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Introduction: Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors., Methods: To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy., Results: A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible., Conclusion: The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights., Competing Interests: Declaration of competing interest PC: Consulting or Advisory Role: Daiichi Sankyo/Lilly, Reveal Genomics, Gilead Sciences; Speakers' Bureau: Roche/Genentech, Novartis, AstraZeneca, Lilly, BMS; Research Funding: Merck KGaA (Inst); Patents, Royalties, Other Intellectual Property: HER2Dx patent; Expert Testimony: AstraZeneca. EC: reports consulting fees from Novartis, Lilly, Pfizer, Roche, AstraZeneca, and Daiichi Sankyo; speaker's bureau from Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo; and travel and accommodations from Pfizer and Roche. GC: received honoraria for speaker's engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medi-cine, Samsung, Celltrion, Mylan; Honoraria for writing engagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, MedI- mmune MDL: advisory boards, activities as a speaker, travel grants, consultancy: Eli Lilly, Novartis, Seagen, Takeda, Roche, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, Sophos, AstraZeneca, Pfizer, Sanofi, Ipsen, Pierre Fabre, GSK. AG: research funding to the Institution: AstraZeneca, Pfizer, Janssen, Roche, MSD, Daichii-Sankyo, GSK/Tesaro, HiFiBio, Merck, Boehringer-Ingelheim, Exelixis, Bayer, Incyte, Bayer, Aileron; travel, accommodation, expenses: Gentili. LDM: advisory role for Agendia, Amgen, AstraZeneca, Collage SpA, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Havas Life, Pfizer, Pierre Fabre, Roche, Seagen Int, Stemline Menarini and Uvet; personal fees as an invited speaker for Accademia Nazionale Medicina, Andromeda E20, Aristea, Delphi international, Editree, Eli Lilly, Ipsen, Meeting SrL, MSD, Novartis, Over Srl, Prex Srl, Symposia and Vyvamed Srl; personal fees for writing engagements for Edizioni Minerva Medica, Pensiero Scientifico Editore and Roche; personal consultancy fees from Eli Lilly, Gilead, Kardo Srl and Sharing Progress in Cancer Care (SPCC)—Switzerland; personal fees for author slide kits from Forum service and Think2it; personal fees for interviews from Infomedica Srl and Think2it; institutional funding as a local PI from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Novartis, Novella Clinical, Roche and Seagen; institutional funding as a national coordinating PI from Roche; institutional research grant from Pfizer; and non-remunerated product samples from FoundationOne. AG: received advisory role from AstraZeneca, Daiichi, Eisai, Lilly, Novartis, Pfizer, Roche, Seagen, Gilead, Teva, and Gentili; lecture honoraria from Novartis, Pfizer, Gilead, Roche, Eisai, Seagen, Teva, and Gentili; and research support from Roche, Eisai, Gilead, and Pharmanutra AL: Research support: Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp&Dhome, Gilead, Daiichi Sankyo; Consulting/advisor: Lilly, Roche, Pfizer, Novartis; Speaker's Bureaus: Lilly, Astrazeneca, Merck Sharp&Dhome, Pfizer, Novartis; Travel support: Roche, Pfizer, Astrazeneca, Merck Sharp&Dhome. MM: Honoraria: Roche/Genentech, Lilly, Pfizer, Novartis, Pierre Fabre, Seagen; Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi-Sankyo; Speakers' Bureau: Lilly/ImClone, Lilly/ImClone, Roche/Genentech, Pierre Fabre; Research Funding: Novartis (Inst), Roche (Inst), Puma Biotechnology (Inst); Travel, Accommodations, Expenses: Daiichi-Sankyo; Other Relationship: Roche, Novartis. FPo: advisory board from AstraZeneca; speaking honoraria and travel grants from Eli Lilly, Novartis, Seagen, Daichii Sankyo, and Gilead. AP: reports grants and personal fees from NanoString Technologies, Veracyte, Novartis, AstraZeneca, DaiichiSankyo, and Roche; in addition, A. Prat has a patent for DNADX pending. FPu: reports honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen - Astrazeneca - Daiichi Sankyo - Celgene - Eisai - Eli Lilly- Exact Sciences- Gilead - Ipsen – Menarini- MSD - Novartis - Pierre Fabre - Pfizer - Roche - Seagen - Takeda – Viatris; Research funding from Astrazeneca – Eisai – Roche. CS: consultancy or advisory role for AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter, F. Hoffmann-La Roche Ltd., International Society for the Study and Exchange of evidence from Clinical research And Medical experience (ISSECAM), Medical Statistics Consulting, MediTech, Merck Sharp and Dohme Corp, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche, Sanofi, Seagen, Zymeworks, and research funding from Aragon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Byondis, CytomX, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, GlaxoSmithKline, Immunomedics, Innoup, International Breast Cancer Study Group (IBCSG), Lilly, Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merck Sharp and Dohme Corp, Merus, Millennium, Novartis, Pfizer, Piqur, Puma, Roche, Sanofi, Seagen, Synthon, and Zenith., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Breast cancer stands as a primary malignancy among women, ranking second in global cancer-related deaths. Despite treatment advancements, many patients progress to metastatic stages, posing a significant therapeutic challenge. Current therapies primarily target cancer cells, overlooking their intricate interactions with the tumor microenvironment (TME) that fuel progression and treatment resistance. Dysregulated innate immunity in breast cancer triggers chronic inflammation, fostering cancer development and therapy resistance. Innate immune pattern recognition receptors (PRRs) have emerged as crucial regulators of the immune response as well as of several immune-mediated or cancer cell-intrinsic mechanisms that either inhibit or promote tumor progression. In particular, several studies showed that the Toll-like receptor 2 (TLR2) and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways play a central role in breast cancer progression. In this review, we present a comprehensive overview of the role of TLR2 and STING in breast cancer, and we explore the potential to target these PRRs for drug development. This information will significantly impact the scientific discussion on the use of PRR agonists or inhibitors in cancer therapy, opening up new and promising avenues for breast cancer treatment.

Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice., Competing Interests: Declaration of Competing Interest CCr reports personal fees for consulting, advisory role and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead and Pfizer. All the competing interests were outside the submitted work. CCo has no potential conflicts of interest to disclose. MDL reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eli Lilly, Novartis, Seagen, Takeda, Roche, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, Sophos; support for attending meetings and/or travel from Gilead, Novartis, Roche, AstraZeneca; fees for participation on a Data Safety Monitoring Board or Advisory Board from Pfizer, AstraZeneca, Sanofi, Seagen, Novartis, Ipsen, Roche, Pierre-Fabre, Daiichi-Sankyo, GSK. All the competing interests were outside the submitted work. GB is a consultant and/or advisory board member for Amgen, AstraZeneca, Chugai, Daiichi Sankyo, EISAI, Eli Lilly, Genomic Health, Merck Sharp & Dohme, Neopharm, Novartis, Pfizer, Roche and Sanofi. All the competing interests were outside the submitted work. BP has no potential conflicts of interest to disclose. SC reports current presidency of the Italian Association of Medical Oncology (AIOM). All the competing interests were outside the submitted work. LC has no potential conflicts of interest to disclose. GA has no potential conflicts of interest to disclose. PC reports personal fees from Novartis, Eli Lilly, AstraZeneca, Tesaro, Daiichi Sankyo, and Gilead, revealing Genomics, BMS, and Roche. All the competing interests were outside the submitted work. FDM has no potential conflicts of interest to disclose. AG has no potential conflicts of interest to disclose. VG reports personal fees from Eli Lilly, Exact Sciences, Novartis, Pfizer, Gilead, MSD, Amgen, Sanofi, Merck Serono, and Eisai. All the competing interests were outside the submitted work. LV has no potential conflicts of interest to disclose. LL has no potential conflicts of interest to disclose. PM declares grants to his Institution from Roche, BMS, Pfizer, Incyte, Novartis, Takeda, MSD, Pierre Fabre; personal payments from Roche, BMS, MSD, Novartis, Pfizer, Pierre Fabre; personal support for congress attendance from BMS, Roche; is President of the Italian Foundation of Personalized Medicine, of AIOM Servizi s.r.l., of the Steering and Verification Board of the ’Regina Elena’ National Cancer Institute. All the competing interests were outside the submitted work. FP reports honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen, AstraZeneca, Daiichi Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris; research funding from AstraZeneca, Eisai, Roche. All the competing interests were outside the submitted work. GV has no potential conflicts of interest to disclose. LDM reports institutional grants or contracts from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, AstraZeneca, Gilead; personal consulting fees from Eli Lilly; personal honoraria for lectures, presentations, speakers bureau, manuscript writing or educational events from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, Agendia, Stemline; support for attending meetings and/or travel from Roche, Pfizer, Eisai, Daiichi Sankyo, AstraZeneca; personal fees for participation on a Data Safety Monitoring Board or Advisory Board from Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sakyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, Astrazeneca, Agendia, GSK, Seagen. All the competing interests were outside the submitted work. SDP reports personal fees for consulting or advisory role from Roche, Novartis, Pfizer, Lilly, Celgene, AstraZeneca/MedImmune, Seattle Genetics, Daiichi Sankyo/AstraZeneca, MSD. All the competing interests were outside the submitted work. GC reports personal fees for consulting, advisory role and speakers’ bureau from Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung and Daiichi Sankyo; honoraria from Ellipses Pharma and fees for travel and accommodations from Roche/Genentech and Pfizer. All the competing interests were outside the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Nicotinamide phosphoribosyltransferase (NAMPT) is a key intracellular enzyme that participates in nicotinamide adenine dinucleotide (NAD) homeostasis as well as a released cytokine (eNAMPT) that is elevated in inflammatory conditions and in cancer. In patients with breast cancer, circulating eNAMPT is elevated and its plasma levels correlate with prognosis and staging. In light of this, we investigated the contribution of eNAMPT in triple negative mammary carcinoma progression by investigating the effect of its neutralization via a specific neutralizing monoclonal antibody (C269)., Methods: We used female BALB/c mice injected with 4T1 clone 5 cells and female C57BL6 injected with EO771 cells, evaluating tumoral size, spleen weight and number of metastases. We injected two times a week the anti-eNAMPT neutralizing antibody and we sacrificed the mice after 28 days. Harvested tumors were analyzed by histopathology, flow cytometry, western blot, immunohistochemistry, immunofluorescence and RNA sequencing to define tumor characteristics (isolating tumor infiltrating lymphocytes and tumoral cells) and to investigate the molecular mechanisms behind the observed phenotype. Moreover, we dissected the functional relationship between T cells and tumoral cells using three-dimensional (3D) co-cultures., Results: The neutralization of eNAMPT with C269 led to decreased tumor size and reduced number of lung metastases. RNA sequencing and functional assays showed that eNAMPT controlled T-cell response via the programmed death-ligand 1/programmed cell death protein 1 (PD-L1/PD-1) axis and its neutralization led to a restoration of antitumoral immune responses. In particular, eNAMPT neutralization was able to activate CD8 + IFNγ + GrzB + T cells, reducing the immunosuppressive phenotype of T regulatory cells., Conclusions: These studies indicate for the first time eNAMPT as a novel immunotherapeutic target for triple negative breast cancer., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We assessed the current practice concerning the axillary management of breast cancer (BC) patients undergoing upfront surgery among radiation oncologists (ROs) practising in Italy., Methods: An online survey via SurveyMonkey (including 21 questions) was distributed amongst ROs in Italy through personal contacts and the Italian Association for Radiotherapy and Clinical Oncology (AIRO) network from August to September 2022. We particularly focused on the emerging omission of axillary lymph node dissection (ALND) in the presence of 1-2 sentinel node-positive patients and the consequent change in the role of regional nodal irradiation (RNI)., Results: A total of 101/195 (51% response rate) Italian Radiotherapy Cancer Care Centres answered the survey. With respect to patients with 1-2 sentinel node-positive, the relative proportion of respondents that offer patients ALND a) always, b) only in selected cases, and c) never was 37.6%, 60.4%, and 2.0%, respectively, with no significant geographical (North vs. Centre-South Italy; p = 0.92) or institutional (Academic vs. non-Academic; p = 0.49) differences. Radiation therapy indications varied widely in patients who did not undergo ALND. Among these, about a third of the respondents (17/56, 30.4%) stated that RNI was constantly performed. On the other hand, half of the respondents offered RNI in selected cases, stating that an unfavourable biologic tumour profile and extracapsular nodal extension were considered drivers of their decision., Conclusions: Results of the present survey show the variability of axillary management offered in clinical practice for BC patients undergoing conserving surgery upfront in Italy. Analysis of these attitudes may trigger the modification of some clinical approaches through multidisciplinary collaboration and create the background for future clinical investigations.

