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Background: Somatic genetic alterations of the estrogen receptor 1 gene (ESR1) are enriched in endocrine therapy-resistant, estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Herein, we investigated and compared the clinical and genomic landscape of ESR1-mutant (ESR1 MUT ) and ESR1 wild type (ESR1 WT ) ER+/ human epidermal growth factor receptor 2 (HER2)- mBCs., Methods: Clinical and genomic data were retrieved from cBioPortal using the publicly-available MSK MetTropism dataset. Metastatic, ER+/HER2- mBC samples were included in the analysis. Only oncogenic and likely oncogenic alterations according to OncoKB were included. Statistical analyses were carried out using alpha level of 0.05, with a false discovery rate threshold of 10% for multiple comparisons using the Benjamini-Hochberg method., Results: Among 679 samples, 136 ESR1 MUT among 131 tumors were found (19.2%). The frequency of ESR1 MUT was higher in ductal versus lobular mBC (21.2% versus 13.8%, P = 0.052) and enriched in liver metastasis compared with other sites (22.5% versus 12.7%; q = 0.02). Compared with ESR1 WT mBC, ESR1 MUT tumors showed higher fraction of genome altered (FGA) {[0.28 interquartile range (IQR), 0.15-0.43] versus 0.22 (0.11-0.38); P = 0.04} and tumor mutational burden (TMB) [4.89 (IQR 3.46-6.85) versus 3.92 (2.59-6.05) mut/Mb; P = 0.001]. Tumors harboring p.E380X alterations showed higher TMB compared with those with H11-12 alterations [8.24 (IQR 5.06-15.3) versus 4.89 (IQR 3.46-6.75) mut/Mb; P = 0.01]. Genetic alterations of TP53 were enriched in ESR1 WT tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, q = 0.001]. Considering signaling pathways, ESR1 MUT tumors showed a lower occurrence of TP53 (OR 0.48, 95% CI 0.30-0.74; q = 0.003) and MAPK (OR 0.29, 95% CI 0.11-0.65; q = 0.009) alterations. TP53 (q < 0.001), CDH1 (q < 0.001), and ERBB2 (q < 0.001) demonstrated mutual exclusivity with ESR1 MUT ., Conclusions: ER+/HER2- mBCs carrying ESR1 MUT exhibit a divergent genomic background, characterized by a lower prevalence of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Following the approval of the first antibody-drug conjugates (ADCs) in the early 2000s, development has increased dramatically, with 14 ADCs now approved and >100 in clinical development. In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small-cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 [datopotamab deruxtecan and sacituzumab govitecan (SG)] and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing. Thus, in the coming years, we are likely to see significant changes to treatment algorithms. As the number of available ADCs increases, biomarkers (of response and resistance) to better select patients are urgently needed. Biopsy sample collection at the time of treatment selection and incorporation of translational research into clinical trial designs are therefore critical. Biopsy samples taken peri- and post-ADC treatment combined with functional genomics screens could provide insights into response/resistance mechanisms as well as the impact of ADCs on tumour biology and the tumour microenvironment, which could improve understanding of the mechanisms underlying these complex molecules. Many ADCs are undergoing evaluation as combination therapy, but a high bar should be set to progress clinical evaluation of any ADC-based combination, particularly considering the high cost and potential toxicity implications. Efforts to optimise ADC dosing/duration, sequencing and the potential for ADC rechallenge are also important, especially considering sustainability aspects. The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access to data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes., Competing Interests: Disclosure SP reports receipt of institutional educational grants and honoraria (all fees to institution) for consultation, attending advisory boards and/or providing lectures for the following organisations: consultation/advisory role: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp & Dohme (MSD), Merck Serono, Merrimack, Mirati, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody; Board of Director role: Galenica SA; presentation at a company-organised public event: AiCME, AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Foundation Medicine, GSK, Illumina, Imedex, Ipsen, Medscape, MSD, Mirati, Novartis, PER, Peerview, Pfizer, Roche/Genentech, RTP, Sanofi, Takeda; receipt of grants/research support: principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Beigene, BMS, GSK, MSD, Roche/Genentech. SL reports receipt of research funding to institution from Novartis, BMS, Merck Sharp & Dohme (MSD), Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca/Daiichi Sankyo, Seattle Genetics; has acted as consultant (not compensated) to Seattle Genetics, Novartis, BMS, MSD, AstraZeneca/Daiichi Sankyo, Eli Lilly, Pfizer, Gilead Therapeutics, Nektar Therapeutics, PUMA Biotechnologies, Roche-Genentech; has acted as consultant (paid to institution) to Novartis, GSK, Roche-Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences, Seattle Genetics, MSD, Eli Lilly, BMS. FA reports research grants (compensated to the hospital) from AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health; honoraria (compensated to the hospital) for advisory board participation or speaker activities from AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, SERVIER, Gilead, Boston Pharmaceutics; personal honoraria for advisory board participation from Lilly. SC reports receipt of personal consulting fees from Novartis, AstraZeneca, Nuvalent, Genesis Therapeutics, Effector Therapeutics, SAGA Diagnostics, Prelude Therapeutics, Gerson Lehman Group; stock options from Effector Therapeutics, Odyssey Biosciences; research funding from AstraZeneca, Daiichi Sankyo. EF reports receipt of personal speaker honoraria from Amgen, AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, Touch Oncology; personal honoraria for advisory board participation from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, Daiichi Sankyo; financial support for meeting attendance and/or travel from AstraZeneca, Janssen, Roche. SPF reports receipt of personal honoraria for advisory board participation from Amgen, AstraZeneca, Illumina, Pfizer; honoraria to institution for advisory board participation from Roche; personal speaker honoraria from Takeda; holds personal stocks/shares in Revolution Medicines. PAJ reports receipt of grants and personal fees from AstraZeneca, Boehringer Ingelheim; personal fees from Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Loxo Oncology; grants and personal fees from Eli Lilly; personal fees from SFJ Pharmaceuticals, Voronoi; grants and personal fees from Daiichi Sankyo; personal fees from Biocartis, Novartis, Sanofi, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Biologics, Blueprint Medicines, Phanes Therapeutics; grants and personal fees from Takeda Oncology; personal fees from Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie; grants from Revolution Medicines; grants from PUMA; grants from Astellas, outside the submitted work. In addition, PAJ is a co-inventor on a DFCI patent on EGFR mutations and receives post-marketing royalties from Lab Corp. KMK reports receipt of personal