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Background: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM., Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint., Results: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine., Conclusions: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine., Methods: This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110., Findings: Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group., Interpretation: Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration., Funding: Daiichi Sankyo and AstraZeneca., Competing Interests: Declaration of interests SAH has received support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received grants or contracts from Ambrx, Amgen, Arvinas, Bayer, Cytomx, Dantar, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI, Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, and Zymeworks; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Daiichi Sankyo and continuing medical education (CME) companies (PER, Clinical Care Options, Research to Practice, etc); has received support for attending meetings or travel from San Antonio Breast Cancer Symposium, American Society of Clinical Oncology, National Comprehensive Cancer Network, and CME companies (PER, Clinical Care Options, and Research to Practice); has participated as a data safety monitoring board member for the I-SPY trial (unpaid); and has served a leadership or fiduciary role in another board for TRIO-US (unpaid chief medical officer of site management organisation). W-PC has received payment or honoraria for lectures and presentations from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Everest Medicine, Foundation Medicine, Kyowa Kirin, MSD, Novartis, Pfizer, Roche, and Sanofi; has received support for attending meetings from Amgen, AstraZeneca, Pfizer, and Roche; has participated in advisory boards for Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Everest Medicine, MSD, Novartis, and Roche; and has participated in a data safety monitoring board for AstraZeneca. S-AI has received grants or contracts from AstraZeneca, Eisai, Daewoong Pharm, Daiichi Sankyo, Pfizer, Roche, and Boryung Pharm; and has received consulting fees from AstraZeneca, Hanmi, Eisai, Lilly, MSD, Idience, Novartis, Pfizer, Roche, GSK, Daiichi Sankyo, and Bertis. WJ has received grants or contracts from AstraZeneca and Daiichi Sankyo; has received support for attending meetings or travel from AstraZeneca, Eisai, Lilly France, Pfizer, Roche, Chugai Pharma, GlaxoSmithKline, Novartis, Pierre Fabre, and Sanofi Aventis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Eisai, Lilly France, Pfizer, Roche, BMS, Daiichi Sankyo, Novartis, MSD, and Seagen. JWYC has received honoraria for manuscript writing from Daiichi Sankyo. BX has received payment or honoraria for lectures and presentations from AstraZeneca, Pfizer Inc, Roche, and Eisai. EH has received institutional support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received institutional grants or contracts from AbbVie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, Arvinas, AtlasMedx, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Cascadian Therapeutics, Clovis, Compugen, Cullen-Florentine, Curis, CytomX, Dana Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millenium, Molecular Templates, Myriad Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Roche/Genentech, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, and Zymeworks; and has received consulting fees paid to the institution from Arcus, Eisai, Greenwich Lifesciences, H3 Biomedicine, iTeos, Janssen, Loxo, Orum Therapeutics, Propella Therapeutics, Puma Biotechnology, Arvinas, Black Diamond, Boehringer Ingelheim, CytomX, Dantari, Deciphera, Lilly, Merck, Mersana, Novartis, Pfizer, Relay Therapeutics, Roche/Genentech, Seagen, and Silverback. SM received consulting fees, support for attending meetings or travel, and participated in an advisory board for Daiichi Sankyo. HI has received consulting fees from Daicihi Sankyo, Chugai, AstraZeneca, Sanofi, Lilly, MSD, Pfizer, and Novartis; and payment or honoraria from Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, and Pfizer. SAl has received institutional payment for advisory boards from Eli Lilly, Pfizer, MSD, AstraZeneca, Novartis, and Bayer; institutional grants from Roche and Sanofi; and received travel and accommodations from Pfizer, Roche, PharmaMar, Novartis, AstraZeneca, Bayer, and Gilead. J-WH has received support for the present manuscript from AstraZeneca and Daiichi Sankyo; has received consulting fees from Novartis, Pfizer, Eli Lilly, Roche, AstraZeneca, Gilead Science, Knight Therapeutic; and has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis and AstraZeneca. GC has received support for the present manuscript from AstraZeneca and Daiichi Sankyo; has received grants or contracts from Merck and AstraZeneca; has received consulting fees from Roche, BMS, Novartis, Lilly, Pfizer, Seagen, AstraZeneca, Ellipsis, Gilead, Merck, Celcuity, Sanofi, Exact Sciences, and Daiichi Sankyo; has received payment or honoraria for