Introduction: [ 18 F]Fluoroestradiol ([ 18 F]FES) PET/CT has been proposed as a tool for detecting the oestrogen receptor density in patients with metastatic breast cancer (BC) non-invasively across all disease localizations. However, its diagnostic potential in terms of the detection rate (DR) of metastases is unclear. In this study, we pitted this method against [ 18 F]FDG PET/CT and tried to identify predictors of the diagnostic superiority of the [ 18 F] FES-based method., Materials and Methods: From a multicentre database, we enrolled all patients with metastatic BC who had undergone both [ 18 F]FES PET/CT and [ 18 F]FDG PET/CT. Two readers assessed both images independently and used a patient-based (PBA) and lesion-based analysis (LBA) to calculate the DR. Pathology-related and clinical factors were tested as predictors of [ 18 F]FES PET/CT superiority using a multivariate model., Results: 92 patients, bearing a total of 2678 metastases, were enrolled. On PBA, the DR of [ 18 F]FDG and [ 18 F]FES PET/CT was 97% and 86%, respectively (p = 0.018). On LBA, the [ 18 F]FES method proved more sensitive than [ 18 F]FDG PET/CT in lymph nodes, bone, lung and soft tissue (p < 0.01). This greater sensitivity was associated with lobular histology, both on PBA (Odds Ratio (OR) 3.4, 95%CI 1.0-12.3) and on LBA (OR 4.4, 95%CI 1.2-16.1 for lymph node metastases and OR 3.29, 95%CI 1.1-10.2 for bone localizations)., Conclusions: The overall DR of [ 18 F]FES PET/CT appears to be lower than that of [ 18 F]FDG PET/CT on PBA. However, the [ 18 F]FES method, if positive, can identify more lesions than [ 18 F]FDG at most sites. The higher sensitivity of [ 18 F]FES PET/CT was associated with lobular histology., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The present white paper, referring to the 4th Assisi Think Tank Meeting on breast cancer, reviews state-of-the-art data, on-going studies and research proposals. <70% agreement in an online questionnaire identified the following clinical challenges: 1: Nodal RT in patients who have a) 1-2 positive sentinel nodes without ALND (axillary lymph node dissection); b) cN1 disease transformed into ypN0 by primary systemic therapy and c) 1-3 positive nodes after mastectomy and ALND. 2. The optimal combination of RT and immunotherapy (IT), patient selection, IT-RT timing, and RT optimal dose, fractionation and target volume. Most experts agreed that RT- IT combination does not enhance toxicity. 3: Re-irradiation for local relapse converged on the use of partial breast irradiation after second breast conserving surgery. Hyperthermia aroused support but is not widely available. Further studies are required to finetune best practice, especially given the increasing use of re-irradiation., Competing Interests: Declaration of Competing Interest On behalf of my co-authors (O. Kaidar-Person, L. Boersma, M. C. Leonardi, B. Offersen, P. Franco, M. Arenas, C. Bourgier, R. Pfeffer, V Kouloulias, Y. Bölükbaşı, I. Meattini, C. Coles, A. Montero Luis, V. Masiello, I. Palumbo, A. Morganti, E. Perrucci, V. Tombolini, M. Krengli, F. Marazzi, L. Trigo, S. Borghesi, A. Ciabattoni, I. Ratoša, V. Valentini, P. Poortmans) I declare there is no conflict of interest in this study and that no funding was received from any source., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: One of the most common disabling complications in breast cancer (BC) patients is breast cancer-related lymphedema (BCRL), a pathological condition affecting both physical and psychological function, with detrimental consequences on health-related quality of life (HR-QoL). Rehabilitation has a key role in the comprehensive management of this condition with several studies reporting positive results after performing complex decongestive therapies (CDT) in these women. Kinesio taping (KT) is a rather recent therapeutic approach to treat BCRL, however, evidence in literature regarding its effectiveness is far from being fully characterized. Therefore, this systematic review aimed at assessing the role of KT among the CDT to treat BCRL., Evidence Acquisition: PubMed, Scopus, and Web of Science were systematically searched from inception until May 5 th , 2022 to determine randomized control trials (RCTs) reporting patients with BCRL; KT as intervention; limb volume as outcome (PROSPERO number: CRD42022349720)., Evidence Synthesis: Out of the documents identified, 123 were eligible for data screening, and only 7 RCTs satisfied the eligibility criteria and were included. We found that KT might have a positive effect on limb volume reduction in patients with BCRL, albeit there is little evidence for low quality of the included studies., Conclusions: Taken together, this systematic review showed that KT did not significantly reduce the upper limb volume in BCRL women, albeit it seemed to increase the flow rate during the passive exercise. Further high-quality-studies are mandatory to improve the knowledge in order to include the KT might into a multidisciplinary rehabilitative approach for the management of BC survivors affected by lymphedema.

