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Dopo una prima sezione introduttiva, in questo capitolo si evidenzieranno le specificità dell’industria italiana evidenziando come, alcune anomalie, portino a corroborare l’ipotesi che l’attuale crisi dell’automotive italiana sia collegata a tali anomalie e a tendenze generali che risultano essere sostanzialmente indipendenti dalla transizione tecnologica. Nella terza sezione si identificheranno le variabili per valutare come e in che misura l’attuale accelerazione dello sviluppo della tecnologia potrà condizionare la trasformazione dell’industria. Nella quarta sezione si commenteranno brevemente alcuni risultati riportati nel capitolo precedente e le implicazioni per la filiera dell’elettrificazione del drivetrain. La quinta sezione chiude il capitolo con alcune indicazioni di policy.

This volume reports the first results of the Observatory on the Transformations of the Italian Automotive Ecosystem. The main focus is on the consequences of the technology acceleration following the European legislation that has decreed the end of the sales of the production of endothermic motors in 2035. The Observatory was founded by CAMI - Department of Management of Ca' Foscari University of Venice and Motus-E, the association of industrial operators that promote electric vehicles. It seeks to identify the key variables to assess whether and to what extent the current technological development is shaping the evolution of the automotive ecosystem, and ultimately whether it represents an opportunity or a threat for incumbents. The main objective of the Observatory is to produce and identify scientific evidence on the ecosystem of mobility to be made available to economic, entrepreneurial, political-institutional and scientific networks. The Observatory is based on a database composed of companies belonging to the industrial chain of road mobility (supply chain for cars, motorcycles, micro-mobility, buses, trucks, as well as companies providing engineering services, components and after-market services and infrastructure for electric and similar refuelling and charging). The technological evolution of recent years is affecting the drive-train of vehicles, which will be subject to radical changes starting from the abandonment of internal combustion engine technology. In this scenario it is no longer enough to continue analysing the ‘traditional supply chain’, but a broader analysis is needed that takes into account the entire mobility ecosystem. Electric mobility is, to date, the most mature technology to replace the endothermic engine and will involve: a radical change in the technological base; an expansion of the boundaries of the automotive supply chain involving those of digitalisation and services; the need for complementary asset development.

The network contract was introduced by the policymaker to help Italian SMEs pursue competitiveness and innovation. As demonstrated by the previous editions of this National Observatory, the network contract has been a useful instrument to get positive results both at the network and firm level, but only if some conditions in terms of network management and organisation are met. The present chapter aims at describing the economic-financial results of networked firms, through the analysis of balance-sheet data of about 16,000 firms, from 2017 to 2021. The goal is to describe the Italian scenario to contribute to the understanding of the network contract phenomenon and to help the policymaker evaluate its results.