consultancy fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, Ventana; personal speaker honoraria from AbbVie, AstraZeneca, Amgen, Boehringer Ingelheim, BMS, Janssen, Merck Serono, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Roche, Sanofi, Ventana, Medscape, Mirati, Prime Oncology, PeerVoice, PER. EM reports receipt of personal honoraria for consulting/advisory roles to Exact Sciences, MSD Oncology, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen, Ipsen; reimbursement of travel, accommodation and expenses from Roche, Pfizer, Lilly, Novartis, Gilead Sciences, AstraZeneca, Pierre Fabre. AP reports receipt of personal honoraria for consulting or an advisory role for AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, Lilly, GSK, Janssen, MSD, Mundipharma, Novartis, Roche; speakers bureaus for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, eCancer, Janssen, MSD, Medscape, PeerVoice, touchONCOLOGY. MP reports receipt of personal honoraria for consultancy to Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, MSD, BMS, Novartis, AstraZeneca, Takeda, Gritstone, Sanofi, GSK, Amgen, AbbVie, Ipsen, Esaï, Daiichi Sankyo, Janssen, AnHeart Therapeutics, Novocure; lecture fees from Eli Lilly, Roche, AstraZeneca, Pfizer, Amgen, Boehringer Ingelheim, BMS, Takeda, MSD, Chugai, Illumina, Sanofi, Janssen; research grants (paid to institution) from Roche, AstraZeneca, Takeda, Boehringer Ingelheim. EFS reports consultancy fees (paid to institution) from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche Sanofi, Takeda; personal honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, Daiichi Sankyo; participation on a Data Safety Monitoring Board for DSI. CS reports grants from AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc.), Ono Pharmaceutical, Personalis; is Chief Investigator and Steering Committee Chair for the AZ MeRmaiD 1 and 2 clinical trials; is Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board; has received consultancy fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also SAB member), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre—Shanghai, Metabomed (until July 2022), Relay Therapeutics SAB member, Saga Diagnostics SAB member, the Sarah Cannon Research Institute; has received honoraria from Amgen, AstraZeneca, BMS, GSK, Illumina, MSD, Novartis, Pfizer, Roche-Ventana; has previously held stock options in Apogen Biotechnologies and GRAIL, currently has stock options in Epic Bioscience and Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics; declares a patent application (PCT/US2017/028013) for methods to lung cancer, targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), methods for lung cancer detection (US20190106751A1), identifying patients who respond to cancer treatment (PCT/GB2018/051912), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), methods for systems and tumour monitoring (PCT/EP2022/077987); is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumour recurrence—this patent has been licensed to a commercial entity and under their terms of employment, he is due a share of any revenue generated from such license(s). GV reports receipt of honoraria for consulting and participation in advisory boards from Roche, AstraZeneca, Daiichi Sankyo, Gilead, Pfizer and Agilent. RAS reports receipt of personal speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Roche; honoraria for advisory board participation from AstraZeneca, Eisai, GSK, Guardant, Janssen, Merck, MSD, Novocure, Pfizer, Pharmamar, Roche; financial compensation for his role as Editor for CTR and Editor in Chief for Lung Cancer; receipt of institutional research grants for ETOP and/or IBCSG studies from Amgen, AstraZeneca, BMS, Celgene, Ipsen, Janssen, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, Roche; is an ETOP IBCSG Partners Foundation Member and President of the Board of Directors (uncompensated)., (Copyright © 2024 European Society for Medical Oncology. All rights reserved.)

Breast cancer represents the most commonly diagnosed neoplasm worldwide and the HER2-positive subtype accounts for nearly 1 in 5 breast cancers. The majority of patients with breast cancer present with an early-stage disease upon diagnosis, which is thus susceptible to virtually curative treatment strategies. For a stage, I T1a/b N0 HER2-positive disease, upfront surgery followed by adjuvant therapy is the preferred approach. However, there is some uncertainty regarding the appropriate management of stage cT1c cN0, as both the neoadjuvant approach and upfront surgery have been proven to be feasible therapeutic options. The aim of this Delphi consensus was to define the best strategies for the treatment of early HER2-positive breast cancer. This work may help clinicians in the management of early HER2-positive breast cancer., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Clinical trials confirmed the beneficial effects of adding pertuzumab (P) to the combination of trastuzumab-chemotherapy (TC) in the (neo)adjuvant setting of high-risk HER2-positive early breast cancer (HER2+BC). We evaluated the clinical, economic and societal impact of adding pertuzumab to neoadjuvant TC combination (TPC) in Italy., Methods: A cost-consequence analysis comparing TPC vs. TC was performed developing a cohort-based multi-state Markov model to estimate the clinical, societal and economic impact of the neoadjuvant therapy of TPC versus TC in HER2+BC at high-risk of recurrence. The model works on a cycle length of 1 month and 5-years-time horizon. Literature review-based data were used to populate the model. The following clinical and economic outcomes were estimated: cumulative incidence of loco-regional/distant recurrences, life of years and QALY and both direct and indirect costs (€). Finally, sensitivity analyses were performed., Results: TPC was associated with a 75,630 € saved of direct costs. Specifically, it was associated with an initial increase of treatment costs (+4.8%) followed by reduction of recurrence management cost (-20.4%). TPC was also associated with an indirect cost reduction of 1.40%, as well as decreased incidence of distant recurrence (-20.14%), days of work lost (-1.53%) and days lived with disability (-0.50%). Furthermore, TPC reported 10,47 QALY gained (+2.77%) compared to TC. The probability to achieve the pathological complete response (pCR) was the parameter that mostly affected the results in the sensitivity analysis., Conclusion: Our findings suggested that TPC combination could be a cost-saving option in patients with HER2+BC at high-risk of recurrence., Competing Interests: Declaration of competing interest AZ, MC, NLV, EM, ICA, SDC, AM, DG have no conflicts of interest to disclose. DG has received Honoraria from Novartis, Lilly, Roche, Pfizer, Istituto Gentili. Research funding from profit organizations as Astrazeneca, Novartis and Myriad. PAC has received a research grant from Baxalta now part of Shire, and speaking honoraria from Pfizer, Roche and Novartis. LGM has received grants and personal fees from Bayer AG, Boehringer Ingelheim, Pfizer and Daiichi-Sankyo. MN is employes of Novartis Pharma AG., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapy (ET) deeply transformed the treatment landscape of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. Randomized clinical trials