presentations, lectures, speaker bureaus, manuscript writing, or educational events from Novartis, Lilly, Pfizer, Seagen, and Daiichi Sankyo; has received support for attending meetings or travel from AstraZeneca and Daiichi Sankyo; and has participated on a data safety monitoring board or advisory board for Roche, BMS, Novartis, Lilly, Pfizer, Seagen, Ellipsis, Gilead, Merck, Celcuity, AstraZeneca, and Daiichi Sankyo. JMP-G has received consulting fees from Roche/AstraZeneca, Daiichi Sankyo, Lilly/Eisai, and Seattle Genetics and has received support for attending meetings or travel from Roche. S-BK has received institutional grants or contracts from Novartis, Sanofi Aventis, and DongKook Pharmaceutical; has received consulting fees from Novartis, AstraZeneca, Lilly, DaeHwa Pharmaceutical, ISU Abxis, Beigene, OBI Pharma, and Daiichi Sankyo; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Pfizer, OBI Pharma, and Legochem Bioscience; has participated on a data safety monitoring board or advisory board for Novartis, AstraZeneca, MSD, Lilly, and Daiichi Sankyo; and has purchased stock or stock options from Genopeaks and NeoGene TC. VP has received consulting fees for advisory boards from Daiichi Sankyo; has received fees for non-CME services received directly from commercial interests or their agents for speakers' bureaus from AstraZeneca, Novartis, Daiichi Sankyo, and Pfizer; and has received travel support for congresses from Roche and Daiichi Sankyo. C-SH has received research grants to his institution for the present manuscript from Daiichi Sankyo; has received institutional grants or contracts from Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, Novartis; has received payment or honoraria for speakers bureaus from Daiichi Sankyo, AstraZeneca, Pfizer, Novartis, Roche; has received support for travel from AstraZeneca, Pfizer, Roche, and Novartis; and has participated on advisory boards for Daiichi Sankyo, AstraZeneca, Eli Lilly, Pfizer, Novartis, and Roche. J-SF has received consulting fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Lilly, Novartis, AstraZeneca, Gilead, Daiichi Sankyo, and Seagen; and has received support for attending meetings or travel from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen. SAn has received consulting fees for advisory boards from Roche, Daiichi Sankyo, Pierre Fabre, and Lilly; and has received fees for non-CME services received directly from commercial interest or their agents (eg, speakers' bureaus) from Roche, Pierre Fabre, and Pfizer. WY has received payment or honoraria for lectures, presentations, advisory boards or educational events from Roche, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Mundipharma, Eisai, and Novartis. GB has received consulting fees from Roche, AstraZeneca, MSD, Daiichi Sankyo, Gilead, Sanofi, and Seagen; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Chugai, Eisai, Gilead, and Seagen; has received support for attending meetings or travel from Roche, Pfizer, MSD, Chugai, Novartis, and AstraZeneca; and has participated on a data safety monitoring board or advisory board for Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, MSD, Chugai, Daiichi Sankyo, Eisai, Gilead, Seagen, Exact Science, and Agendia. SL has received institutional grants or contracts from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech, and Seattle Genetics; has received consulting fees paid to her institution from Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb; and serves as a consultant (not paid) for Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. JT has received support for the present manuscript in the form of grants, contracts, or consulting fees from Daiichi Sankyo and AstraZeneca; has received payment or honoraria for lectures from Daiichi Sankyo and AstraZeneca; has received payment for expert testimony from Daiichi Sankyo and Taiho; has received support for attending meetings or travel from Daiichi Sankyo and Chugai; and has served as an advisor for West Japan Oncology Group. AE, YL, JCa, and SAs are employees of Daiichi Sankyo and AE and YL have stock in Daiichi Sankyo. JCo has received support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received institutional grants or contracts from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; has received consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, and Reveal Genomics; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; has received support for attending meetings or travel from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, and Gilead; has patents planned, issued, or pending (WO 2014/199294 A; US 2019/ 0338368 A1); and has stock or stock options with MedSIR, Nektar Pharmaceuticals, and Leuko. All other authors declare no completing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies., Methods: ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine., Results: Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS., Conclusion: First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adjuvant radiotherapy is one of the major anticancer treatments in early breast cancer