Objective:Novel therapies for HER2-(ultra)low breast cancer (BC) have changed the traditional binary classification of HER2 status into a multi-tiered system that captures the full spectrum of expression as determined by immunohistochemistry (IHC). Several pre-analytical and analytical variables can influence the accurate identification of HER2 expression within the lowest IHC range. Herein, we present the findings of a national Italian project addressing the diagnostic challenges associated with HER2-(ultra)low BCs and their proper classification. Material and methods:A total of 121 pathologists from various regions and institutions were recruited and asked to: i) complete an online survey addressing key pre-analytical and analytical issues affecting HER2 status reporting in BC; ii) score 8 cases of IHC HER2-(ultra)low whole slide images (WSI) shared online; iii) participate in on-site meetings to discuss the results and evaluate 8 additional challenging WSIs. The assessments were subsequently compared to those of an expert panel. Results:Several pre-analytical and analytical concerns emerged from the questionnaire, such as reporting resection cold ischemia time and decalcification agent of choice and the employment of adequate HER2 controls. Regarding the WSIs, a substantial overall agreement (69%) with the expert panel was observed (74% in the online phase and 64% in the on-site phase), along with substantial to excellent consensus (≥ 61%) in over 60% of the samples. Most discordances emerged in the on- site cohort, which was enriched with challenging cases, particularly within the HER2 0+/ultralow spectrum, which demonstrated an overall agreement of 48%. Conclusions:This nationwide study highlights the complexities of accurately classifying HER2-(ultra)low breast cancers, particularly within the HER2-ultralow subset. While a substantial level of agreement with expert assessments was achieved, the variability observed in more challenging cases underscores the need for standardized interpretation criteria, enhanced training, and continuous quality assurance measures.

Currently, percutaneous sampling via core needle or vacuum-assisted biopsy is the primary choice to guide the management of patients with clinical or screen-detected breast lesions. Preoperative biopsies allow physicians to get pathological diagnoses as well as key prognostic and predictive data about the nature of the investigated process. Namely, adequate biopsy sampling is crucial for assigning lesions to one diagnostic category (B1-B5). Similarly, evaluating morphological (histotype, vascular invasion, necrosis, etc.) and immunohistochemical/molecular features (ER, PR, Ki-67, and HER2) is the key to address the most effective therapies, especially in the neoadjuvant setting. The multidisciplinary team should always discuss the results of percutaneous biopsies, whose global integration with clinical and radiological findings will drive the adoption of specific treatment options, particularly for uncertain (B3) and suspicious/malignant (B4-B5) lesions. In the present work, we report a comprehensive overview of breast percutaneous biopsy techniques, diagnostic categories, and multidisciplinary management based on widely acknowledged evidence of good clinical practice.

Estrogen receptor (ER)-low breast cancer (BC) is a rare subtype of BC defined by ER expression between 1% and 10% and is biologically more similar to triple-negative than hormone receptor-positive BC. Conflicting data have been published regarding the benefit of endocrine therapy (ET) in this subtype, whereas the response to neoadjuvant chemotherapy and prognosis seems to be comparable with that of TNBC. ER-low BC was not included in most of the randomized clinical trials conducted among patients with TNBC, missing the opportunity to access new drugs and collect data. Recent evidence has suggested that ER-low BC might benefit from an immune-chemotherapy regimen, aligning to TNBC. International guidelines should recognize ER-low BC as a unique and heterogeneous entity that needs specific prospective clinical trials to cover the gap of knowledge for determining the best management for these patients. On the basis of the published evidence, ER-low BC should be treated as TNBC and included in clinical trials designed for TNBC. Molecular subtypes and immune biomarkers could help to tailor the treatment and identify the subgroup of patients with ER-low BC for whom ET might still play a role. In this setting, considering the recent scientific publications and current guidelines, the CamE-Lot project was developed to improve the management and diagnosis of ER-low BC by fostering collaboration between pathologists and oncologists. By using real-life data from leading centers nationwide, the project aims to describe standardized practices for diagnosing and treating this particular subtype of BC. This approach could significantly enhance consistency in clinical care, improve patient outcomes, and contribute to a deeper understanding of ER-low BC.