BACKGROUND: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses mainly on prolonging patients (pts) survival and improving their quality of life. As a consequence, management of treatment related adverse events (AE) is very important. Eribulin (E) is a microtubule inhibitor that has shown to increase overall survival in pre-treated MBC pts. Its most common AEs are asthenia, neutropenia and peripheral neuropathy (N). PATIENTS AND METHODS: PAINTER (Clinical trial registration: NCT 0286403) is a multicenter, interventional, single-arm, phase IV study, aimed at surveying the tolerability of E (dose 1.4 mg/m2 day 1, 8 every 21 days) in an unselected MBC pts population pre-treated with taxanes and antracyclines. The secondary objective was to investigate the relationship between specific polymorphisms and incidence and severity of peripheral N. Toxicity (T) was reported according to the NCI CTCAE v4.0. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit-Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with available genomic data and who started E treatment N was evaluated by medical examination. RESULTS: From May 2014 to June 2018, 180 pts were enrolled from 20 Italian centres and 170 were evaluable. Pts and tumors characteristics were as follows: median age 60 years, ductal carcinoma 76.3%, visceral disease 68.8%, luminal type 64.7%, Her2 positive 18.3%, triple negative 17%, median previous treatment lines for MBC 5, median years from first diagnosis 6.1. Pts received E for 4.5 median cycles (Q1-Q3: 3.0-7.0; min-max: 1-23); 48.8% of pts experienced dose reduction, due to neutropenia (23.9%) and liver injury (12%) and 5.2% of pts discontinued E for T or for pts refusal. Previous neuropathy was reported in 15.9% of pts. Table 1 shows the incidence of expected AEs. N (all grades) during E treatment was reported in 33.9% of patients (G2-G3-G4: 15%). The risk of N occurrence in the first 5 cycles was 32.5% (for any grade N) and 13.2% (for severe N). Other G1-G4 toxicities were: dermatological in 8.6% pts, liver injury in 13.6%, pulmonary in 13.6%. Interestingly, 40.7% of pts reported pain, especially osteo-muscular, abdominal and at tumor site. Ten serious AEs were reported and only two were E related. 159 pts were evaluable for the analysis of polymorphism. Among the selected SNPs, the allelic variant T of the polymorphism rs2233335 in NDRG1 gene (Fisher test p CONCLUSIONS: PAINTER study offers a wide spectrum of information about E tolerability. Asthenia, neuropathy and neutropenia were the most common T, but few pts experienced severe AEs. Schedule and dosage modifications were common, as expected in pre-treated pts, but T rarely led to treatment discontinuation. Importantly, we found for first time that the SNPs rs2233335 (G/T and T/T) in NDRG1 gene and rs7214723 (CC and CT) in CAMKK1 gene were associated with E induced N. These data on pharmacogenetic testing, if validated, could allow a tailored treatment with E. Table 1. Incidence of expected AEsAEsG1G2G3G4Severe T (G3+G4) N=170n (%)n (%)n (%)n (%)% [%95%CI]Neuropathy 31 (18.2)20 (11.8)5 (2.9)0 (0.0)14.7 [9.75 - 20.9] #Neutropenia 15 (8.8)11 (6.5)16 (9.4)10 (5.9)15.3 [10.2 - 21.6]Constipation 16 (9.4)8 (4.7)1 (0.6)0 (0.0)0.6 [0.02 - 3.23]Alopecia 25 (14.7)13 (7.6)N.A.*N.A.*7.6 [4.13 - 12.7]Asthenia 38 (22.4)38 (22.4)10 (5.9)0 (0.0)5.9 [2.86 - 10.6]Nausea 19 (11.2)6 (3.5)0 (0.0)0 (0.0)0.0#: G2 for neuropathy and alopecia were considered as severe T *N.A.: Not applicable Citation Format: Nicla La Verde, Giovanna Damia, Ornella Garrone, Loretta D'Onofrio, Alessandra Fabi, Mariangela Ciccarese, Daniele Generali, Martina Nunzi, Elena Poletto, Paolo Pedrazzoli, Elisabetta Cretella, Giuseppa Scandurra, Icro Meattini, Alessandro S Bertolini, Luigi Cavanna, Emanuela Romagnoli, Lorenzo Legramandi, Federica Guffanti, Eliana Rulli, Anna Moretti, Barbara Bocci, Gabriella Farina. Eribulin tolerability and correlation between neuropathy and a set of polymorphisms in metastatic breast cancer patients. Results from the PAINTER (Polymorphism And Incidence of Toxicity in ERibulin treatment) study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-01.

The current study presents the effects of strain and temperature on the mechanical response and microstructure evolution in AA7075-T651 at high strain rates. Compression tests have been performed at room temperature (RT), 200, 300 and 400 °C using a Split-Hopkinson pressure bar (SHPB) setup with strain rates ranging between 1400 and 5300 s−1. For deformation at RT, the flow stress increases with increase in strain rate. Whereas deformation at elevated temperatures show a non-monotonous behavior of the flow stress with respect to the strain rate. This trait is attributed to the pronounced effects from the adiabatic shear bands (ASBs); namely, distorted shear bands (DSBs) and transformed shear bands (TSBs); and cracks resulting from the plastic deformation instability during hot deformation. The sequence of microstructure evolution is: inhomogeneity in the initial microstructure – DSB – TSB – crack –fracture. The feasibility of formation and growth of ASBs and cracks increases with increase in strain and temperature, neglecting any significant effect from the strain rate. During the compression tests, temperature of the material rises due to adiabatic heating. Considering a certain strain developed in the material, this adiabatic temperature rise decreases as the deformation temperature is increased. Furthermore, during individual deformation processes, the temperature rise increases with increasing strain. The adiabatic temperature leading to the formation of TSB is approximated to be 0.7 times of the melting temperature of the alloy. These results from the current study are to be used in developing a physics-based material model for the alloy.Article Highlights At elevated temperatures, compression with Split-Hopkinson bars produce two types of shear bands and cracks. Evolution of shear bands and cracks is promoted by increase in strain and temperature irrespective of strain rate. Adiabatic temperature approximating to 70% of the melting point forms refined grain structure of transformed band.