suggest that second progression-free survival (PFS2) was not compromised and time to subsequent chemotherapy (TTC) may be delayed. We carried out a meta-analysis to assess the benefit on PFS2 and on delaying the TTC., Methods: We conducted a systematic literature search of randomized clinical trials with CDK4/6 inhibitors and ET reporting PFS2 or TTC of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC using random-effects models with 95% confidence intervals (CI). I 2 was used to quantify heterogeneity between results of the studies., Results: Eight studies (MONALEESA-2/3/7, MONARCH-2/3, PALOMA-1/2/3) were included in this analysis (N = 4580 patients). PFS2 benefit was observed in patients who received CDK4/6 inhibitors plus ET (pooled HR = 0.68, 95% CI = 0.62-0.74, I 2  = 0%) and also a delay in subsequent TTC (pooled HR = 0.65, 95% CI = 0.60-0.71, I 2  = 0%). A benefit in terms of PFS (pooled HR = 0.55, 95% CI = 0.51-0.59, I 2  = 0%) and overall survival (pooled HR = 0.76, 95% CI = 0.69-0.84, I 2  = 0%) was also observed., Conclusions: CDK4/6 inhibitors plus ET compared with ET alone improve PFS2 and TTC. The delay of chemotherapy may postpone the start of a more toxic treatment option, delaying related toxicities and potentially maintaining a better quality of life for patients, for a longer time. The benefit in PFS2 may postpone the onset of endocrine resistance and help further validate this treatment approach., Competing Interests: Disclosure EMu has acted as a consultant to Pierre Fabre, Genomic Health and Eisai; EMo had consulting or advisory role from Pierre Fabre; MC has received a research grant from Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Triple negative breast cancer encompasses several biological entities with different outcomes and is a priority to identify which patients require more treatment to reduce the risk of recurrence and which patients need less treatment., Patients and Methods: Among the 210 women with first primary invasive apocrine non metastatic breast cancer operated on between January 1998 and December 2016 at the European Institute Oncology, Milan, we identified 24 patients with a pT1-pT2, node-negative, triple negative subtype and Ki-67 ≤ 20% who did not receive adjuvant chemotherapy (CT). We compared the outcome of this cohort with a similar group of 24 patients with ductal tumors who received adjuvant chemotherapy, matched by pathological stage and biological features and also with a similar group of 12 patients with apocrine tumors who received adjuvant chemotherapy., Results: The median age was 64 and 61 years in the apocrine (w/o CT) and ductal group, respectively. The median value of Ki-67 expression was 12% in the apocrine group (w/o CT) and 16% in the ductal group (p < 0.001). After a median follow-up of 7.5 years, no patients in the apocrine group (w/o CT) experienced a breast cancer related event compared with 4 events in the ductal carcinoma group (Gray test p-value = 0.11)., Conclusions: The outcome of selected apocrine triple negative breast cancer patients who did not received adjuvant chemotherapy is excellent and supports a treatment de-escalation. Multicenter projects focusing on the possibility of avoiding adjuvant chemotherapy in selected subtypes of triple negative breast cancers with favorable outcome are warranted., Competing Interests: Declaration of competing interest Emilia Montagna and Giuseppe Cancello received a honorarium for consultant/advisory role from Pierre Fabre. Elisabetta Munzone received a honorarium for consultant/advisory role from Pierre Fabre and Genomic health. Giuseppe Viale has received a honorarium for consultant/advisory role from Dako, Roche, Astellas Pharma, Novartis and he has received funding from Roche, Ventane, Dako. Marco Colleoni has received a honorarium for consultant/advisory role from Novartis, Pierre Fabre, Pfizer, Obi-Pharma, Puba biotechnology, Celldex, Astrazeneca. Eleonora Pagan, Vincenzo Bagnardi, Silvia Dellapasqua, Monica Iorfida, Manueliata Mazza, Giovanni Mazzarol, Paolo Veronesi, Viviana Galimberti, Giorgia Santomauro have no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Equivocal HER2 status has been variably defined in the past, and its clinical implications have long been debated. In the 2018 focused update, ASCO/CAP guidelines recommended that tumours with double-equivocal (by immunohistochemistry and in situ hybridization assays) HER2 status should be considered HER2-negative due to the lack of evidence for any benefit of HER2-targeted therapy. The biology and the response to systemic therapies of tumours co-expressing HR and HER2 is quite complex. There is an extensive bi-directional cross-talk between these 2 pathways, that may result in both intrinsic and acquired resistance to endocrine agents, as well as in lower sensitivity to HER2-targeted therapies. In fact, neoadjuvant studies indicate that pCR rates are significantly lower in HER2-positive/ER-positive than ER-negative tumours, regardless the type of HER2 targeted treatment. The recent identification of different subtypes of HER2-positive breast cancer, according to the co-expression of HR and/or the molecular (intrinsic) subtyping, has prompted a renewed interest for clinical studies aimed at better tailoring the systemic therapy for these patients. A subgroup of them might not need chemotherapy if treated with dual HER2 blockade, and this option has been tested in a number of neo-adjuvant trials. In addition, triple targeting of HR, HER2, and CDK4/6 pathways simultaneously may be an effective treatment and overcome the drug resistance mechanisms that are typical of the disease. Finally, HER2-positive breast cancer may well benefit from immunotherapeutic interventions with anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) agents., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Inflammatory breast cancer (IBC) is a rare and highly aggressive disease. A neoadjuvant regimen with chemotherapy and an antiangiogenic strategy was investigated., Patients and Methods: Patients with primary or recurrent IBC who were candidates for neoadjuvant treatment received weekly carboplatin and paclitaxel plus bevacizumab every 3 weeks and oral metronomic cyclophosphamide for 6 months. Trastuzumab was added for patients with HER2 + tumors and endocrine therapy was added for patients with estrogen receptor and/or progesterone receptor ≥ 10% tumors. Oral metronomic capecitabine and cyclophosphamide was continued for 6 months after surgery in those patients with a response. The primary efficacy endpoints were pathologic complete remission (pCR) and the objective response., Results: From July 2010 to December 2013, 34 patients with IBC were included. The surrogate intrinsic tumor subtypes were as follows: luminal B-like (HER2 - ), 10 (29%); luminal B-like (HER2 + ), 8 (24%); HER2 + (nonluminal), 6 (18%); and triple negative, 10 (29%). An objective response was obtained in 30 patients (88%; 95% confidence interval, 73%-97%) and a pCR in 10 patients (29%; 95% confidence interval, 15%-48%). The proportion of pCR was significantly greater in the patients with HER2 + tumors (57%) than in patients with triple-negative (20%) or luminal B-like (HER2 - ) tumors (0%; P = .019). After a median follow-up of 4.4 years, the 5-year disease-free survival and overall