Rehabilitation might improve bone health in breast cancer (BC) patients, but the effects on bone biomarkers are still debated. Thus, this meta-analysis of randomized controlled trials (RCTs) aims at characterizing the impact of rehabilitation on bone health biomarkers in BC survivors. On 2 May 2022, PubMed, Scopus, Web of Science, Cochrane, and PEDro were systematically searched for RCTs assessing bone biomarker modifications induced by physical exercise in BC survivors. The quality assessment was performed with the Jadad scale and the Cochrane risk-of-bias tool for randomized trials (RoBv.2). Trial registration number: CRD42022329766. Ten studies were included for a total of 873 patients. The meta-analysis showed overall significant mean difference percentage decrease in collagen type 1 cross-linked N-telopeptide (NTX) serum level [ES: -11.65 (-21.13, -2.17), p = 0.02)] and an increase in bone-specific alkaline phosphatase (BSAP) levels [ES: +6.09 (1.56, 10.62). According to the Jadad scale, eight RCTs were considered high-quality studies. Four studies showed a low overall risk of bias, according to RoBv.2. The significant effects of rehabilitation on bone biomarkers suggested a possible implication for a precision medicine approach targeting bone remodeling. Future research might clarify the role of bone biomarkers monitoring in rehabilitation management of cancer treatment induced bone-loss.

Background: Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials., Methods: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC., Results: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration., Conclusions: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology., Competing Interests: Declaration of competing interest FM personal fee from Roche, Novartis and Gilead outside the submitted work. MVD: personal fees from Eli Lilly, MSD, Exact Sciences, Novartis, Pfizer, Seagen, outside the submitted work; CC: consultan-cy/advisory role/speaker bureau: Pfizer, Novartis, Lilly, Roche, Gilead, MSD, Seagen, outside the submitted work; FM: Fees for advisory board participation; Novartis, Astra Zeneca, Daiichi Sankyo, SeaGen, MSD, Pfizer, Roche, PUMA, outside the submitted work; LDM: grants from Eli Lilly, personal fees from Eli Lilly, personal fees from Novartis, personal fees and non-financial support from Roche, personal fees from MSD, personal fees and non-financial support from Pfiz-er, personal fees from Genomic health, personal fees from Pierre Fabre, personal fees from Daiichi Sankyo, personal fees from Astrazeneca, personal fees from Seagen, personal fees and non-financial support from Eisai, personal fees from Ipsen, personal fees from Gilead, outside the submitted work; AZ: fees for advisory board; Lilly, Novartis, Astra Zeneca, Daiichi Sankyo, SeaGen, MSD, Pfizer, Roche, ExactSciences; LB: honoraria, consulting or advisory role Astra-Zeneca, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Seattle Genetics; research Funding Celgene, Genomic Health, Novartis, all outside the submitted work; CM: personal consultancy fees from Bayer, Roche, Astrazeneca, Daiichi Sankyo, outside the submitted work., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report on the third Assisi Think Tank Meeting (ATTM) on breast cancer, a brainstorming project which involved European radiation and clinical oncologists who were dedicated to breast cancer research and treatment. Held on February 2020, the ATTM aimed at identifying key clinical questions in current clinical practice and "grey" areas requiring research to improve management and outcomes. Before the meeting, three key topics were selected: 1) managing patients with frailty due to either age and/or multi-morbidity; 2) stereotactic radiation therapy and systemic therapy in the management of oligometastatic disease; 3) contralateral breast tumour prevention in BCRA-mutated patients. Clinical practice in these areas was investigated by means of an online questionnaire. In the lapse period between the survey and the meeting, the working groups reviewed data, on-going studies and the clinical challenges which were then discussed in-depth and subjected to intense brainstorming during the meeting; research protocols were also proposed. Methodology, outcome of discussions, conclusions and study proposals are summarized in the present paper. In conclusion, this report presents an in-depth analysis of the state of the art, grey areas and controversies in breast cancer radiation therapy and discusses how to confront them in the absence of evidence-based data to guide clinical decision-making., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Breast cancer (BC) is the most frequent malignant tumor in women in Europe and North America, and the use of aromatase inhibitors (AIs) is recommended in women affected by estrogen receptor-positive BCs. AIs, by inhibiting the enzyme that converts androgens into estrogen, cause a decrement in bone mineral density (BMD), with a consequent increased risk of fragility fractures. This study aimed to evaluate the role of vitamin D3 deficiency in women with breast cancer and its correlation with osteoporosis and BMD modifications. This observational cross-sectional study collected the following data regarding bone health: osteoporosis and osteopenia diagnosis, lumbar spine (LS) and femoral neck bone mineral density (BMD), serum levels of 25-hydroxyvitamin D3 (25(OH)D3), calcium and parathyroid hormone. The study included 54 women with BC, mean age 67.3 ± 8.16 years. Given a significantly low correlation with the LS BMD value (r 2 = 0.30, p = 0.025), we assessed the role of vitamin D3 via multiple factor analysis and found that BMD and vitamin D3 contributed to the arrangement of clusters, reported as vectors, providing similar trajectories of influence to the construction of the machine learning model. Thus, in a cohort of women with BC undergoing Ais, we identified a very low prevalence (5.6%) of patients with adequate bone health and a normal vitamin D3 status. According to our cluster model, we may conclude that the assessment and management of bone health and vitamin D3 status are crucial in BC survivors.