Life sciences industry is of particular importance both for its economic dimension (in terms of turnover, employees, and R&D investments), and for its critical role in improving humans’ living conditions, a central element of the Sustainable Development Goals program. The industry is going through a critical transition that’s changing and has partly already changed the rules of the game. The dimensions along which firms are competing are changing, and the industry’s complexity is continuously increasing. In this scenario, inter-organizational relationships emerge as a key factor to face uncertainty and change, pursuing efficiency and competitiveness goals.

Nel 2021 il mondo ha dovuto fare i conti per il secondo anno di fila con la crisi sanitaria ed economica determinata dalla diffusione del virus COVID-19. Per l’industria dell’auto la crisi ha prodotto una serie di effetti sia sull’offerta sia sulla domanda, tra cui la crisi dei semiconduttori, l’incertezza economica legata alla crisi sanitaria, e la decisa accelerazione, a trazione EU, della transizione verso la mobilità elettrica. Per la filiera automotive italiana, ulteriori incognite sono legate alla formazione di Stellantis e il conseguente spostamento del baricentro decisionale fuori dall’Italia. Il quadro che emerge dal rapporto 2021 dell’Osservatorio è quello di una filiera i cui risultati in termini di fatturato, produzione ed export continuano ad essere in contrazione, e che necessita con urgenza dell’avvio di un programma di investimenti pubblici per sostenere l’attrattività di investimenti privati in Italia, e del rilancio dei poli italiani di eccellenza attraverso nuovi investimenti in ricerca e sviluppo, struttura manageriale, risorse finanziarie e una rinnovata capacità di ‘fare rete’.

Purpose: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor—positive (HR+), HER2-negative (HER2−), advanced breast cancer (HR+/HER2− aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. Experimental Design: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2− aBC treated with everolimus-exemestane. Results: We evaluated 809 patients with HR+/HER2− aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15–2.69; P = 0.008). Conclusions: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2− aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2− aBC.

L’anno 2020 ha visto svilupparsi una crisi senzaprecedenti a causa della pandemia. A fronte di questa situazione, l’edizione 2020 dell’Osservatorio vuole proporre una riflessione su come le reti d’imprese possano rappresentare uno strumento di resilienza delle imprese, guardando alle relazioni inter-organizzative come strumento di flessibilità, cambiamento eadattamento. L’edizione 2020 dell’Osservatorio sviluppa unapprofondimento sulla relazione tra il funzionamento della rete e la performance delle imprese in rete ed è arricchito da alcuni approfondimenti settoriali. I risultati presentati aiuteranno i manager a massimizzare le opportunità offerte dalla rete ed i policy maker ad orientare in modo ancora più efficace l’utilizzo dei contratti di rete come strumento di resilienza.

Nell’anno 2020 l’Italia ha dovuto fare i conti con la crisi sanitaria ed economica determinata dalla diffusione del virus COVID-19. La straordinarietà della situazione, con l’Europa alle prese con lockdown e fermi produttivi, ha portato l’Osservatorio a far seguire alla tradizionale rilevazione avviata a fine Febbraio 2020 una seconda indagine di approfondimento mirata a raccogliere le prime reazioni delle imprese della filiera alla crisi da coronavirus. Questa edizione del volume è, quindi, particolarmente ricca di spunti in quanto collega la fotografia del 2019 alla situazione generata dalla pandemia nel 2020. Il quadro complessivo è quello di una filiera i cui risultati in termini di fatturato, produzione ed export erano già in contrazione nel 2019 e, di conseguenza, particolarmente esposta alla crisi del 2020, soprattutto per alcune categorie di imprese meno resilienti. Il superamento di questa situazione critica potrà giocarsi sulla capacità di sviluppare aggregazioni e reti per l’innovazione, con obiettivi importanti di competitività dell’intera filiera sullo scenario internazionale.