survival was 58% and 72%, respectively. The achievement of pCR was associated with longer disease-free (P = .12) and overall (P = .029) survival., Conclusion: In patients with IBC, neoadjuvant treatment with the investigated regimen was successful and well tolerated. Further studies evaluating the potential benefit of an antiangiogenic strategy in this setting are awaited., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated., Patients and Methods: One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity., Results: Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P =0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related., Conclusion: The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial., Patients and Methods: The intention-to-treat BIG 1-98 monotherapy cohort (5 years of therapy with tamoxifen or letrozole) included 4922 women, of whom 4091 had central pathology review. Histotype groups were defined as: mucinous (N = 100), tubular/cribriform (N = 83), ductal (N = 3257), and other (N = 651). Of 183 women with either mucinous or tubular/cribriform tumors, 96 were randomly assigned to letrozole and 87 to tamoxifen. Outcomes assessed were disease-free survival (DFS), overall survival (OS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Median follow-up in the analytic cohort was 8.1 years., Results: Women with tubular/cribriform breast cancer had the best outcomes for all end points compared with the other three histotypes, and had less breast cancer recurrence (97.5% 5-year BCFI) than those with mucinous (93.5%), ductal (88.9%), or other (89.9%) histotypes. Patients with mucinous or tubular/cribriform carcinoma had better DRFI (5-year rates 97.8% and 98.8%, respectively) than those with ductal (90.9%) or other (92.1%) carcinomas. Within the subgroup of women with special histotypes, we observed a nonsignificant increase in the hazard of breast cancer recurrence with letrozole [hazard (letrozole versus tamoxifen): 3.31, 95% confidence interval 0.94-11.7; P = 0.06]., Conclusions: Women with mucinous or tubular/cribriform breast cancer have better outcomes than those with other histotypes, although the observation is based on a limited number of events. In postmenopausal women with these histotypes, the magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with mucinous or tubular/cribriform disease., Clinicaltrialsgov: NCT00004205., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Endocrine treatments are key component of the adjuvant strategy for pre-menopausal patients with luminal tumors. Treatment options should be based not only upon the risk of relapse and level of endocrine responsiveness, but also on co-morbidities, preferences of the patient and degree of side effects. Tamoxifen should still be considered as an appropriate endocrine therapy in a large group of premenopausal patients (e.g. lower risk patient, presence of co-morbidities, patient preference). However, the results of the SOFT and TEXT trials, evaluating the value of ovarian function suppression (OFS) as well as the role of adjuvant aromatase inhibitor (AI), raised questions about the use of tamoxifen alone in selected higher risk patient. In the SOFT study, premenopausal patients did not benefit from the addition of OFS, but for those women at sufficient risk of recurrence to deserve adjuvant chemotherapy and who maintained pre-menopausal estradiol, the addition of OFS to tamoxifen reduced the risk of recurrence. Moreover, in the TEXT trial, adjuvant treatment with exemestane plus OFS, as compared with tamoxifen plus OFS, significantly improved disease-free survival, breast cancer-free interval and distant disease-free survival, thus representing a new treatment option. Recent available information on endocrine options for younger patients with luminal tumors support the use of tailored endocrine treatments. Issues specific for younger patients related to pregnancies desire, family planning, safety, quality of life and subjective side effects should be a priority in the therapeutic algorithm., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The long-term prognostic relevance of immediate breast reconstruction (IBR) for patients with estrogen receptor (ER)-negative breast cancer (BC) has not been fully elucidated., Patients and Methods: The study population included 444 patients with ER-negative BC who underwent total mastectomy with complete axillary dissection between 1995 and 2006, 339 patients with and 105 patients without IBR. The median follow-up was 8.6 years., Results: Patients treated with IBR were younger (P < .001) and received surgery more recently (2003-2006: 53.1% vs. 39%; P = .0003), and had a lower number of metastatic lymph nodes (>4 lymph nodes involvement: 29.5% vs. 45.7%; P = .0026), smaller tumors (pT1/2: 15% vs. 26.7%; P = .0007), and lower extent of peritumoral vascular invasion (15.9% vs. 21%; P = .032). The 5-year cumulative incidence of locoregional recurrence was 7.1% in the IBR group and 11.7% in the no IBR group (hazard ratio [HR], 0.81; P = .63). The 5-year cumulative incidence of distant metastases were similar in the 2 groups (P = .79). The 5-year overall and disease-free survival proportions were 79.9% versus 69.5% (HR, 1.11; P = .67) and 66.6% versus 54.1% (HR, 1.04; P = .83) in the IBR group and no IBR group, respectively., Conclusion: IBR intervention does not significantly affect prognosis of ER-negative BC patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Breast cancer occurs rarely in men, accounting for approximately 1% of all breast carcinomas. Data on prognosis principally derive from retrospective studies and from extrapolation of female breast cancer series., Patients and Methods: A total of 99 men with invasive breast cancer were matched with 198 women with breast cancer who had surgery at the same institution from 1999 to 2010. Matching variables were year of surgery, age, primary tumor size, nodal involvement, hormone receptor status, status of HER2 (human epidermal growth factor receptor 2 [ERBB2]), Ki-67, and grade. Median follow-up was 8.6 years., Results: Disease-free survival (DFS) was significantly poorer in the men (10-year DFS, 51.7% vs. 66.5%; hazard ratio [HR], 1.79; 95% CI, 1.19-2.68; P = .004). Similar results were observed for overall survival (OS) (10-year OS, 70.7% vs. 84.2%; HR, 1.79; 95% CI, 1.01-3.15; P = .043). The cumulative incidence of death for causes not related to the primary breast cancer was significantly higher for men than for women (HR, 2.87; 95% CI, 1.58-5.22; P = .001), whereas the breast cancer-specific survival (BCSS) was similar between the 2 groups (10-year BCSS, 81.5% vs. 88%; HR, 1.27; 95% CI, 0.62-2.59; P = .517)., Conclusion: This comparative series found that men with breast cancer had a poorer DFS and OS when compared with women. The men also had a higher risk of contralateral tumors and second primaries. Appropriate counseling, surveillance, and prevention are recommended to improve survival for these individuals., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Metronomic therapy (MT) refers to repetitive, low doses of chemotherapy drugs. MT exerts an effect not only on tumour cells, but also on their microenvironment. In particular, the low-dose schedule compromises the repairing process of endothelial cells, leading to an