patients. Acute and late radio-induced effects may occur during or after breast cancer radiotherapy, and their medical management is a major issue for radiation oncologists. Here, the present review of literature embraces complementary non-pharmacological interventions, which could be combined to adjuvant radiotherapy in order to improve patients care., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Research Question: What are the real-life oncofertility practices in young women diagnosed with breast cancer?, Design: The FEERIC (FErtility, prEgnancy, contRaceptIon after breast Cancer in France) study is a web-based cohort study launched with the French collaborative research platform Seintinelles. The current work is based on the enrolment self-administered questionnaire of 517 patients with prior breast cancer diagnosis, free from relapse and aged 18 to 43 years at inclusion (from 12 March 2018 to 27 June 2019)., Results: Median age at breast cancer diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counselling, 181 patients underwent at least one fertility preservation procedure (FPP); 125 (24.2%) underwent one or more FPP with material preservation (oocytes n = 108, 20.9%; embryos n = 31, 6.0%; ovarian cryopreservation n = 6, 1.2%) and 78 patients received gonadotrophin-releasing hormone agonists (15.1%). With a median follow-up of 26.9 months after the end of treatments, 133 pregnancies had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were natural conceptions (n = 113, 87.6%), while 16 (12.4%) required medical interventions. For the planned pregnancies, median time to the occurrence of an ongoing pregnancy was 3 months. Patients who had an unplanned pregnancy reported lower rates of information on the consequences of the treatments on fertility (P = 0.036) at diagnosis., Conclusions: Most of the patients were not offered proper specialized oncofertility counselling at the time of breast cancer diagnosis. Naturally conceived pregnancies after breast cancer were much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counselling seems as important as information about fertility and might prevent unplanned pregnancies., (Copyright © 2022. Published by Elsevier Ltd.)

The relationship between cancer and primary Sjögren's syndrome (pSS) is uncertain. While the increased risk of hematological malignancies is well-known, data on the comparative incidence of solid neoplasms is conflicting. This study aimed to explore the associations between cancer and pSS. This nationwide population-based retrospective study from the French health insurance database (PMSI) evaluated patients hospitalized with new-onset pSS from 2011 to 2018 against age- and sex-matched hospitalized controls (1:10). The incidence of hematological malignancies and solid neoplasms was compared between the two groups. Mortality and multiple cancer incidence were also evaluated. Adjusted Hazard Ratios (aHR) calculations included confounding factors, such as low socioeconomic status. Among 25,661 hospitalized patients with pSS versus 252,543 matched patients (median follow-up of 3.96 years), we observed a higher incidence rate of lymphomas (aHR, 1.97 [95% CI, 1.59-2.43]), Waldenström macroglobulinemia (aHR, 10.8 [6.5-18.0]), and leukemia (aHR, 1.61 [1.1-2.4]). Thyroid cancer incidence was higher (aHR, 1.7 [1.1-2.8]), whereas bladder and breast cancer incidences were lower (aHR, 0.58 [0.37-0.89] and 0.60 [0.49-0.74], respectively). pSS patients with breast cancer exhibited a lower mortality rate. A limitation was that the database only encompasses hospitalized patients, and immunological and histological details are not listed. We confirmed the increased risk of hematological malignancies and thyroid cancers among patients with pSS. The lower risk of breast cancer suggests a role of hormonal factors and raises questions of the concept of immune surveillance within breast tissue. Epidemiological and translational studies are required to elucidate the relationships between pSS and cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Metastatic breast cancer is the second most common cause of brain metastasis (BM), and this problem is particularly marked for the amplified HER2 subtype (HER2+), with a cumulative incidence reaching up to 49 % in the ER-/HER2+ subgroup. Literature review shows that therapeutic progress has been major since the marketing of systemic anti-HER2+ treatments, with life expectancies now relatively unaffected by brain development. The recommended treatments are, on the one hand, specific treatment for brain development and, on the other hand, appropriate systemic treatment. Regarding local treatments, we will always favor surgery when possible, especially for large metastases, and stereotaxic radiotherapy, possibly iterative. One should be wary of whole brain irradiation which has never been shown to improve overall survival, but which is clearly associated with more cognitive toxicities. All the systemic anti-HER2 treatments currently on the market have shown efficacy on BM from HER2+ breast cancer and must therefore be chosen above all on the basis of their