The management of hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) relies on molecular testing to inform treatment decisions. PIK3CA mutations, present in ~40% of cases, represent a key predictive biomarker for PI3K-pathway-targeted therapies. Despite its clinical relevance, PIK3CA testing continues to face challenges related to laboratory organization, standardization, and access. We conducted a nationwide, cross-sectional survey to evaluate current practices and institutional readiness for PIK3CA testing in Italy, in the context of the anticipated expansion of PI3K-targeted therapies, including inavolisib. A total of 118 healthcare professionals from institutions across 15 regions participated, providing data on test availability, laboratory workflows, analytical methodologies, accreditation status, and implementation barriers. Descriptive statistics were used for analysis. Overall, 88.1% of institutions reported the ability to perform PIK3CA testing, with 57.6% offering on-site analysis. Testing was predominantly performed in pathology laboratories (76.5%), followed by molecular biology (16.2%) and genetics laboratories (7.4%). However, 46.6% of institutions lacked formal molecular accreditation, and ISO:15189 certification remained uncommon. Pre-analytical workflows relied mainly on formalin-fixed paraffin-embedded (FFPE) tissue samples (89.7%), with limited routine use of liquid biopsy. Next-generation sequencing (NGS) was the most frequently adopted analytical approach (45.6%), followed by combined NGS and PCR-based strategies (36.8%). Most institutions reported turnaround times of 7-15 days. In conclusion, this updated survey indicates progress in access to PIK3CA testing and consolidation of NGS-based methodologies in Italy. Nevertheless, persistent gaps in accreditation, heterogeneous workflows, and limited integration of liquid biopsy highlight ongoing challenges in standardization and diagnostic equity. Coordinated national strategies will be essential to ensure consistent, high-quality molecular diagnostics in HR+/HER2- MBC.

An Italian guideline panel issued the national recommendations for breast cancer diagnosis, staging, and preoperative planning. The panel employed the ADOLOPMENT process to adopt or adapt the guidelines developed by the European Commission Initiative on Breast Cancer (ECIBC). This process utilises the Grading of Recommendations Assessment, Development and Evaluation evidence-to-decision framework. Hereby, we present 15 prioritised recommendations from the second chapter of the Italian guidelines. All of the recommendations as originally developed by the ECIBC were adopted. For the assessment of women with positive screening result, the diagnostic recommendations suggest using digital breast tomosynthesis instead of additional mammographic projections. Recommendations include using needle core biopsy (NCB) instead of fine-needle aspiration for suspicious lesions, and stereotactic-guided –rather than ultrasound-guided– NCB for suspicious calcifications. For preoperative planning, they recommend clip marking after biopsy and not using additional magnetic resonance imaging (MRI) for confirmed ductal carcinoma in situ. Contrast-enhanced mammography is preferred over MRI for presurgical planning, when needed. Other imaging tests are not recommended for stage I, IIa, and IIb BC without signs of metastasis, while positron emission tomography-computed tomography alone is suggested for stage III BC. Adjuvant hormone therapy is recommended when 1

Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples. Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR (epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS (Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1 (c-ros oncogene 1)-unknown gene fusion, and MET (MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated. Overall, a median DNA concentration of 3.3 ng/µL (range 0.1–10.0 ng/µL) and 13.4 ng/µL (range 2.0–45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2–11.9 ng/µL) and 9.3 ng/µL (range 0.5–18.0 ng/µL) were also detected. KRAS exon 2 p.G12C, EGFR exon 19 p.E736_A750del hotspot mutations, and ROS1 aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7

This work explores the complex field of HER2 testing in the HER2-low breast cancer era, with a focus on methodological aspects. We aim to propose clear positions to scientific societies, institutions, pathologists, and oncologists to guide and shape the appropriate diagnostic strategies for HER2-low breast cancer. The fundamental question at hand is whether the necessary tools to effectively translate our knowledge about HER2 into practical diagnostic schemes for the lower spectrum of expression are available. Our investigation is centered on the significance of distinguishing between an immunohistochemistry (IHC) score 0 and score 1+ in light of the clinical implications now apparent, as patients with HER2-low breast cancer become eligible for trastuzumab-deruxtecan treatment. Furthermore, we discuss the definition of HER2-low beyond its conventional boundaries and assess the reliability of established diagnostic procedures designed at a time when therapeutic perspectives were non-existent for these cases. In this regard, we examine potential complementary technologies, such as gene expression analysis and liquid biopsy. Ultimately, we consider the potential role of artificial intelligence (AI) in the field of digital pathology and its integration into HER2 testing, with a particular emphasis on its application in the context of HER2-low breast cancer.

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of ≥ 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD-L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC.