Breast cancer (BC) represents the most common cancer in women, while overweight and obesity are the second preventable cause of cancer. Weight gain and fat accumulation are common after BC diagnosis; moreover, weight gain during the treatment decreases the survival rate and increases the risk of recurrence in breast cancer survivors (BCS). To reduce the risk of second primary cancer or BC recurrence, and all-cause mortality in BCS, multiple interventions have been investigated to obtain reduction in weight, BMI and/or waist circumference. The aim of this narrative review is to analyze evidence on BCS for their risk of recurrence or mortality related to increased weight or fat deposition, and the effects of interventions with healthy dietary patterns to achieve a proper weight and to reduce fat-related risk. The primary focus was on dietary patterns instead of single nutrients and supplements, as the purpose was to investigate on secondary prevention in women free from disease at the end of their cancer treatment. In addition, BC relation with insulin resistance, dietary carbohydrate, and glycemic index/glycemic load is discussed. In conclusion, obesity and overweight, low rates of physical activity, and hormone receptor-status are associated with poorer BC-treatment outcomes. To date, there is a lack of evidence to suggest which dietary pattern is the best approach for weight management in BCS. In the future, multimodal lifestyle interventions with dietary, physical activity and psychological support after BC diagnosis should be studied with the aim of reducing the risk of BC recurrence or mortality.

Immune Checkpoint Inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/ neoadjuvant setting); iii) most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). In this article, we review the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

High-quality randomised clinical trials testing moderately fractionated breast radiotherapy have clearly shown that local control and survival is at least as effective as with 2 Gy daily fractions with similar or reduced normal tissue toxicity. Fewer treatment visits are welcomed by patients and their families, and reduced fractions produce substantial savings for health-care systems. Implementation of hypofractionation, however, has moved at a slow pace. The oncology community have now reached an inflection point created by new evidence from the FAST-Forward five-fraction randomised trial and catalysed by the need for the global radiation oncology community to unite during the COVID-19 pandemic and rapidly rethink hypofractionation implementation. The aim of this paper is to support equity of access for all patients to receive evidence-based breast external beam radiotherapy and to facilitate the translation of new evidence into routine daily practice. The results from this European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus state that moderately hypofractionated radiotherapy can be offered to any patient for whole breast, chest wall (with or without reconstruction), and nodal volumes. Ultrafractionation (five fractions) can also be offered for non-nodal breast or chest wall (without reconstruction) radiotherapy either as standard of care or within a randomised trial or prospective cohort. The consensus is timely; not only is it a pragmatic framework for radiation oncologists, but it provides a measured proposal for the path forward to influence policy makers and empower patients to ensure equity of access to evidence-based radiotherapy., Competing Interests: Declaration of interests IM received a small fee for occasional attendance at the advisory board supported by Eli Lilly, Novartis, Istituto Gentili, Roche, Pfizer, Ipsen, and Pierre Fabre. MCA received a grant from the Cancer Research UK. ClB declares honoraria from C-RAD and Elekta. PP is a medical adviser of Sordina IORT Technologies. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Breast cancer is the most common malignant tumor and the most prevalent cause of mortality in women. Advances in early diagnosis and more effective adjuvant therapies have improved the long-term survival of these patients. Pharmacotherapies and intrinsic tumor-related factors may lead to a wide spectrum of treatment-related disabling complications, such as breast cancer-related lymphedema, axillary web syndrome, persistent pain, bone loss, arthralgia, and fatigue. These conditions have a detrimental impact on the health-related quality of life of survivors. Here, we sought to provide a portrait of the role that rehabilitation plays in breast cancer survivors. Particular emphasis has been put in terms of recovering function, improving independence in activities of daily living, and reducing disability. This complex scenario requires a precision medicine approach to provide more effective decision-making and adequate treatment compliance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Estrogen receptor (ER) status assessment by immunohistochemistry (IHC) is the gold standard test for the identification of patients with breast cancer who may benefit from endocrine therapy (ET). Whilst most ER+ breast cancers have a high IHC score, about 3% of cases display a low positivity, with 1% to 10% of cells being weakly stained. These tumors are generally classified within the luminal-like category; however, their risk profile seems to be more similar to that of ER-negative breast cancers. The decision on ET for patients with a diagnosis of ER-low breast cancer should be carefully considered in light of the risks and possible benefits of the treatment. Potential pitfalls hinder pathologists and oncologists from establishing an appropriate threshold for "low positivity". Furthermore, several pre-analytical and analytical variables might trouble the pathological identification of these clinically challenging cases. In this review, we sought to discuss the adversities that can be accounted for the pathological identification of ER-low breast cancers in real-world clinical practice, and to provide practical suggestions for the perfect ER testing in light of the most updated recommendations and guidelines.