Introduction Metastatic breast cancer (MBC) is a life-threatening disease, and although some data suggest a trend in survival improvement, it has not yet been unequivocally demonstrated. This study aimed to evaluate the overall survival (OS) of MBC patients, assessing its correlation with prognostic factors. Patients and Methods COSMO (Checking Overall Survival in a MBC Observational study) is an Italian longitudinal retrospective multicenter study that enrolled patients with MBC diagnosed between 2000 and 2008. The primary objective was to detect a temporal difference in OS; the secondary objective was to identify prognostic factors as causal factors of the temporal variation in OS. Results A total of 3721 of 3930 patients from 31 centers were distributed in 3 periods: 886 (23.8%), 1302 (35.0%), and 1533 (41.2%) in 2000-2002, 2003-2005, and 2006-2008, respectively. With a median follow-up of 9.3 years, median OS was 2.8 years (95% confidence interval, 2.6-2.9). No difference in OS was found in the 3 cohorts (P for trend = .563). The worst prognosis was observed for patients with triple-negative MBC (OS, 1.5 years) and for those with central nervous system metastases (1.7 years); the best prognosis was observed in those with bone metastases or nonvisceral disease (3.4 and 3.2 years, respectively) and in patients with a disease-free interval, defined as the time between resection of the primary malignancy and diagnosis of MBC, of > 2 years (3 years). Conclusions The COSMO study found improvement in OS between 2000 and 2008. Molecular subtype remained the strongest prognostic factor, and the role of other prognostic factors was confirmed, in particular disease-free interval, site of metastasis, and age.

This chapter synthesizes the main contributions of the book and identifies new avenues of research: luxury fashion firms compete in an environment in which two different sets of competitive variables, traditional and new, coexist. However, these two sets are coherent and complementary within their own boundaries and less so with each other and challenge firms willing to design a new competitive landscape; luxury fashion firms are tightropes in between zeroing the brand and respecting the heritage; in between craftmanship, increased number of collections and sustainability; in between street style, increased number of collections and perception of uniqueness and rarity; and in between speed and creativity; additional studies are needed to understand how Maisons will cope with the above trade-offs, which variables will lead to superior competitive advantage, how new technologies and their usage will shape competitive advantaged.

Through an explorative case study, this paper provides insights on how the adoption of a digital collaboration tool (i) can create a more trust-based relationship between ITO client and suppliers, and (ii) can foster collaborative relationships that result in both operational and strategic innovation outcomes. Our case study is based on an ITO project developed by Infocert, the first Certification Authority in Italy, having issued and managed more than 4,500,000 qualified certificates of digital signature. Our findings show how digital collaboration can affect trust before and during the engagement phase of the IT outsourcing process. The digital media tool increased communication flexibility and supported temporary relationships based on explicit rather than implicit agreements. This case, therefore, highlights how the use of a digital collaboration tool can change relational governance in a short time frame as trust among client and suppliers switched swiftly from affective attitudes to a more objective relations based on competencies.

BACKGROUND - Metastatic breast cancer (MBC) is a life-threatening disease. It is important to provide data about real-life MBC patients (pts) to understand the current prognostic factors. The aim of the present observational study, named COSMO (Checking Overall Survival in a MBC Observational study) is to describe the overall survival (OS) in a large cohort of MBC pts, assessing its correlation with specific prognostic factors (demographic, clinic, pathologic and biological). PATIENTS AND METHODS - The COSMO study is a multicenter, retrospective, cohort study, developed throughout the collaboration of 31 Italian oncological centers. Data about pts diagnosed as metastatic from 01/01/2000 to 31/12/2008, were collected. The association between molecular subtypes, metastatic sites, disease free interval (DFI) and OS were assessed. Pts were classified in three subgroups, based on the biological characteristics of their tumor: luminal, HER2-positive (regardless of hormone receptor) and triple negative (TN). Metastatic sites were categorized as visceral versus non-visceral disease, only bone and central nervous system (CNS) metastases. DFI was calculated from diagnosis to first relapse only for M0 pts. RESULTS - Of 3931 MBC pts enrolled in the study, 3720 were evaluable, with a median age of 61 years (interquartile range, IQR, 51-71). 1804 (62,1%) pts had a luminal disease, 691 (23,8%) HER2-positive, 410 (14.1%) TN. Median DFI was 3.2 years (IQR 1.7- 6.0). Regarding metastatic sites, pts with visceral disease were 2332 (63%); 826 (22,2%) pts had bone isolated metastases; in 306 (8,3%) pts, CNS metastases were reported. With a median follow up of 9 years (IQR 5.7-11.0) and 3098 (83.3%) recorded events, we founded a median OS of 2.8 years (95%CI: 2.7-2.9) years. OS was strictly depending from molecular subtypes with a better prognosis for HER2-positive versus luminal and TN MBC pts, median OS of 3.1 (95%CI 2.8-3.4), 3.0 (95%CI: 2.9-3.1) and 1.5 (95%CI: 1.3-1.7) years respectively (p-value2 years show a median OS of 3 years (95% CI: 2.9 – 3.2), while those with DFI CONCLUSIONS - Molecular subtype is crucial for prognosis: HER2-positive subtype has the best prognosis, while TN subtype has the shorter OS. Having a longer DFI from diagnosis (>2 years) correlate with a better prognosis. Our study confirm that sites of metastasis affects outcome: visceral involvement correlates with poor prognosis and, particularly, pts with brain metastasis represent the worst subgroup, while pts with solely bone disease have the best prognosis. The COSMO study provides a view on the Italian landscape of MBC between 2000 and 2008, adding new insights about pts prognosis. Citation Format: La Verde N, Collovà E, Blasi L, Pinotti G, Bernardo A, Bonotto M, Garrone O, Brunello A, Cavazzini MG, Bareggi C, Prochilo T, Porcu L, Moretti A, Barni S, On Behalf of COSMO Study Group. Overall survival in metastatic breast cancer patients in the third millennium: Results of an Italian study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-04.