anti-angiogenic effect. In addition to the anti-angiogenic effect, MT could have an immunological action through the restoration of the anticancer effect of the immune system and induction of tumour dormancy. Consequently the association of targeted therapy with anti-angiogenic properties or specific immunologic drugs could enhance the efficacy of MT. During the past 15 years, several studies have been published evaluating the metronomic strategy in breast cancer. We conducted a systematic review of the results of phase I, II and III studies testing MT in breast cancer patients. The analyses included the efficacy and toxicity data of MT, and the future development of this strategy in breast cancer are also discussed. The systematic review presented here suggests that MT is a treatment option for breast cancer patients, has a low toxicity profile, efficacy in most patients and has potentially significant cost-effective advantages for public health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction and Aims: There is a biological rationale for expecting benefit from longer duration therapy in the subpopulation of patients with endocrine non-responsive disease. Such tumors have a rapid cell proliferation and are associated with a high risk of relapse despite adjuvant chemotherapy. Moreover, prolonged duration of chemotherapy may be particularly relevant for patients with triple negative disease to inhibit the growth of tumors that are not susceptible to the effects of endocrine therapies due to lack of steroid hormone receptors, or to the effects of anti-HER2 target treatment., Methods and Results: The question of duration of adjuvant chemotherapy for breast cancer has been directly addressed in several trials herein presented. Most of these were small and, therefore, unsuitable for detecting differences of modest magnitude in intrinsic biological subtypes. In addition, a number of trials examine regimens which differ in duration of therapy, but also in the drugs given. In these trials the effects of duration and choice of drug are inextricably confounded. However incremental chemotherapy strategies, compared with less extensive therapies, were more effective in past studies particularly in patients with endocrine non-responsive disease., Conclusions: The evidence resulting from past trials indicates that conventional-dose chemotherapy for 4-6 months is an adequate option in patients whose tumors present a low or no expression of steroid hormone receptors. These tumor subtypes are part of a highly heterogeneous subgroup (e.g., basal-like, molecular apocrine, claudin-low, HER-enriched). Tailored research through international cooperation is key to solidify consensus on how to treat individual patients with endocrine non-responsive breast cancer., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Patients with metastatic breast cancer to the ovary, without tumor debulking and after systemic therapy, have a 5-year survival rate < 10%., Patients and Methods: We analyzed a series of 37 patients, operated in one institution over 10 years, for both the primary tumor (PT) and ovarian/pelvic metastases (OPM). Estrogen receptors (ER), progesterone receptors (PgR), HER-2 and Ki-67 were determined., Results: Patients were predominantly young: 27 (73%) patients were < 50 years. Average ER/PgR expression did not change significantly between PT (mean ER = 66%, PgR = 35%) and OPM (mean ER = 67%, PgR = 28%). Median time to OPM was 42 months (range 0-176); 5-year OS after OPM was 51% (95% confidence interval 32% to 67%). When combining ER and PgR status, patients with ER > 50% on both PT and OPM and with PgR > 50% on PT and/or OPM (good prognosis, 11 patients) had a better outcome versus0 patients with ER and PgR ≤ 50% on both PT and OPM (bad prognosis, eight patients) and also versus the remaining patients (intermediate prognosis, 18 patients), P value = 0.010., Conclusion: Patients with OPM from breast cancer show a favorable prognosis after tumor debulking, whether it was radical or not, especially when a high expression of ER and PgR is present in both PT and OPM.

Background: Breast cancer is a heterogeneous disease. Circulating tumor cell (CTC) enumeration might be useful to identify different risk categories within each molecular subtype., Methods: We retrospectively analyzed 203 consecutive patients with metastatic breast cancer with baseline CTC enumeration performed with CellSearch (Veridex Corp, Warren, NJ) between March 2005 and July 2011. Patients were categorized into 3 prognostic groups based on the number of CTCs (0, 1-4, and ≥ 5) and into 5 categories based on tumor biological characteristics: luminal-A (estrogen receptor [ER] and progesterone receptor [PR] > 1%, grade 1/2, human epidermal growth factor 2 [HER2]-negative [HER2(-)], Ki67 value < 14%); luminal-B (ER and/or PR > 1%, grade 3, HER2(-), Ki67 value > 14%); luminal-B HER2-positive [HER2(+)] (ER and/or PR > 1%, any grade, HER2(+), Ki-67 value any); HER2(+) (HER2 overexpressed/fluorescence in situ hybridization [FISH] amplified, ER and PR absent); triple negative (TN) (ER and PR 0%, HER2 not overexpressed/FISH not amplified)., Results: Median age was 57 years (range 31-78 years). Twenty-seven patients (13.3%) had luminal-A category, 105 (51.7%) patients had luminal-B, 29 (14.3%) patients had luminal-B HER2(+), 24 patients (11.8%) had HER2(+), and 18 patients (8.9%) had TN. CTCs were mostly found in patients with luminal-A/luminal-B HER2(-) subtype. At multivariable analysis, CTC count was a significant predictive factor for overall survival (OS) in all molecular subtypes (log-rank P < .01). Patients with 0 CTCs/7.5 mL blood and all subtypes, except HER2(+), seem to perform better compared with other categories., Conclusion: These findings confirm CTCs as an important prognostic factor for metastatic breast cancer in all molecular subtypes. Larger studies could help identify metastatic breast cancer subgroups in which CTC analysis would be particularly useful., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Over the last 35 years, classical CMF (combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil) has been a milestone in the adjuvant treatment of women with breast cancer. However, after an early burst of success lasted just over 10 years, classical CMF has been supplanted by 'third-generation' regimens containing taxanes and anthracyclines. Questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients and particularly, recent retrospective data support the fact that the CMF might have a role in the treatment of patients with triple-negative breast cancer. One possible justification for supporting this role of CMF may be sought in the mechanism of action of drugs used in the regimen, as triple-negative cells may be sensitive to alkylating agents that cause double-strand breaks in DNA. The lesson learned from the CMF could lead us to identify new combinations of drugs that could include the optimal chemotherapy backbone for triple-negative breast cancer such as platinum compounds or alkylating agents or Poly (ADP-ribose) polymerase inhibitors. In conclusion, although we have learned a lot from the use of CMF, many questions are still open and hopefully stimulate our thinking, as clinicians, leading us to find new and more effective ways to treat breast cancer.