potential activity on the systemic disease at the time of cerebral evolution. If BM evolution happen without concomitant systemic progression, and local treatment can control it, it is not recommended to change the current medical treatment. Finally, randomized clinical studies opened to patients with active brain disease are starting to be published. The first of them showed the benefit of the triple combination tucatinib-trastuzumab-capecitabine in this context., (Copyright © 2021 Société FranÇaise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Purpose: Among metastatic breast cancer (MBC) patients, those with a triple-negative breast cancer phenotype (mTNBC) have the worst prognosis, but the benefit of chemotherapy beyond second line on outcome remains uncertain. The purpose of this study was to identify predictive factors of outcome after third- or fourth-line chemotherapy., Methods: The ESME-MBC database is a French prospective real-life cohort with homogeneous data collection, including patients who initiated first-line treatment for MBC (2008-2016) in 18 cancer centers. After selection of mTNBC cases, we searched for independent predictive factors (Cox proportional-hazards regression models) for overall survival (OS) on third- and fourth-line chemotherapy (OS3, OS4). We built prognostic nomograms based on the main prognostic factors identified., Results: Of the 22,266 MBC cases in the ESME cohort, 2903 were mTNBC, 1074 (37%) and 598 (20%) of which had received at least 3 or 4 lines of chemotherapy. PFS after first- and second-line chemotherapy (PFS1, PFS2) and number of metastatic sites ≥3 at baseline were identified by multivariate analysis as prognostic factors for both OS3 (HR = 0.76 95%CI[0.66-0.88], HR = 0.55 95%CI[0.46-0.65], HR = 1.36 95%CI[1.14-1.62], respectively), and OS4 (HR = 0.76 95%CI[0.63-0.91], HR = 0.56 95%CI[0.45-0.7], HR = 1.37 95%CI[1.07-1.74]), respectively. In addition, metastasis-free interval was identified as a prognostic factor for OS3 (p = 0.01), while PFS3 influenced OS4 (HR = 0.75 95%CI[0.57-0.98]). Nomograms predicting OS3 and OS4 achieved a C-index of 0.62 and 0.61, respectively., Conclusion: The duration of each previous PFS is a major prognostic factor for OS in mTNBC patients receiving third- or fourth-line chemotherapy. The clinical utility of nomograms including this information was not demonstrated., Competing Interests: Declaration of competing interest Dr. De La Motte Rouge reports personal fees and non-financial support from ASTRAZENECA, grants, personal fees and non-financial support from PFIZER, grants from NOVARTIS, personal fees and non-financial support from EISAI, personal fees and non-financial support from ROCHE, grants and non-financial support from MSD, outside the submitted work. Dr. Robain reports ESME Platform was supported by Roche, Astra Zeneca, BMS, Pfizer, Daiichi Sankyo, Eisai. Prof. Campone reports grants from Pfizer, grants from AstraZeneca, grants from Sanofi, grants from Pierre Fabre, grants from Takeda, personal fees from Novartis, personal fees from Lilly, outside the submitted work. Dr. MOURET-REYNIER reports grants from Novartis, Lilly, Pfizer, Roche, Pierre Fabre, MSD, outside the submitted work. All other authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: There has been increasing interest in the potential benefit of vitamin D in improving breast cancer outcome. Preclinical studies suggest that vitamin D enhances chemotherapy-induced cell death. We investigated the impact of serum vitamin D levels during neoadjuvant chemotherapy (NAC) on the rates of achieving pathologic complete response (pCR) after breast cancer NAC., Patients and Methods: Patients from 1 of 2 Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled onto a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. A Firth penalized logistic regression multivariable model was used., Results: The study included 144 women. There was no difference between the French and Iowan cohorts with regard to age at diagnosis (P = .20), clinical stage (P = .22), receptor status (P = .32), and pCR rate (P = .34). French women had lower body mass index (mean 24.8 vs. 28.8, P < .01) and lower vitamin D levels (mean 21.5 vs. 27.5, P < .01) compared to Iowan patients. In multivariable analysis, after adjusting for the effects of cohort, clinical stage, and receptor status, vitamin D deficiency increased the odds of not attaining pCR by 2.68 times (95% confidence interval, 1.12-6.41, P = .03)., Conclusion: Low serum vitamin D levels were associated with not attaining a pCR. Prospective trials could elucidate if maintaining vitamin D levels during NAC, a highly modifiable variable, may be utilized to improve cancer outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Several prognostic scores have been developed to estimate survival of breast cancer (BC) patients with brain metastases (BM). Modified Breast Graded Prognostic Assessment (GPA), based on a single-institution cohort of 1552 patients, has been proposed as refinement of Breast-GPA. In addition to age, tumour subtype and KPS, Modified Breast-GPA comprises number of