Neoadjuvant therapy (NAT) in breast cancer is administered to downstage the tumor, de-escalate surgery, and provide prognostic information that can be used to tailor subsequent adjuvant therapy. In this respect, the pathological evaluation of both pre-NAT biopsies and post-NAT surgical specimens is crucial to precisely assess the treatment response. With the increasing possibilities of NAT protocols and the rising number of eligible patients, it has become extremely important to standardize the pathological response assessment. Here, we provide an update on the recommendations of the Italian Group for the Study of Breast Pathology - the Italian Society of Pathology (GIPaM-SIAPeC) for the analysis of breast cancer samples before and after NAT.

Pathologic evaluation of early breast cancer after neoadjuvant therapy is essential to provide prognostic information based on tumor response to treatment (pathologic complete response [pCR] or non-pCR) and to inform therapy decisions after surgery. To harmonize the pathologist's handling of surgical specimens after neoadjuvant therapy, a panel of experts in breast cancer convened to developed a consensus on six main topics: (1) definition of pCR, (2) required clinical information, (3) gross examination and sampling, (4) microscopic examination, (5) evaluation of lymph node status, and (6) staging of residual breast tumor. The resulting consensus statements reported in this document highlight the role of an accurate evaluation of tumor response and define the minimum requirements to standardize the assessment of breast cancer specimens after neoadjuvant therapy.

OBJECTIVES:Gut microbiota has been widely reported to be involved in systemic inflammation through microbial translocation and T cell activation in several diseases. In this work we aimed to investigate bacterial infiltration and epithelial impairment in the gut of patients with IBD-associated SpA (SpA-IBD), as well as the relationship of microbial translocation with immune system activation and their putative role in the pathogenesis of joint inflammation in IBD patients.METHODS:Tight-junction proteins (TJPs) occludin and claudin-1/-4 and bacteria were assessed by real-time PCR analysis and immunohistochemical staining of the ileum. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPS), soluble CD14 (sCD14), sclerostin and anti-sclerostin antibodies (anti-sclerostin-IgG) were assayed with ELISAs and peripheral mononuclear blood cells with flow cytometry. LPS and sCD14 were used in vitro to stimulate a human osteoblast cell line.RESULTS:Compared with IBD, ileal samples from SpA-IBD patients showed bacterial infiltration, epithelial damage and downregulation of TJPs. In sera, they showed higher serum levels of I-FABP, LPS, sCD14 (the latter correlating with sclerostin and anti-sclerostin-IgG) and higher CD80+/CD163+ and lower CD14+ mononuclear cells. In vitro experiments demonstrated that only the LPS and sCD14 synergic action downregulates sclerostin expression in osteoblast cells.CONCLUSION:SpA-IBD patients are characterized by gut epithelium impairment with consequent translocation of microbial products into the bloodstream, immune system activation and an increase of specific soluble biomarkers. These findings suggest that gut dysbiosis could be involved in the pathogenesis of SpA-IBD and it could hopefully prompt the use of these biomarkers in the follow-up and management of IBD patients.

Cancer therapy is limited, in part, by lack of specificity. Thus, identifying molecules that are selectively expressed by, and relevant for, cancer cells is of paramount medical importance. Here, we show that peptidyl-prolyl-cis-trans-isomerase (PPIase) FK506-binding protein 10 (FKBP10)-positive cells are present in cancer lesions but absent in the healthy parenchyma of human lung. FKBP10 expression negatively correlates with survival of lung cancer patients, and its downregulation causes a dramatic diminution of lung tumor burden in mice. Mechanistically, our results from gain- and loss-of-function assays show that FKBP10 boosts cancer growth and stemness via its PPIase activity. Also, FKBP10 interacts with ribosomes, and its downregulation leads to reduction of translation elongation at the beginning of open reading frames (ORFs), particularly upon insertion of proline residues. Thus, our data unveil FKBP10 as a cancer-selective molecule with a key role in translational reprogramming, stem-like traits, and growth of lung cancer.