Bolus serves as a tissue equivalent material that shifts the 95-100% isodose line towards the skin and subcutaneous tissue. The need for bolus for all breast cancer patients planned for postmastectomy radiation therapy (PMRT) has been questioned. The work was initiated by the faculty of the European SocieTy for Radiotherapy & Oncology (ESTRO) breast cancer courses and represents a multidisciplinary international breast cancer expert collaboration to optimize PMRT. Due to the lack of randomised trials evaluating the benefits of bolus, we designed a stepwise project to evaluate the existing evidence about the use of bolus in the setting of PMRT to achieve an international consensus for the indications of bolus in PMRT, based on the Delphi method., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Breast conserving surgery (BCS) plus radiation therapy (RT) or mastectomy have shown comparable oncological outcomes in early-stage breast cancer and are considered standard of care treatments. Postmastectomy radiation therapy (PMRT) targeted to both the chest wall and regional lymph nodes is recommended in high-risk patients. Oncoplastic breast conserving surgery (OBCS) represents a significant recent improvement in breast surgery. Nevertheless, it represents a challenge for radiation oncologists as it triggers different decision-making strategies related to treatment volume definition and target delineation. Hence, the choice of the best combination and timing when offering RT to breast cancer patients who underwent or are planned to undergo reconstruction procedures should be carefully evaluated and based on individual considerations. We present an Italian expert Delphi Consensus statements and critical review, led by a core group of all the professional profiles involved in the management of breast cancer patients undergoing reconstructive procedures and RT. The report was structured as to consider the main recommendations on breast reconstruction and RT and analyse the current open issues deserving investigation and consensus. We used a three key-phases and a Delphi process. The final expert panel of 40 colleagues selected key topics as identified by the core group of the project. A final consensus on 26 key statements on RT and breast reconstruction after three rounds of the Delphi voting process and harmonisation was reached. An accompanying critical review of available literature was summarized. A clear communication and cooperation between surgeon and radiation oncologist is of paramount relevance both in the setting of breast reconstruction following mastectomy when PMRT is planned and when extensive glandular rearrangements as OBCS is performed. A shared-decision making, relying on outcome-based and patient-centred considerations, is essential, while waiting for higher level-of-evidence data., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To assess the prognostic role of different inter and intralesional expression (heterogeneity) of oestrogen receptor (ER) in bone metastases, as identified by the combined use of [18F]FES PET/CT and [18F]FDG PET/CT in patients with oestrogen receptor-positive (ER+) metastatic breast cancer (BC)., Methods: We analysed patients with a new diagnosis of bone metastases who were candidates for first-line systemic endocrine therapy. Before starting therapy, patients underwent baseline [18F]FES PET/CT and [18]FDG PET/CT. Semi-quantitative evaluation of whole-body bone metabolic burden (WB-B-MB) was performed on [18F]FES and [18F]FDG PET/CT in order to evaluate disease extent, tumour metabolism and ER heterogeneity. We used time-to-event analyses (Kaplan-Meier and Cox proportional-hazards methods) to estimate progression-free (PFS) and overall survival (OS), in order to assess the independent prognostic value of [18F]FES PET/CT and [18F]FDG PET/CT, alone and in combination., Results: According to our criteria, we enrolled 49 patients. Over a median follow-up of 44.7 months, 35 patients suffered disease progression (71.4 %) and 15 died of disease (30.6 %). When the risk of disease progression was calculated by means of the Cox model, only [18F]FDG WB-B-MB was independently and directly associated to PFS (p = 0.02). On analysing the association between all prognostic parameters and survival, the Cox model showed that the only parameter associated with OS was the WB-B-MB FES/FDG ratio (p = 0.01)., Conclusion: The combined use of [18F]FES-PET/CT and [18F]FDG-PET/CT can identify ER heterogeneity in BC bone metastases. This heterogeneity is significantly associated with survival. Moreover, the extension of the FDG-avid component correlates with the risk of disease progression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Post mastectomy radiation therapy (PMRT) reduces locoregional recurrence (LRR) and breast cancer mortality for selected patients. Bolus overcomes the skin-sparing effect of external-beam radiotherapy, ensuring adequate dose to superficial regions at risk of local recurrence (LR). This systematic review summarizes the current evidence regarding the impact of bolus on LR and acute toxicity in the setting of PMRT., Results: 27 studies were included. The use of bolus led to higher rates of acute grade 3 radiation dermatitis (pooled rates of 9.6% with bolus vs. 1.2% without). Pooled crude LR rates from thirteen studies (n = 3756) were similar with (3.5%) and without (3.6%) bolus., Conclusions: Bolus may be indicated in cases with a high risk of LR in the skin, but seems not to be necessary for all patients. Further work is needed to define the role of bolus in PMRT., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite the remarkable advances in the diagnosis and treatment of breast cancer patients, the presence or development of metastasis remains an incurable condition. Bone is one of the most frequent sites of distant dissemination and negatively impacts on patient's survival and overall frailty. The interplay between tumor cells and the bone microenvironment induces bone destruction and tumor progression. To date, the clinical management of bone metastatic breast cancer encompasses anti-tumor systemic therapies along with bone-targeting agents, aimed at slowing bone resorption to reduce the risk of skeletal-related events. However, their effect on patients' survival remains controversial. Unraveling the biology that governs the interplay between breast neoplastic cells and bone tissue would provide means for the development of new therapeutic agents. This article outlines the state-of-the art in the characterization and targeting the bone metastasis in breast cancer, focusing on the major clinical and translational studies on this clinically relevant topic.

Muscle maintenance relies on a multidimensional biologic balance that is extremely delicate in breast cancer patients, particularly those with advanced-stage disease. The biology that underpins breast cancer tumorigenesis, tumor progression and response to pharmacotherapies can modify muscle homeostasis, resulting in volumetric muscle loss. This condition dramatically increases the overall patients' frailty, leading to reduced survival and impaired quality of life. Physical activity may potentially improve muscle health in these patients, providing that an optimal patients selection is performed. The understanding of volumetric muscle loss biology in breast cancer survivors, coupled with focused clinical studies, would allow for the implementation of individualized rehabilitation protocols., Competing Interests: Conflict of interest statement M.I. received consultation honoraria from Errekappa Euroterapici S. p.a. N.F. has received honoraria for consulting, advisory role, and/or speaker bureau from Merck Sharp & Dohme (MSD), Boehringer Ingelheim, and Novartis. These companies had no role in the design of the study, in the collection, analyses, or interpretation of data, and in the writing of the manuscript. All other authors declare no potential conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Breast cancer is the most common malignancy in women worldwide, with a relatively high proportion of patients experiencing resistance to standard treatments. Cellular immunotherapy (CI), which is based on the extraction, modification, and re-infusion of the patient's immune cells, is showing promising results in these patients. Among CI possible approaches, adoptive cell therapy (ACT) and dendritic cell (DC) vaccination are the most comprehensively explored in both primary/translational research studies and clinical trials. ACT may include the use of tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR)-, or chimeric antigen receptor (CAR)-engineered T-cells. There are indications suggesting that a biomarker-based approach might be beneficial in effectively selecting breast cancer patients for CI. Here, we sought to provide the current knowledge of CI in breast cancer, focusing on candidate biomarkers, ongoing clinical trials, limitations, and immediate future perspectives., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Axillary web syndrome (AWS) is a complication of surgical procedures in breast cancer (BC) patients. This condition with poorly understood incidence and etiology is characterized by the locoregional development of scar tissue, leading to subcutaneous cording, motion impairment and pain. The early identification of patients at risk for AWS would improve their clinical management. Here, we sought to characterize the prevalence of and the risk factors associated with AWS in BC women after surgery., Patients and Methods: All patients with BC that underwent axillary surgery referred to an Outpatient Service for Oncological Rehabilitation were retrospectively collected. These women were assessed two weeks after the surgical procedure for their clinicopathologic features, type of therapeutic interventions, and AWS presence, laterality, pain, localization, cords type, and number of cords., Results: Altogether, 177 patients (mean aged 60.65 ± 12.26 years) were included and divided into two groups: AWSPOS (n=52; 29.4%) and AWSNEG (n=125; 70.6%). Patients with tumor N ≥1 (OR=3.7; p<0.001), subjected to mastectomy, axillary lymph node dissection (ALND) and chemotherapy showed significant correlations with AWS onset (p<0.05). The range of shoulder motion limitation (OR=11.2; p<0.001) and the presence of breast cancer related lymphedema (OR=3.5; p=0.020) were associated with AWS., Conclusions: Mastectomy, ALND, chemotherapy, low staging tumors, shoulder range of motion limitations, and BCRL represent risk factors for AWS onset. Realizing new strategies for assessing the individual risk of AWS is a crucial clinical need to improve the health-related quality of life of BC survivors.