BM. This study was designed to validate Modified Breast-GPA., Patients and Methods: Clinical data of 668 BC patients diagnosed with BM at four institutions between 1996 and 2016 were reviewed. Patients were classified by Breast-GPA and Modified Breast-GPA. Overall survival (OS) was calculated from time of BM diagnosis to death or last follow-up. Cox proportional models were used to calculate hazard-ratios and their 95% CI. The performances of Breast-GPA and Modified Breast-GPA were compared using Harrell's concordance index., Results: Median age at BM diagnosis was 56 years (range 24-85). At last follow-up, 632 patients (94.6%) had died. Median OS was 8.1 months (95% CI 6.9-9.4). The number of BM (1-3 vs. >3) was significantly associated with OS in univariate analysis (p < 0.001) and having >3 BM was identified as a negative prognostic factor in multivariate analysis. Both Breast-GPA and Modified Breast-GPA accurately predicted OS (p < 0.001 for both scores). Performance of Modified Breast-GPA was better: concordance indices were 0.6390 (95% CI, 0.6381 to 0.6399) and 0.6647 (95% CI, 0.6639 to 0.6655) for Breast-GPA and Modified Breast-GPA, respectively (p < 0.001)., Conclusions: This work provides the first external independent validation of Modified Breast-GPA and confirms its better performance as compared to Breast-GPA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Breast cancer remains a potentially lethal disease, which requires aggressive treatments and is associated with long-term consequences. Its prognosis is linked to both tumor biology and burden at diagnosis. Although treatments have allowed important improvements in prognosis over the past 20 years, breast cancer screening remains necessary. Mammographic screening allows earlier stage diagnoses and a decrease of breast cancer specific mortality. However, breast cancer screening modalities should be revised with the objective to address demonstrated limitations of mammographic screening (limited benefit, imperfect sensitivity and specificity, overdiagnoses, radiation-induced morbidity). Furthermore, both objective and perceived performances of screening procedures should be improved. Numerous large international efforts are ongoing, leading to scientific progresses that should have rapid clinical implications in this area. Among them is improvement of imaging techniques performance, development of real time diagnosis, and development of new non radiological screening techniques such as the search for circulating tumor DNA, development of biomarkers able to allow precise risk evaluation and stratified screening. As well, overtreatment is currently addressed by biomarker-based de-escalation clinical trials. These advances need to be associated with strong societal support, as well as major paradigm changes regarding the way health and cancer prevention is perceived by individuals., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To describe the French routine use of G-CSF in patients treated for breast cancer as per the EORTC recommendations., Patients and Methods: A prospective multicenter observational study conducted between February 2008 and September 2009 in 869 breast cancer patients treated by chemotherapy (CT) and for whom G-CSF treatment will be delivered in primary (PP) or secondary prophylaxis., Results: The mean age was 55 years. A total of 80.3% of CT was in neoadjuvant/adjuvant setting (NAS). PP was delivered in 78.9% of the NAS patients and 67.5% in metastatic situation. Of the 702 evaluable patients, incidences of severe (SN) and febrile neutropenias (FN) in patients who received PP were 9.3% and 4.2%, respectively. In patients who did not received G-CSF at first cycle, SN and FN were 12.4% and 7.3%, respectively. The use of PP was mainly driven by the type of CT for patients treated in the NAS and by patient or disease related risk factors in the locally advanced/metastatic setting., Conclusion: This study has shown that the use of G-CSF was in accordance with the 2010 updates of the EORTC recommendations. However, G-CSF appears more widely used in the routine practice., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Iron plays a fundamental role in cell life and its concentration in living organisms is precisely regulated. Different molecules for iron storage and transport are used to maintain its intracellular homeostasis which is often altered in cancer cells. Specifically, recent studies have demonstrated that in breast cancer cells, the expression/activity of several iron-related proteins, such as ferritin, hepcidin and ferroportin, is deregulated and that these alterations may have a prognostic impact in patients with breast cancer. Moreover, molecules that regulate iron metabolism could become therapeutic targets. This review focuses on recent findings on iron metabolism particularly in breast cancer and on the development of new biomarkers that may be used in the clinical routine for the diagnosis, prognosis and management of cancer-associated anemia as well as for monitoring personalized treatments., (Copyright © 2014 Elsevier B.V. All rights reserved.)

