad Electroforética , Regulación de la Expresión Génica/efectos de los fármacos , Genes MHC Clase I/efectos de los fármacos , Glucosa/farmacología , Metimazol/análogos & derivados , Metimazol/farmacología , Ratas , Tionas/farmacología , Timosina/farmacología , Glándula Tiroides/citología , Glándula Tiroides/efectos de los fármacos , Tiroiditis Autoinmune/genética , Tiroiditis Autoinmune/patología , Tirotropina/farmacología , Factores de Transcripción/genéticaRESUMEN
Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.
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The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65-10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25-15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.
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Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Linfocitos/patología , Terapia Neoadyuvante , Neutrófilos/patología , Adulto , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Supervivencia sin Enfermedad , Femenino , Humanos , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2-positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.