Purpose: To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients., Methods: CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses., Results: Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found., Conclusion: Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies., Clinical Trial Registration: Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26).

Accurate prediction of long-term outcomes remains a challenge in the care of cancer patients. Due to the difficulty of serial tumor sampling, previous prediction tools have focused on pretreatment factors. However, emerging non-invasive diagnostics have increased opportunities for serial tumor assessments. We describe the Continuous Individualized Risk Index (CIRI), a method to dynamically determine outcome probabilities for individual patients utilizing risk predictors acquired over time. Similar to "win probability" models in other fields, CIRI provides a real-time probability by integrating risk assessments throughout a patient's course. Applying CIRI to patients with diffuse large B cell lymphoma, we demonstrate improved outcome prediction compared to conventional risk models. We demonstrate CIRI's broader utility in analogous models of chronic lymphocytic leukemia and breast adenocarcinoma and perform a proof-of-concept analysis demonstrating how CIRI could be used to develop predictive biomarkers for therapy selection. We envision that dynamic risk assessment will facilitate personalized medicine and enable innovative therapeutic paradigms., (Copyright © 2019. Published by Elsevier Inc.)

Lessons Learned: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity., Background: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC)., Methods: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early., Results: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites., Conclusion: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Purpose: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC)., Methods: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m 2  + cyclophosphamide (C) 600 mg/m 2  × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS)., Results: One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6-50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8-10.4) in arm A and 9.9 (95% CI 7.4-11.5) in arm B (P = 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6-11.7) versus 8.5 (95% CI 5.8-9.7) in those with HOMA index ≥ 2.5 (P = 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (P = 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS., Conclusions: The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.

Background: The role of forkhead-box A1 (FOXA1) and Androgen receptor (AR) in breast cancer (BC) has been extensively studied. However, the prognostic role of their co-expression in Estrogen receptor positive (ER+) BC has not been investigated so far. The aim of the present study was thus to assess the co-expression (protein and mRNA) of FOXA1 and AR in BC patients, in order to evaluate their prognostic impact according to ER status., Methods: Immunohistochemical expression of AR and FOXA1 was evaluated on 479 consecutive BC, with complete clinical-pathological and follow up data. Fresh-frozen tissues from 65 cases were available. The expression of AR and FOXA1 with ER was validated using mRNA analyses. Survival and Cox proportional hazard analyses were used to evaluate the relationship between FOXA1, AR and prognosis., Results: Expression of ER, AR and FOXA1 was observed in 78, 60 and 85% of cases respectively. Most AR+ cases (97%) were also FOXA1+. The level of FOXA1 mRNA positively correlated with level of both AR mRNA (r = 0.8975; P < 0.001) and ER mRNA (r = 0.7326; P < 0.001). In ER+ BC, FOXA1 was associated with a good prognosis independently of AR expression in the three subgroups analyzed (FOXA1+/AR+; FOXA1+/AR-; FOXA1-/AR-). Multivariate analyses confirmed that FOXA1 may provide more information than AR in Disease-Free Interval (DFI) of ER+ BC patients., Conclusion: Our results suggest that in BC the expression of FOXA1 is directly related to the expression of AR. Despite that, FOXA1 is found as superior predicting marker of recurrences compared to AR in ER+ BC patients.

Researchers often attempt to categorize tumors into more homogeneous subtypes to better predict prognosis or understand pathogenic mechanisms. In clinical research, typically the focus is on prognosis: the tumor subtypes are intended to be associated with specific responses to treatment and/or different clinical outcomes. In aetiological research, the focus is on identifying distinct pathogenic mechanisms, which may involve different risk factors. We used directed acyclic graphs to present a framework for considering potential biases arising in aetiological research of tumor subtypes, when there is incomplete correspondence between the identified subtypes and the underlying pathogenic mechanisms. We identified two main scenarios: (1) weak effect, when the tumor subtypes are identified through combinations of characteristics and some of these characteristics are affected by factors that are unrelated with the underlying pathogenic mechanisms; and (2) lack of causality, when the set of characteristics corresponds with a mechanism that is actually not a cause of the tumor of interest. Examples of the magnitude of bias that can be introduced in these situations are provided. Although categorization of tumors into homogenous subtypes may have important implications for aetiological research and identification of risk factors, the characteristics used to classify tumors into subtypes should be as close as possible to the actual pathogenic mechanisms to avoid interpretative biases. Whenever our knowledge of these mechanisms is limited, research into risk factors for tumor subtypes should first aim to causally link the characteristics to the pathogenic mechanisms.