There is a recent increase in interest of vitamin D and breast cancer, facing the number of publications on the subject. This increase have several reasons, on the one hand, vitamin D deficiency is more and more prevalent and, on the other hand, there are new data that highlights the extra-bone effects of vitamin D, especially in breast cancer, the vitamin D is involved in the breast cancer risk factor, the prognosis, and the interaction with breast cancer treatments. This combination between vitamin D deficiency and breast cancer is extremely usual, and combined with all cancer clinical parameters: the incidence, the tumour biology, the clinical presentation, the prognosis, and the antineoplastic treatment tolerance. This vitamin D deficiency is increased after adjuvant cancer treatments. And yet, this problem increases bone metabolism disruptions in breast cancer patients, inducing osteoporotic risk at long time, even though this population is curable. This problem is therefore serious in the adjuvant breast cancer treatment. Unfortunately, in this population, the current recommendations are clearly insufficient, and the current randomized clinical trial results would contribute to define the best way to correct the vitamin D deficiency, quickly and secure.

Exercise practice and appropriate nutrition have been advanced as non pharmacological supportive care to reduce side effects related to cancer and its treatment, but large sample-sized randomized controlled trials are needed to confirm such results. The Adapted Physical Activity and Diet counseling (APAD) study is a prospective randomized controlled trial designed to evaluate the effectiveness of a 26-week hospital- and home-based lifestyle intervention on cancer-related fatigue in women receiving breast cancer adjuvant treatment (chemotherapy and radiotherapy). The aim of this paper is to describe the APAD study protocol. Study recruitment goal is 264 adult breast cancer women with newly, histologically proven, incident and non metastatic breast cancer scheduled for 6 cycles of adjuvant chemotherapy followed by radiotherapy. Patients are randomized either in the experimental arm with tailored exercise training and diet counseling program or in the control arm without any lifestyle intervention (usual care). Outcome measures are collected at baseline, and at 15 weeks (i.e., mid-intervention), 26 weeks (i.e., immediately post-intervention), and at 12-month and 18-month of follow-up. Intervention effect is assessed on fatigue (emotional, cognitive, physical), quality-of-life, anxiety, depression, body weight and composition. In addition, levels of physical activity, dietary intakes and adjuvant therapy observance are measured and a cost-utility analysis will be performed. If improvements in fatigue, quality-of-life and a better weight control are observed, the APAD study could demonstrate the feasibility and the effectiveness of such exercise and nutrition supportive care with limited additional cost in patients receiving adjuvant breast cancer therapy., (© 2013 Elsevier Inc. All rights reserved.)

Introduction: Brain metastases (BM) from breast cancer are associated with poor prognosis. This study was made to determine the prognostic influence of breast cancer biological subtypes, and to define the best therapeutic options in this setting, with a special focus on the HER2-positive population., Patients and Methods: Breast cancer patients with known hormone receptors (HR) and HER2 status presenting with BM treated between 1995 and 2010 in our two institutions were considered for this retrospective study., Results: 250 patients were included. The study population consisted of 25.6% patients categorized as triple-negative (HR-/HER2-), 30.8% as HR+/HER2- and 43.6% as HER2+ breast cancer. Median overall survival (OS) was 8.9 months (95% CI, 6.9-10.3 months). Cerebral progression remained the most frequent cause of death (57.1%). On multivariate analysis, HER2 positivity and the RPA score were the two most important prognostic factors. Local treatment (surgery or stereotactic radiotherapy) and chemotherapy were significantly associated with an increased survival. On multivariate analysis of the RPA1-2 population, local treatment and chemotherapy were independent prognostic factors in addition to biological subtypes, RPA class, liver metastases and clinical signs of intra-cranial hypertension. Anti-HER2 therapies administered after BM diagnosis significantly and independently increased OS. Median OS in patients receiving both trastuzumab and lapatinib after BM diagnosis was significantly better than that the one of patients receiving only one of the 2 targeted therapies (25.7 vs. 9.6 months, p < 0.001)., Conclusions: Biological subtypes are independent prognostic determinants. Chemotherapy and targeted therapies positively affect the prognosis after first BM., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The transmembrane protein HER2 is over-expressed in approximately 15% of invasive breast cancers as a result of HER2 gene amplification. HER2 proteolytic cleavage (HER2 shedding) generates soluble truncated HER2 molecules that include only the extracellular domain and the concentration of which can be measured in the serum fraction of blood. HER2 shedding also generates a constitutively active truncated intracellular receptor of 95kDa (p95(HER2)). Another