Metastases involving the clivus and craniocervical junction (CCJ) are extremely rare. Skull base involvement can result in cranial nerve palsies, while an extensive CCJ involvement can lead to spinal instability. We describe an unusual case of clival and CCJ metastases presenting with VI cranial nerve palsy and neck pain secondary to CCJ instability from metastatic bladder urothelial carcinoma. The patient was first treated with an endoscopic endonasal approach to the clivus for decompression of the VI cranial nerve and then with occipitocervical fixation and fusion to treat CCJ instability. At the 6-month follow-up, the patient experienced complete recovery of VI cranial nerve palsy. To the best of our knowledge, the simultaneous involvement of the clivus and the CCJ due to metastatic bladder carcinoma has never been reported in the literature. Another peculiarity of this case was the presence of both VI cranial nerve deficit and spinal instability. For this reason, the choice of treatment and timing were challenging. In fact, in case of no neurological deficit and spinal stability, palliative chemo- and radiotherapy are usually indicated. In our patient, the presence of progressive diplopia due to VI cranial nerve palsy required an emergent surgical decompression. In this scenario, the extended endoscopic endonasal approach was chosen as a minimally invasive approach to decompress the VI cranial nerve. Posterior occipitocervical stabilization is highly effective in avoiding patient’s neck pain and spinal instability, representing the approach of choice.

INTRODUCTION:A reliable risk stratification on the basis of tumor biology and host factors of HER2-positive (HER2+) early breast cancer (eBC) patients is needed. The aim of our study was to assess the prognostic role of body mass index (BMI) and hormone receptor (HR) expression in this setting. PATIENTS AND METHODS:We retrospectively evaluated 238 women with stage I to III HER2+ breast cancer who completed adjuvant chemotherapy (CHT) and 1 year of treatment with trastuzumab. The end point was 3-year distant disease-free survival (3yDDFS). Survival analysis was evaluated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional-hazards model adjusting for HR status, BMI, tumor staging, size, nodal status, and type of adjuvant CHT. Association among categorical variables was assessed using χ2 test. RESULTS:The early recurrence rate after 3 years resulted as 4.2% (40% HR+ patients and 60% HR- patients). Neither HR status nor BMI alone showed an association with 3yDDFS in multivariate analysis. However, the hazard ratios for patients with HR- tumors who had also BMI ≥25 (3yDDFS 86.9%; 95% confidence interval [CI], 75.0%-97.7%) were amplified compared with patients with HR+ tumors and with BMI <25 (3yDDFS 98%; 95% CI, 94.8%-100.0%) and other subgroups (P = .003). This observation was confirmed in multivariate analysis (hazard ratio, 1.79; 95% CI, 1.04-3.07; P = .03). CONCLUSION:Our real-life data highlight a different risk of eBC recurrence after grouping patients according to HR status and BMI. These results might help clinicians to identify correct treatment strategies. Patients who are HR- and have BMI ≥25 might benefit from escalation approaches, whereas those who are HR+ and have BMI <25 might be eligible for a shorter duration of adjuvant treatment with anti-HER2 agents.

OBJECTIVE:Assess the correlation between MRI characteristics of invasive breast cancer and tumor prognostic features.MATERIALS AND METHODS:95 women with invasive breast cancer underwent pre-treatment MR. Morphological findings and quantitative ADC were retrospectively evaluated.RESULTS:Smaller size, round shape, spiculated margins and homogeneous internal enhancement pattern on dynamic MRI were independently associated with established predictors of good prognosis, while larger size and rim enhancement pattern were related to predictors of poor prognosis. A positive correlation was observed between ADC value and clinical stage.CONCLUSIONS:MRI may be a useful tool for breast cancer aggressiveness prediction and for guiding subsequent clinical-therapeutic management.

Introduction: Dynamic contrast–enhanced magnetic resonance (DCE-MR) imaging of the breast is increasingly used as an adjunct to mammography and ultrasonography (US) to improve the detection and characterization of primary and recurrent breast cancers. Correlation between morphological features, DCE-MRI and prognostic factors of breast cancer (BC), including tumor size, axillary lymph node status, histological grade, presence of vascular invasion and necrosis, ER, PR, c-erbB-2 status and Ki-67, has been previously analysed. The aim of this study was to analyse the relation between DCE-kinetic parameters of BC and the presence of stromal tumour-infiltrating lymphocytes (TILs). Patients and methods: Patients with newly diagnosed breast cancer who underwent DCE-MRI examination within two weeks prior to surgery from January 2013 to January 2017 were selected. Patients who underwent MR imaging beyond two weeks prior to surgery or previous neoadjuvant chemotherapy (NAC), with BC histotype different from Invasive Ductal or Lobular Ccexcluded. TILs was evaluated according to the International TILs Working Group 2014 recommendation. TILs was reported as a continuous variable. Based on the TILs Score proposed by Adam et al., patients have been classified into four subgroups based on the range of TILs percentage. MR imaging was performed with a 1.5 imager ((Philips Achieva, software v. 2.6) and the post-contrast kinetic sequences were analyzed. Results: 109 patients have been analysed. 53% tumors were poorly differentiated (G3). 25 (23%) Luminal A, 46 (42%) Luminal B/HER2 negative, 20 (18%) Luminal B/HER2 positive, 7 (6%) HER2 and 11(10%) TN subtype. Luminal tumors were associated with high values of Wash-in rate and Absolute Maximum Enhancement. On the other hand, HER2 + and TNBC tumors are characterized by slower or reduced Wash-in rate and lower values of Absolute Maximum Enhancement. Time-to-peak in TNBC and HER2 + have significantly higher values than Luminals. Brevity of Enhancement, analysed in type III curve, related to cluttered vascularization, was statistically correlated to high percentage of TILs (p = 0.02). Presence of TILs correlates with Area under curve higher than 500.000 and low values of Absolute Max Enhancement. Conclusion: At the best of our knowledge, this is the first study investigating whether MRI kinetic imaging can predict the presence and the percentage of TILs in BC tissue.