Dopo un iniziale entusiasmo verso i benefici dell’esternalizzazione dell’innovazione attraverso lo sviluppo di relazioni inter-organizzative finalizzate a co-progettare componenti e sistemi, la letteratura ha iniziato a osservare che la scelta di basare i propri processi innovativi su fonti esterne, per avere successo nel tempo, deve associarsi allo sviluppo di risorse e competenze interne e a sofisticate pratiche inter-organizzative. Lo studio presentato in questo articolo ha ad oggetto lo sviluppo delle relazioni verticali nel settore automotive italiano. In linea con le pratiche internazionali, la filiera italiana si e configurata secondo una logica gerarchica e multi livello. Essa, tuttavia, non sembra essere ancora nelle condizioni di sfruttare a pieno i vantaggi dell’innovazione distribuita. Lo studio individua due ragioni principali, tra di loro collegate: (1) la scarsa qualificazione della forza lavoro che rende difficile un miglioramento nelle attivita di innovazione svolte all’interno dell’impresa; (2) il basso ricorso a fonti esterne di innovazione e la conseguente impossibilita di sfruttare le sinergie normalmente rese possibili dalle relazioni di fornitura.

The report on state of art in modelling of microstructure and deformation behaviour of selected alloys focuses on inelastic behaviour of alloys that is strongly dependent on their microstructure. The focus in the project is on the following alloys; · Ti - 6Al -4V, · Alloy 718, and · AA 7075 -T6

La collana rappresenta un importante strumento d’indagine del settore autoveicolare. È realizzato, in collaborazione, da ANFIA (Associazione Nazionale Filiera Industria Automobilistica), Camera di commercio di Torino, e il CAMI (Center for Automotive and Mobility Innovation dell’Università Ca’ Foscari Venezia). Raccoglie i rapporti annuali dell’Osservatorio sulla componentistica automotive italiana, che offre un quadro complessivo sull’intera filiera autoveicolare. In particolare, sono indagati aspetti sia di carattere strutturale (classificazione per sistemi di prodotto, standard qualitativi, eventuale decentramento produttivo, livello di subfornitura, internazionalizzazione, innovazione, relazioni interorganizzative, ecc.) sia congiunturale (andamento della produzione, andamento delle esportazioni, previsioni, ecc.) relativi al settore.

BackgroundEribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy.MethodsPatients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study.ResultsIn stage I of the study 13 women were enrolled, median age 43 years, tumor size 2-5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR.ConclusionsDespite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial-mesenchymal transition, claims for further investigation.Trial registrationEU Clinical Trial Register, EudraCT number 2012-004956-12.

Purpose: Early breast cancer follow-up guidelines for patients who underwent surgery suggest a regular and accurate clinical examination of the breast area, for an early identification of cutaneous or subcutaneous breast cancer relapse. Nonetheless, breast skin lesions arising in patients treated with mastectomy for breast cancer can be caused by several diseases. A series of diagnostic hypotheses should be considered, not only focusing on cutaneous metastasis, but also on dermatologic and systemic diseases. Case report: In February 2015, a 37-year-old patient underwent a right subcutaneous mastectomy for stage IIA breast cancer. Five months after beginning adjuvant chemotherapy, she noted hyperpigmentation and thickening of the skin on the right breast. Differential diagnosis included local relapse, skin infection, lymphoma, or primary cutaneous disease, and a skin biopsy was performed. The histopathologic specimen showed full-thickness sclerosis, with features of localized morphea. Therapy with clobetasol was prescribed, with progressive resolution of the thickness. The collaboration between many professionals in a multidisciplinary team (oncologist, dermatologist, plastic surgeon, and pathologist) was crucial to achieving the diagnosis. Conclusion: In the literature, some articles describe correlation between connective tissue diseases and silicone breast implants, but the pathogenetic mechanisms are unknown. We report a rare case of breast morphea after positioning a silicone implant in a patient who had undergone mastectomy. This clinical report represents an interesting model of multidisciplinary management of a patient with breast cancer who developed an uncommon dermatologic disease. Further studies are needed to clarify the association between silicone implants and breast morphea.