soluble truncated HER2 protein (Herstatin), which can also be found in serum, is the product of an alternatively spliced HER2 transcript. Recent preclinical findings may provide crucial insights into the biological and clinical relevance of increased sHER2 concentrations for the outcome of HER2-positive breast cancer and sensitivity to trastuzumab and lapatinib treatment. We present here the most recent findings about the role and biology of sHER2 based on data obtained using a standardized test, which has been cleared by FDA in 2000, for measuring sHER2. This test includes quality control assessments and has been already widely used to evaluate the clinical utility of sHER2 as a biomarker in breast cancer. We will describe in detail data concerning the assessment of sHER2 as a surrogate maker to optimize the evaluation of the HER2 status of a primary tumor and as a prognosis and predictive marker of response to therapies, both in early and metastatic breast cancer., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Breast cancer remains a major public health problem. Even if there is an increase in this cancer curability, metastatic breast cancer remains a lethal disease in the vast majority of cases. Therapeutic advances in the chemotherapeutic and targeted therapies fields induced an increase in survival, however the proportion of long survivors remains low. Phenotypic instability, an early process initiated during tumour progression, and continued on the metastatic stage of the disease, can be one of the putative hypotheses explaining these results. An increasing amount of scientific data are pledging for a reanalysis of the phenotypic profile regarding hormone receptors and HER-2 status of metastatic lesions in order to identify drugable targets and allow individualisation of the treatment of these metastatic breast cancer patients. Phenotypic changes between the primary tumour and the paired metastatic lymph nodes are a challenging pitfall, raising the question of which site has to be assessed in the adjuvant treatment decision process. This article presents a comprehensive analysis of the frequency of theses phenotypic changes altogether with new modalities to evaluate this phenotypic status.

Apart from therapeutic advances related to new treatments, our practices in the management of early breast cancer have been modified by to key organizational settings (1) mass screening, substantially altering the presentation and epidemiology of breast cancer and (2) the development of guidelines to ensure that any patient management is in agreement with the demonstrated impact in the adjuvant treatment. In daily practice, the impact of screening and guidelines recommendations has put us now in a paradoxical situation: while the majority of non-metastatic breast cancers treated in the hexagon are node negative, most of the results of clinical studies on chemotherapy and targeted therapies today arise from populations predominantly node positive. Therefore, it seemed legitimate to convene a working group around a reflection on the directions of adjuvant chemotherapy in a growing node negative population in order to better respond to the questions of the field oncologists, trying to address the discrepancies between different existing guidelines.

Introduction: High circulating serum vascular endothelial growth factor (VEGF) levels might reflect enhanced angiogenesis in patients suffering from non-small cell lung cancer (NSCLC). This study aimed at determining the prognostic significance of circulating VEGF as a prognostic factor in NSCLC., Methods: Four hundred fifty-one histologically or cytologically proven and previously untreated NSCLC patients have been studied. Median follow-up was 13 years and 9 months. Eleven clinical and biologic variables were recorded. The levels of circulating VEGF were measured in the serum by quantitative immunoassay. Patients have had received conventional treatment (without anti-VEGF therapy) according to the international guidelines. All statistical tests were two-sided., Results: Receiver operating characteristic curves (area under the ROC curve: 0.66 +/- 0.05) showed that circulating VEGF serum level did not demonstrate a high sensitivity-specificity relationship, and therefore, demonstrated a low ability to differentiate NSCLC from benign lung diseases. A 600 pg/mL level of circulating VEGF serum was considered as threshold with 40.8% of NSCLC patients presenting with a high level. The circulating VEGF distribution differed significantly according to disease stage, nodal status, and performance status (PS), with the highest levels observed in metastatic stage, positive mediastinal nodal status, and poor PS. In univariate survival analysis, patients with a high pretreatment circulating VEGF serum level proved to have a shorter overall survival when compared with patients presenting with a circulating VEGF serum level /=2, nodal status N2-3, metastatic disease, neuron-specific enolase >12.5 ng/mL, CYFRA 21-1 >3.6 ng/mL., Conclusion: The prognostic information given by a high circulating VEGF serum level is not an independent determinant of survival owing to a high relationship with main prognostic variables such as PS, stage of the disease, and nodal status. This finding does not preclude a putative prognostic impact of in situ detection of VEGF and VEGF receptors in tumor specimen.