Background: Triple negative breast cancer (TNBC) is an aggressive subgroup of breast cancer (BC) with poor clinical outcome. The lack of target therapies switches attention on the role of immune interaction between host and tumor. Tumor-infiltrating lymphocytes (TILs) is a biomarker of immunogenity that in TNBC can correlate with DFS and OS. The aim of our study was to evaluate the prognostic role of TILs and its association with clinicopathological parameters in TNBC. Materials and methods: Nine-three consecutive patients with primary diagnosis of TNBC referred to our institution between January 2009 and December 2015 were enrolled. We collected their clinicopathological data. In each tumor sample the pathologist evaluated stromal intratumoral TIL percentage (area of stroma occupied by infiltrating lympochytes) and stromal peritumoral TIL percentage (percentage of stroma lymphocytes encountered in entire circumferential invasive tumor front). Lymphocytes predominant breast cancer (LPBC) were the ones with TILs higher than 60%. TILs were correlated with clinicopathological data, OS (time between diagnosis and death or last follow up) and DFS (time between diagnosis and relapse either as local recurrence or distant metastasis). All data were analyzed by Chi square test. Kaplan-Meier curves for OS and DFS were applied. Univariate and multivariate Cox proportional hazard models were conducted to correlate between TIL, OS and DFS. Level of significance p value was set at 0.05. Results: We found a significant association between stromal intratumoral TIL and stromal peritumoral TIL (p = 0.0082). A significant difference was also seen in LPBC subgroup (p = 0.0001 95% CI 3,4761-33,5857). There was no significant correlation between both intratumoral and peritumoral TIL and the clinicopathological data examined. Peritumoral TIL was significantly associated with OS (p = 0.0119 95% CI 1,7109-75,541) and DFS (p = 0.0113 95%CI 1,5723-34,8046), the latter regardless of TIL percentage of expression. Intratumoral TIL did not demonstrate significant correlation with DFS, unless a TIL percentage =1% (p = 0,029 95%CI 1,1266-10,3296), nor with OS. At the multivariate analysis TIL did not show a significant correlation with OS and DFS. Conclusions: Peritumoral TIL correlates with DFS and OS in TNBC. This is an intriguing data not enough considered in literature yet which suggest that the location of TIL may help to stratify prognostic BC subgroups to guide future therapeutic decisions.

Background Lung cancer seems to have different epidemiological, biomolecular and clinical characteristics in females than in males, with a better prognosis for women. The aim of the study is to determine gender differences in lung adenocarcinoma in terms of androgen (AR), estrogen (ER)α and progesterone (PgR) receptors expression and their impact on outcome. Results Overall survival was significantly better in ERα and in PgR positive lung adenocarcinoma patients (median survival 45 vs. 19 months). Eight out of 62 patients showed positive expression of nuclear (n) AR and 18 of cytoplasmic (c) AR with a significantly better survival (49 vs. 19 and 45 vs. 19 months, respectively). There was a significant difference in survival between patients with vs. without c-AR expression (30 vs. 17 months). Finally, in the subgroup of women, median survival was greater in positive expression of c-AR than for women with negative c-AR (45 vs. 21 months). Materials and Methods We conducted an analysis on a cohort of 62 patients with advanced NSCLC treated at our institution. We investigated the immunohistochemical expression of n/c AR, ERα and PgR in 62 NSCLC and we correlated it with patients' clinic-pathologic characteristics and with prognosis. Conclusions Our results showed that the positive expression of one hormonal receptor could represent a prognostic factor. Furthermore our study suggests that AR should become object of close examination in a larger series of lung adenocarcinoma patients, also for selection of the patients with best prognosis that can perform more chemotherapy lines.