Background: Currently, the acquisition of tissue from metastatic deposits is not recommended as a routine practice. Our aim was to evaluate the discordance rate of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) receptor status between primary tumor and liver metastases and its potential impact on treatment choice., Patients and Methods: We retrospectively analyzed a database including 1250 ultrasound-guided liver biopsies carried out at the European Institute of Oncology from August 1999 to March 2009. ER, PgR, and HER2 status were determined by immunohistochemistry and/or FISH. Differences between proportions were evaluated using Fisher's exact test., Results: We identified 255 consecutive patients with matched primary and liver tissue samples. Changes in ER status were observed in 37 of 255 patients (14.5%). Changes in PgR status were observed in 124 of 255 patients (48.6%). Changes in HER2 status were observed in 24 of 172 assessable patients (13.9%). We observed a discordance in receptor status (ER, PgR, and HER2) between primary tumor and liver metastases, which led to change in therapy for 31 of 255 of patients (12.1%)., Conclusions: Biopsy of metastases for reassessment of biological features should be considered in all patients, when safe and easy to carry out, since it is likely to impact treatment choice.

Background: HER2/neu status of tumor cells at metastatic sites in patients with advanced disease may differ from that of the primary tumor. Assessing the presence of target antigens on circulating tumor cells (CTCs) might affect treatment choice., Patients and Methods: From June 2007 to October 2008, we collected 23 mL of blood from each of the 76 consecutive patients before and during chemotherapy to determine CTC numbers and HER2 overexpression. CTCs were isolated with the CellSearch System® (Veridex, LLC; Raritan, NJ) and fluorescently stained with the Epithelial Cell Kit®. Tumor Phenotyping Reagent® was used to investigate HER2/neu overexpression., Results: Concordance of HER2 status between the primary tumor and CTCs was 86% (49 out of 57 patients) at baseline and 82% (50 out of 61 patients) in the treatment samples. HER2 overexpression in CTCs was acquired in 8 out of 45 patients (18%) and lost in 3 out of 16 patients (19%) during a treatment containing trastuzumab. The overall discordance rate between the primary tumor and CTCs was 18% (11 out of 61 patients). Patients with HER2 overexpression in CTCs had poorer progression-free survival compared with those without CTCs or with HER2- CTCs (log-rank P =.036)., Conclusion: Information on the presence or absence of HER2 overexpression can be obtained in CTCs. Larger trials are needed to evaluate the activity of HER2-targeted therapy in patients with acquired HER2 overexpression in CTCs.

Background: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. Pegylated liposomal-doxorubicin (PLD) pharmacokinetic characteristics support the rationale for using the drug in a metronomic fashion, potentially able to combine anthracyclines efficacy to a low toxicity profile., Patients and Methods: In a case-series report carried out in both anthracycline-naive and pre-treated metastatic breast cancer patients, we tested feasibility, clinical efficacy and tolerability of PLD administered with a novel metronomic schedule of 20mg/m(2) i.v. every two weeks., Results: 52 patients were enrolled and 45 were evaluated. Forty-four patients were assessed for either response or toxicity. Eight patients (18%) had partial responses (PR) and 17 (39%) stable disease (SD), with a clinical benefit (CB) of 45% (95% CI: 30.3%-59.7%). Nineteen patients (43%) had progressive disease (PD). Neither grade 3 nor grade 4 haematological or clinical side effects were recorded, except for 2 patients with grade 3 palmar-plantar erythrodysesthesia (PPE). No cardiac toxicity was recorded., Conclusion: Metronomic administration of PLD is a feasible and active treatment for extensively pre-treated metastatic breast cancer patients, alternative to classic anthracyclines, balancing clinical efficacy with a good quality of life in terms of reduced side effects and low personal costs for the patient., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Background: This study aimed to evaluate the prognostic significance of circulating tumor cells (CTCs) detection in advanced breast cancer patients., Patients and Methods: We tested 80 patients for CTC levels before starting a new treatment and after 4, 8 weeks, at the first clinical evaluation and every 2 months thereafter. CTCs were detected using the CellSearch System., Results: Forty-nine patients had >or=5 CTCs at baseline. At the multivariate analysis, baseline number of CTCs was significantly associated with progression-free survival [hazard ratio (HR) 2.5; 95% confidence interval (CI) 1.2-5.4]. The risk of progression for patients with CTCs >or=5 at last available blood draw was five times the risk of patients with 0-4 CTCs at the same time point (HR 5.3; 95% CI 2.8-10.4). Patients with rising or persistent >or=5 CTCs at last available blood draw showed a statistically significant higher risk of progression with respect to patients with <5 CTCs at both blood draws (HR 6.4; 95% CI 2.8-14.6)., Conclusion: CTCs basal value is a predictive indicator of prognosis and changes in CTC levels during therapy may indicate a clinical response. Testing CTC levels during targeted treatments might substitute other measurement parameters for response evaluation.

Background: Trastuzumab (T) combined with i.v. vinorelbine (i.v.VNR) is an active regimen for patients with advanced breast cancer (ABC). In order to further improve quality of life of patients undergoing treatment for ABC, a new regimen using oral vinorelbine (oVNR) (d1 + d3) plus q3wks T was tested (ToVNR)., Patients and Methods: Thirty-nine patients with ABC, human epidermal growth factor receptor 2/neu 3+ or FISH positive received 288 treatment cycles with T 6 mg/kg (loading dose, 8 mg/kg) on d1 and oVNR 55 mg/m(2) on d1 + d3, q3wks until disease progression or unacceptable toxicity., Results: Thirty-seven patients and 286 treatment cycles were evaluated (two patients were lost to follow-up). Treatment was very well tolerated. Two patients had complete response (CR), 14 partial response (PR), 17 stable disease (SD) and four disease progression (PD) (overall response rate: 43%). Clinical benefit rate (CR + PR + SD >24 months) was 73%. Median time to progression was 8.9 months (range 2-27) and median duration of response was 10.9 months (range 2-27)., Conclusions: The ToVNR combination is active and very well tolerated. It favorably compares with the combination of T and weekly i.v. administered VNR, allowing a more convenient once every three weeks hospital admission and leaving patients and care providers free from the unpleasant effect of i.v.VNR.