The idea of conducting a geographical analysis of cancer incidence in Vercelli, a city with about 46,000 population in the Province of Vercelli (Piedmont, northern Italy), originated from the need to respond to concerns of the population and local administrators regarding the presence of a solid waste incinerator just a few kilometers from the city, and the ongoing intense agricultural activity in the area. The study also aimed to verify the excess risk identified in a similar study on mortality. We obtained census data and mortality data for the years 2002 to 2009, from the Italian Institute of Statistics (ISTAT) and analysed these from both an epidemiological point of view, through standardised mortality rates, and spatial analysis through the use of Bayesian models. Both approaches highlighted an overall increased risk for cancers and increased risks for colorectal and lung cancer, in persons residing south of the capital. They also identified an increased cancer risk in the young adult population of both sexes, which deserves further investigation.

Aims: Cytokeratin 19 (CK19) mRNA copy number predicts the probability of tumour load in axillary lymph nodes (ALN) and can help in decision-making regarding the axillary dissection. The purpose of this study was to define a new cut-off of CK19 mRNA copy number using the one-step nucleic acid amplification (OSNA) assay on metastatic sentinel lymph nodes (SLN) in order to identify cases at risk of having one or more positive ALN., Methods: 1296 SLN from 1080 patients were analysed with the OSNA assay. 194 patients with positive SLN underwent ALN dissection and the mean value of CK19 copy number (320 000) of their SLN was set as initial cut-off. Receiver operative characteristics curve identify a best cut-off of 7700 (sensitivity 78%, specificity 57%). A comparison between our and the traditional cut-off (5000) was performed., Results: The cut-off of 7700 successfully identifies patients with positive ALN (p=0.001, false- negative cases: 17%). In the range between 5000 and 7700, one patient with positive ALN would not undergo axillary dissection, whereas eight patients with negative ALN would be correctly identified., Conclusions: We suggest that the level of CK19 mRNA copy number could be the only parameter to consider in the intraoperative management of the axilla., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia and has activity in vitro against several solid tumour cell lines, where induction of differentiation and apoptosis are the prime effects. To investigate the potential therapeutic application of As2O3 to breast cancer, we analysed the effects of As2O3 on the growth of four human breast cancer cell lines: MCF7, MDA-MB-231, T-47D and BT-20. Cells were cultured in 0.5, 2 and 5 microM AS2O3, a range of pharmacologically achievable concentrations of AS2O3. At > or = 2 microM, AS2O3 rapidly induced cell death by apoptosis in MCF7 and MDA-MB-231 while T-47D and BT-20 were partially resistant. At 0.5 microM, As2O3 was subapoptotic but induced features of differentiation consisting in upregulation of ICAM-1 (CD54), a marker of mammary epithelial differentiation, and cell cultures appeared morphologically more organized. Furthermore, we demonstrate by standard cytotoxicity assays that As2O3 treatment can augment breast cancer cell lysis by lymphokine-activated killer cells and demonstrate an important role of the ICAM-1/LFA-1 interaction in this process. This additional activity of As2O3 could translate into improved antitumour immunosurveillance in vivo. In conclusion, As2O3 induced varying degrees of differentiation, apoptosis and lysis in these model cell lines, and may be a promising adjuvant to current treatments of breast cancer by virtue of its triple apoptotic, differentiative and immunomodulatory effects.

During the last three decades, research focused on cancer treatment has led to the development of many cytotoxic agents. Despite the fact that these efforts have significantly improved the prognosis of certain malignancies such as some lymphomas, leukemias and testicular carcinomas, other tumors such as ovarian, lung and metastatic breast cancer are still associated with a poor prognosis. An innovative approach has recently emerged, thanks to a better understanding of tumor cell biology and many efforts are aimed at finding compounds capable of restoring a more differentiated phenotype to tumor cells, thereby reducing the tumor's aggressiveness and ultimately reverting it to its normal counterpart [1, 2]. Retinoids are the prototype of this new therapeutical approach called "differentiation therapy".

All-trans retinoic acid (ATRA) is currently used in clinical trials for breast cancer, in virtue of its ability to inhibit cell growth and to promote cell differentiation. Elucidation of the molecular mechanism(s) underlying the pleiotropic pharmacological activity of ATRA is of fundamental relevance for an effective use of the compound in clinics. This paper reports on the effects of ATRA treatment on the cell surface expression of a panel of adhesion molecules known to regulate the interactions between the effectors of the immune system and tumor targets. Results indicate that breast cancer (BC) cell lines exposed to ATRA selectively up-modulate the surface expression of ICAM-1/CD54, a molecule regulating cell/cell contacts. Such effect could be reproduced in all the BC cell lines analyzed, independently of their hormone receptor status, indicating that estrogens and progesterone are irrelevant in this process. The regulatory effects on ICAM-1 expression are time- and dose-dependent and reversible. Moreover, other differentiating and proliferating agents comparatively tested, e.g. dimethyl sulfoxide, estradiol or dexamethas one, are ineffective, indicating that ICAM-1 up-modulation is uniquely featured by ATRA. A second observation is that ATRA treated cells are, only apparently, less sensitive to lysis by lymphocytes activated by IL-2, as determined by means of a standard 51Cr release assay. In fact, notwithstanding this effect, a marked reduction in the ability to form colonies was highlighted in ATRA treated versus control lines after incubation with LAK. Finally, the clonogenic killing effect could be reversed using anti-CD54 mAbs as blocking tools, indicating that ICAM-1 plays a key role in the phenomena.