Background: There is a strong body of evidence regarding the relation between dietary behaviours, Body Mass Index (BMI), breast cancer (BC) incidence and risk of relapse. Recent data also suggest that overweight/obesity cause the activation of multiple inflammatory signaling pathways leading to the development and progression of BC. The purpose of our analysis was to understand if BMI can influence locally advanced breast cancer's development and clinical-pathological features and its relation with prognosis and response to neoadjuvant chemotherapy. Patients and methods: Data of consecutive patients undergoing NAC for LABC (stage II-III) between January 2007 and September 2015 from our Institution were retrospectively collected. According to BMI at diagnosis, three groups were identified: (a) ≤ 24.9(normal/underweight), (b)25.0 to 29.9(overweight), and (c) ≥ 30(obese). Blood-derived inflammatory indexes were collected. Chi-square test was used to test for interaction between patients' BMI and clinical-pathological features and to determine its value as prognostic and predictive factor. Relapse free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier method. Results: 124 patients with LABC were identified: 47% of them were overweight/obese, with a significant percentage of them was over 50 years old. No statistically significant relations were noted between groups b/c and pathological characteristics (bilateral/multifocal tumor, initial ER/PgR and HER2 status and its variation after chemotherapy, Ki-67%, lympho-vascular invasion) neither with pCR rate after NAC (p = 0.6), relapse-free survival and overall survival. Interestingly, overweight and obesity increased the risk (Odd ratio of 2,6) and were associated to the development of advanced stages of BC (53,2% vs 46,8%, p = 0.02). Groups b/c were significantly associated with higher levels of platelet/lymphocyte ratio (p= 0.04). Conclusion: Lower adherence or more challenges in Mammography Screening could explain an almost three-times increased risk of developing locally advanced BC, which is one of the main factors affecting breast cancer patients' prognosis. Obesity represents it-self a condition related to systemic inflammation and cancer. Much efforts in educational programs and closer monitoring programs should be taken in this subgroup patients, especially after 50 years.

Background: HER2 amplification is uncommon in breast cancer (BC) tumors with BRCA1/2 mutations. We aimed to assess the relevance of both BRCA mutations and the expression of insulin-like growth factor receptor-1&bgr; (IGF-R1&bgr;) in a series of patients with HER2-positive BC who met clinical criteria for BRCA testing treated with Trastuzumab for early stages or for metastatic disease. Furthermore, we investigated by pathway reconstruction analysis the relationship among HER2 overexpression, BRCA mutations and IGF-1R expression. Patients and methods: We analyzed data from 35 patients treated with adjuvant/neoadjuvant Trastuzumab (82.9%) or after development of metastasis (17.1%). We performed immunochemistry for HER2, ER/PR, Ki67 and IGF-R1ß. Bioinformatic analysis was carried out to identify a possible correlation among HER2 overexpression, BRCA mutations and IGF-1Rß expression. Results: We found that 19 tumors (54%) presented BRCA mutations; of them, 11 (57.9%) were pathogenic mutations. Median IGF-1Rß IHC score was 80 (range, 0 to 285). IGF1Rß IHC score above median was found in 78.6% (10/14) of BRCA mutated patients and 26.7% (4/15) of BRCA not-mutated patients (p = 0.027). Median PFS was 15.1 months in the overall population and 9.7 months in patients harboring BRCA mutations. Median DFS was 60.3 months in patients with HER2+ BRCA mutated tumors, whilst was not reached in HER2+ BRCA not-mutated patients (p = 0.018). Interestingly, a trend toward a longer DFS was observed in HER2+ BRCA2 vs BRCA1 mutated patients. As for IGF-R1ß score, median DFS was 92.4 months in patients with IGF-R1&bgr;+ tumors treated with adjuvant and/or neoadjuvant Trastuzumab and was not reached in patients with IGF-R1&bgr;- tumors (p = 0.234). Reconstructed pathway showed that BRCA1 mutations lead to IGF-1R overexpression and to increased phosphorylation of AKT and, as a consequence, of the transcription factor Y box binding protein 1 (YB-1). YB-1 translocates into the nucleus where it binds to HER2 promoter, leading to HER2 overexpression, and increases the expression of Epithelial growth factor receptor (EGFR). Conclusions: Our results support that sensitivity to Trastuzumab seems to be associated with BRCA mutational status and to IGF-1R expression in a subset of HER2 positive BC patients.