The characterization of tumor antigens recognized by immune effector cells has opened the perspective of developing therapeutic vaccines in the field of breast cancer. The potential advantages of the vaccines are: (i) the induction of a robust immune response against tumors that are spontaneously weekly immunogenic; (ii) the tumor specificity for some antigens; (iii) the good tolerance and safety profile and (iv) the long-term immune memory, critical to prevent efficiently tumor recurrence. Most trials evaluating breast cancer vaccines have been carried out in patients with extended metastatic breast cancer, characterized by aggressive tumors, resistant to standard cytotoxic treatments, so that clinical efficacy was difficult to achieve. However, some significant immune responses against tumor antigens induced upon vaccinations were recorded. The aim of this review is to analyze the activity of vaccination strategies in current clinical trials. Data of clinical activity have been observed by using vaccines targeting HER2/neu protein, human telomerase reverse transcriptase, carcinoembryonic antigen and carbohydrate antigen given after stem cell rescue. The review discusses possible future directions for vaccine development and applications in the adjuvant setting.

Purpose: A phase I study was performed to determine the maximal tolerated dose, recommended doses (RDs), safety and efficacy of oral vinorelbine when combined with capecitabine in an all-oral chemotherapy regimen in patients with metastatic breast cancer (MBC), with pharmacokinetic blood sampling to investigate potential drug-drug interactions., Patients and Methods: Forty-four patients with MBC received as first- or second-line chemotherapy, oral vinorelbine at a dose of 60 or 80 mg/m2 on days 1 and 8 (and 15) with escalating doses of capecitabine from 1650 to 2500 mg/m2/day days 1-14 every 3 or 4 weeks. Three schedules were tested: day 1, day 8 and weekly regimens of oral vinorelbine with a 14-day course of capecitabine every 3 weeks; and a days 1 and 8 regimen of oral vinorelbine with a 14-day course of capecitabine every 4 weeks., Results: With oral vinorelbine at 60 mg/m2, the RDs were established as oral vinorelbine 60 mg/m2 on days 1 and 8 plus capecitabine 2250 mg/m2/day days 1-14 and oral vinorelbine 60 mg/m2/week plus capecitabine 2000 mg/m2/day days 1-14. With oral vinorelbine at 80 mg/m2, the RD was oral vinorelbine 80 mg/m2 on days 1 and 8 plus capecitabine 2000 mg/m2/day days 1-14. Neutropenia was the main dose-limiting toxicity of the combination; it was reported in 40 patients (90.9%), with grade 3 in 14 patients (31.8%) and 6.2% of cycles, and grade 4 in 12 patients (27.3%) and 4.3% of cycles. Complications were rare with only three patients experiencing febrile neutropenia (one episode each). The most frequent non-haematological toxicity was gastrointestinal; however, the incidence of grade 3 was low, with no episode of grade 4. Hand-foot syndrome was reported in 14 patients (31.8%) and 22.6% of cycles, with grade 2 in two patients (4.5%) and 1.2% of cycles (two episodes each). No episode of grade 3 was observed. Objective responses were reported in 18 patients (three complete responses and 15 partial responses), yielding a response rate of 40.9% in the intention-to-treat population according to the investigator assessment. Results from the pharmacokinetic study demonstrated the absence of mutual pharmacokinetic interactions when both drugs were co-administered., Conclusions: The combination of oral vinorelbine and capecitabine is safe and easy to administer in an outpatient setting. This all-oral combination chemotherapy may offer a good alternative to the intravenous route for patients with MBC. Based on these promising results, a phase II study has started using oral vinorelbine 60 mg/m2/week with capecitabine 2000 mg/m2/day days 1-14 every 3 weeks as first-line chemotherapy in patients with MBC.

Background: The combination of capecitabine and vinorelbine is a potentially valuable treatment regimen for patients with advanced-stage breast cancer. The drugs are easy to administer and do not cause significant alopecia. In order to identify the spectrum of toxicity of a regimen containing 2 drugs, we conducted an extended phase I study aimed at defining maximum tolerated doses, recommended doses, safety, and efficacy in patients with pretreated advanced-stage breast cancer., Patients and Methods: Forty-nine patients with advanced-stage breast cancer were treated with escalating doses of oral capecitabine from 500 mg/m2 to 1375 mg/m2 twice daily on days 1-14 and escalating doses of vinorelbine from 12.5 mg/m2 to 25 mg/m2 intravenously (I.V.) on days 1 and 3 every 3 weeks. Almost all patients (90%) had received >or= 3 previous treatments for metastatic disease (anthracyclines, 76%; 5-flourouracil, 76%; taxanes, 29%)., Results: Dose level 9 (capecitabine 1250 mg/m2 twice daily on days 1-14 and vinorelbine 22.5 mg/m2 I.V. on days 1 and 3) was identified as the maximum tolerated dose. The most frequent clinical adverse events were nausea (78%), asthenia (59%), constipation (51%), mucositis (47%), and hand-foot syndrome (41%). The majority of events were mild to moderate; the only grade 4 clinical adverse events were diarrhea, fever, and thromboembolism, each of which occurred in 1 patient (2%) at dose level 8. Objective confirmed responses were observed in 18 patients (37%), including 1 complete response (2%) and 17 partial responses (35%). Disease was stable in an additional 10 patients (20%), with a median duration of 6.3 months (range, 4-24 months)., Conclusion: The combination of the 2 drugs is very well tolerated and effective, especially considering the previous exposure to chemotherapy. The recommended dose for further phase II studies should be capecitabine 1250 mg/m2 twice daily on days 1-14 and vinorelbine 22.5 mg/m2 I.V. on days 1 and 3.

Intraocular metastases, especially those of the choroidal plexus, are not common in metastatic breast cancer patients and are typically associated with a poor prognosis and impaired quality of life. A 45-year-old woman with breast cancer overexpressing HER2 and metastasizing to choroidal plexus, lymph nodes and skin received a combination of trastuzumab and paclitaxel as first-line treatment. Subsequently, at progression, trastuzumab was reintroduced together with vinorelbine. Administration of trastuzumab with either paclitaxel or vinorelbine led to a rapid improvement of the ocular symptoms, associated with a rapid objective response of all metastatic lesions and a prompt improvement in the quality of life. Choroidal metastases from breast cancer overexpressing HER2 are responsive to trastuzumab and chemotherapy (paclitaxel or vinorelbine). The susceptibility of ocular metastases to this approach seems different to that of other sanctuary disease sites.