Hypothesis: Lung cancer remains the leading cause of cancer-related mortality worldwide. Currently known serum markers do not efficiently diagnose lung cancer at early stage., Methods: In the present study, we developed a serum proteomic fingerprinting approach coupled with a three-step classification method to address two important clinical questions: (i) to determine whether or not proteomic profiling differs between lung cancer and benign lung diseases in a population of smokers and (ii) to assess the prognostic impact of this profiling in lung cancer. Proteomic spectra were obtained from 170 pathologically confirmed lung cancer or smoking patients with benign chronic lung disease serum samples., Results: Among the 228 protein peaks differentially expressed in the whole population, 88 differed significantly between lung cancer patients and benign lung disease, with area under the curve diagnostic values ranging from 0.63 to 0.84. Multiprotein classifiers based on differentially expressed peaks allowed the classification of lung cancer and benign disease with an area under the curve ranging from 0.991 to 0.994. Using a cross-validation methodology, diagnostic accuracy was 93.1% (sensitivity 94.3%, specificity 85.9%), and more than 90% of the stage I/II lung cancers were correctly classified. Finally, in the prognosis part of the study, a 4628 Da protein was found to be significantly and independently associated with prognosis in advanced stage non-small cell lung cancer patients (p = 0.0005)., Conclusions: The potential markers that we identified through proteomic fingerprinting could accurately classify lung cancers in a high-risk population and predict survival in a non-small cell lung cancer population.

Anti-Hu antibodies are directed against lung cancer cell antigens. The anti-tumor effect of anti-Hu antibodies has been suggested by several studies demonstrating that patients presenting with anti-Hu antibodies have a longer survival. In this case report, we suggest that the immunology of HuAb paraneplastic syndrome by itself could induce tumor response.

Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy/toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. Qualy methods based on time without symptoms and toxicity (TWiST) allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing gemcitabine--navelbine or gemcitabine--taxane combinations with either single-drug chemotherapy or standard chemotherapy based on cisplatin. The choice of end-points is discussed.

Gemcitabine is a pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors including bladder, non-small cell lung and pancreatic cancers. Gemcitabine is a potent radiosensitizer of human tumor cells. This review summarizes preclinical studies designed to elucidate the mechanism of action of gemcitabine with ionizing radiation. Phase I-II ongoing trials of combination of radiation therapy and gemcitabine are trying to determine the optimal dose and schedule which could be used in daily clinical activity. The mechanism of radiosensitization is thought to be simultaneously gemcitabine-induced dATP (deoxyadenosine triphosphate) depletion and cell cycle redistribution into the S phase. Although there are no real study which has proven supra-additive combination, the recent acute side effects in several clinical studies oblige physicists to determine with precision the maximum tolerated dose of gemcitabine in association with ionizing radiation. Radiosensitization conditions can be obtained either with a long exposition to a low concentration or a short exposition to a high concentration. Radiation sensitivity begin to be detected four hours after treatment for 48 hours. A dose about 100 mg/m2/week of gemcitabine could be used with radiation therapy according to recent phase I results. This limiting dose is approaching to a radiosensitization context where the effect of one agent is increased by another agent which is inactive or poorly active for the effect under consideration. In this type of regimen, the two modalities do interact with a frequent inhibition of recovery from potentially lethal damage and a probably increase of late side effects of radiation therapy. In contrast, radio-chemotherapy combination is used for a therapeutic advantage when the drug by itself is active against the tumor but does not enhance late side effects of radiation on the critical normal tissues within the irradiated volume. Gemcitabine surely is a strong radiosensitizer even at low doses with future extended combined modality therapeutic indications. The ultimate goal of combined treatments should be an increased therapeutic ratio.