Infiltrating lobular carcinoma (ILC) represents about 10% of breast cancer and rarely shows overexpression of human epidermal growth factor receptor 2 (HER2). We compared biological and clinical characteristics of HER2-positive ILC versus HER2-positive infiltrating ductal carcinoma (IDC).We retrospectively analyzed the data of 328 patients with HER2-positive pure ductal or lobular breast carcinoma, comparing clinical and biological data at diagnosis as well as outcome between the 2 histologies. A gene-mutation analysis was performed in a subset of patients.Two hundred ninety-one patients (88.7%) had IDC and 37 patients (11.3%) ILC. ILC resulted more frequently in multicenter (24.3% vs. 6.5%, P .0001) and node-positive (54.1% vs. 45%, P = .013) disease of lower proliferative activity (Mib1 20%: 51.4% vs. 22.3%, P .0001) and lower histologic grade (grade 3: 32.4% vs. 57.4%, P = .038). Disease recurred in 57 patients (17.4%) and involved the bone in 40% of ILC patients (vs. 17% of IDC patients) and the viscera in 30% of ILC patients (vs. 59.6% of IDC patients). No difference in the recurrence rate between the 2 histologies was observed in patients treated with adjuvant trastuzumab (12.5% of ILC patients and 8.3% of IDC patients). Exploratory molecular analysis revealed a higher frequency of mutations in ILC, with more cases of multiple mutations.HER2-positive ILC shows different biological behavior than IDC, with a possible higher mutation load. Despite lower proliferation activity and estrogen receptor expression in ILC breast cancer, trastuzumab is clearly an effective therapy for this histologic subtype.

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Approximately 70% of breast cancers (BCs) express estrogen receptor alpha (ERα) and are treated with endocrine therapy. However, the effectiveness of this therapy is limited by innate or acquired resistance in approximately one-third of patients. Activating mutations in the ESR1 gene that encodes ERα promote critical resistance mechanisms. Here, we developed a high sensitivity approach based on enhanced-ice-COLD-PCR for detecting ESR1 mutations. The method produced an enrichment up to 100-fold and allowed the unambiguous detection of ESR1 mutations even when they consisted of only 0.01% of the total ESR1 allelic fraction. After COLD-PCR enrichment, methods based on next-generation sequencing or droplet-digital PCR were employed to detect and quantify ESR1 mutations. We applied the method to detect ESR1 mutations in circulating free DNA from the plasma of 56 patients with metastatic ER-positive BC. Fifteen of these patients were found to have ESR1 mutations at codons 536–538. This study demonstrates the utility of the enhanced-ice-COLD-PCR approach for simplifying and improving the detection of ESR1 tumor mutations in liquid biopsies. Because of its high sensitivity, the approach may potentially be applicable to patients with non-metastatic disease.

Aims and background Patients with hereditary breast cancer (BC) may benefit from genetic counseling and testing for detection of causative mutations, definition of therapeutic and preventive strategies, and identification of at-risk relatives. Italy has few oncogenetic centers and genetic evaluation of all patients with BC is not feasible. Moreover, lack of uniformity in the selection of patients generates inappropriate referral to the geneticist. We designed a model that may represent a reproducible way to select patients at risk for hereditary BC, with the aims of rationalizing access to genetic centers and improving clinical management and surveillance. Methods The genetic unit of a Cancer Center and the Departments of Oncology from 2 public Hospitals in Milan were involved in the project. After training sessions at the genetic unit, operators from the 2 hospitals evaluated all patients with BC attending a first oncologic visit, through a specific interview. Patients considered at risk of hereditary BC attended counseling at the genetic unit. Results Of 419 patients, 61 (14.5%) were eligible for genetic counseling after the interview. Of these, 46 (10.9%) strictly met testing criteria. Overall, 52 (12.4%) patients underwent genetic counseling and 47 were tested for BRCA1/ BRCA2 mutation. After genetic test results, the available options for treatment/surveillance were discussed by a multidisciplinary team, according to the level of genetic risk. Conclusions It is possible to improve the process of referring patients with suspected hereditary BC for genetic risk assessment. The application of clinical screening reduced the genetics unit's workload and enabled optimization of time and resources.