Background: The efficacy and safety of prolonged fluoropyrimidines, either intravenously or orally, prompted their integration with taxanes and anthracyclines in the treatment of advanced breast cancer (ABC). We conducted three subsequent dose-finding studies on first-line chemotherapy in ABC with anthracyclines, either epirubicin (E) or doxorubicin (A), and docetaxel (T), both given on days 1 and 8 every 3 weeks, plus continuous infusion (CI) 5-fluorouracil (F) or capecitabine (X)., Patients and Methods: Sixty-two patients (37% dominant visceral disease, 48% locally advanced disease, 45% two or more sites involved), received different doses of T (60--80 mg/m(2)), A (40--50 mg/m(2)) or E (60--90 mg/m(2)) and X (1,650 and 2,000 mg/m(2)), or CI F at a fixed daily dose of 200 mg/m(2). Cardiac function was monitored at baseline and then every four cycles by echocardiography., Results: The median number of cycles per patient with all regimens was four (range one to eight). Haematological and gastrointestinal toxicity defined the maximum tolerated doses, at T-80/E-90 mg/m(2) with TEF, T-70/A50/X-2,000 mg/m(2) with TAX and T-70/E-80/X-1,650 mg/m(2) with TEX. Two patients treated with TEF developed transient cardiac toxicity (dilatative cardiomyopathy and coronary subtotal stenosis requiring stenting) after cumulative E doses of 400 mg and 1,100 mg/m(2), respectively. Fifty-nine patients were evaluable for response; the overall response rates (ORR) were comparable between regimens (54% with TEF, 71% with TAX and 86% with TEX), with an 81% ORR in 31 patients with locally advanced disease., Conclusions: The addition of fluoropyrimidines to weekly, intermittent ET is well tolerated and active in ABC.

Purpose: Chemotherapy regimens for patients with advanced breast cancer or large primary tumours (including locally advanced disease) usually contain anthracyclines, taxanes or both. We investigated a multi-agent regimen for patients for whom anthracyclines and/or taxanes may not be suitable. We assessed efficacy in terms of response rate and time to progression of a combination with continuous infusion 5-fluorouracil (5-FU), vinorelbine and cisplatin (ViFuP regimen), as a first or subsequent line treatment for metastatic breast cancer patients., Patients and Methods: One hundred consecutive patients with advanced breast cancer were treated with 5-FU 200 mg/m2 administered continuously through a permanent central venous line; vinorelbine was given on days 1 and 3 at a dose of 20 mg and cisplatin was administered at 60 mg/m2 on day one. Therapy was given every three weeks. The median age was 50 years (range 23-72). Fifty-two patients had received prior chemotherapy for metastatic breast cancer, and sixty-one percent had previously received anthracyclines, thirty-five percent taxanes and twenty-nine percent 5-FU as a bolus injection. All patients were assessable for toxicity, four patients were not assessable for response., Results: There were four complete responses (4%). Forty-nine patients had a partial response (overall response rate, 55%; 95% confidence interval (CI): 45%-65%). After a median follow-up of 10.2 months, median duration of response is 5.2 months (range 1.5-20.7+ months), time to progression (TTP) is 6.8 months (range 0.3-24.7 months). Acute toxicity, including myelosuppression, was mild: only 18% of patients had grade 4 granulocytopenia and one patient experienced grade 4 diarrhea. Only 15% of patients had any non-hematological grade 3 toxicity including nausea (4%), stomatitis (4%), diarrhea (2%), fatigue (1%), fever (1%), photosensitivity (1%), hand-foot syndrome (1%). Grade 2 alopecia was observed only in six patients (6%). Eleven patients developed a right diaphragmatic supra elevation, while deep vein thrombosis, central venous catheter associated, occurred in eight patients., Conclusions: We identified a combination chemotherapy with noteworthy efficacy and well tolerated subjectively as either a first- or second-line treatment for metastatic breast cancer patients. The regimen warrants further development focusing on the comparison with either continuous administration of oral fluoropyrimidine derivatives.

Background: Biological considerations support the use of primary chemotherapy in operable breast cancer; and despite wide variations of used regimens, clinical studies consistently show a significant tumor response allowing breast conservation in many patients otherwise candidates for mastectomy. We investigated the efficacy and the acceptance of a combination chemotherapy with vinorelbine, 5-fluorouracil and high-dose folinic acid in operable breast cancer with favorable prognostic factors and tested the relationship of hormone receptor status, Ki67,p53, c-erbB2 and bcl-2 with treatment response., Patients and Methods: Thirty-nine patients (median age 51 years, range 36-71 years), eight with T1, twenty-eight with T2 and two with T3 lesions, were treated with 5-fluorouracil (350 mg/m2, i.v. on day 1 to 3) preceded by folinic acid (100 mg/m2 i.v. on day 1 to 3) and vinorelbine, given on days 1 and 3 at the dose of 20 mg/m2 (FLN regimen). Therapy was administered on an outpatient basis every three weeks. Non responders had surgery after three courses, while complete or partial responders underwent surgery after six courses. All but one were evaluable for response and toxicity., Results: Objective responses were observed in 23 of the 38 evaluable patients (61%; 95% CI: 46%-76%): three complete responses (8%) and 20 partial responses (53%). Fifteen patients (39%) had stable disease, of whom nine (23%) had minor response. None of the patients had disease progression during treatment. Objective responses were significantly associated with no expression of estrogen and/or progesterone receptors and > 50% decrease in Ki67 after induction chemotherapy. Tolerance was excellent and none of the patients experienced grade 2 alopecia., Conclusions: The 'moderate' efficacy of this regimen might be partially due to the selection of patients with high expression of steroid hormone receptors and low proliferation rate, which have an unfavorable impact on response to this chemotherapy.

Background: Adriamycin (ADM) and ifosfamide (IFO) are the two most active agents in the treatment of soft tissue sarcomas (STS) with a clear dose-response relationship. We evaluated the feasibility and toxicity of a high-dose IFO-plus-ADM combination., Patients and Methods: Fourteen patients with advanced disease and nine patients in adjuvant setting received IFO 12.5 g/m2 in 120-hour continuous infusion with Mesna uroprotection and ADM 20 mg/m2 on days 1-3 and G-CSF every three weeks., Results: Twenty-three patients received 89 chemotherapy cycles (70 cycles at full dose). Seventeen patients received the planned treatment, and nine patients required dose reductions. We observed grade 3-4 neutropenia in 52 cycles (59%)/20 patients; grade 3-4 thrombocytopenia in 16 cycles (18%)/nine patients; grade 3-4 anaemia in 24 cycles (27%)/11 patients. Eight patients experienced febrile neutropenia and six patients required blood transfusions., Conclusions: While feasible, this regimen showed heavy toxicity. Nevertheless, 74% of the patients were able to complete the planned treatment. Adjustment of the schedule of IFO continuous infusion to improve this combination is currently under investigation.