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Background: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8 + lymphocytes were also evaluated in the same cohort., Patients and Methods: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8 + lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8 + lymphocytes in tumor stroma (sCD8) as well as the total number of CD8 + lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry., Results: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8 + T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome., Conclusions: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8 + lymphocytes in BC patients with early-stage disease., Competing Interests: Declaration of competing interest GA: Advisory Boards: Novartis, BMS, Roche Hellas, Astra Zeneca, Sanofi, Amgen, Genesis Pharma, Merck, Pfizer. DP: Advisory Role: Roche, MSD, Astellas. Honoraria: Roche, MSD, Astellas. AK: Speaker fees: Roche, MSD, Pfizer. Educational grant: Pfizer. Advisory Boards: ENETS. Adverse Events Monitoring: EOF. GR: Research funding: Tesaro, IQvia, ICON Clinical Research, MSD, PPD Global. Consulting fees: Roche, Pfizer, IQvia. Honoraria: Ipsen, MSD, Myriad. Travel: Pfizer, Merck, Sanofi, Astellas Pharma, MSD Oncology, Servier, AstraZeneca, ICON Clinical Research. FZ: Honoraria for lectures and have served in an advisory role for AstraZeneca, Daiichi, Eli- Lilly, Merck, Novartis, MSD, Pfizer, Genesis- Pharma, Roche and Gilead. GF: Advisory Board: Pfizer, Novartis. Honoraria: AstraZeneca, Novartis. Stock ownership: Genprex, Daiichi Sankyo, RFL Holdings, Formycon., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Melanuria is the dark brown discoloration of the urine and an uncommon manifestation in patients with melanoma. It is an ominous sign, usually indicating widespread disease. In this article, through an illustrative case, we discuss the pathophysiological, clinical, and prognostic characteristics of melanuria in melanoma. Moreover, we aim to provide the available data for the prompt diagnosis and treatment of patients presenting with melanuria. We present the case of a 47-year-old man presenting with melanuria and diffure melanosis cutis, who was eventually diagnosed with a BRAF-mutated metastatic melanoma of unknown primary. The patient was started on a BRAF and MEK inhibitor, but he had a rapid disease progression and succumbed to the disease. There is only a limited number of case reports of melanoma patients with melanuria receiving targeted therapies or immune checkpoint inhibitors. In these reports, variable treatment responses have been described. In view of the increasing significance of targeted therapies and immunotherapy for melanoma, more cases are needed to improve our understanding on the prognostic significance of melanuria in the era of novel therapies for melanoma., Competing Interests: Declaration of Competing Interest PD reports personal fees from Roche and Novartis, outside the submitted work. HG reports grants and personal fees from BMS, grants and personal fees from Roche, grants and personal fees from MSD, personal fees from Novartis, personal fees from Amgen, personal fees from Pierre Fabre, outside the submitted work. The remaining authors report no conflict of interests., (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Marching into the second decade after the approval of ipilimumab, it is clear that immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of melanoma. Although the current edge is already high, with a 4-year OS% of 77.9% for adjuvant nivolumab and a 6.5-year OS% of 49% for nivolumab/ipilimumab combination in the metastatic setting, a high proportion of patients with advanced melanoma have no benefit from immunotherapy, or experience an early disease relapse/progression in the first few months of treatment, surviving much less. Reasonably, the primary and acquired resistance to ICIs has entered into the focus of clinical research with positive (e.g., nivolumab and relatlimab combination) and negative feedbacks (e.g., nivolumab with pegylated-IL2, pembrolizumab with T-VEC, nivolumab with epacadostat, and combinatorial triplets of BRAF/MEK inhibitors with immunotherapy). Many intrinsic (intracellular or intra-tumoral) but also extrinsic (systematic) events are considered to be involved in the development of this resistance to ICIs: i) melanoma cell immunogenicity (e.g., tumor mutational burden, antigen-processing machinery and immunogenic cell death, neoantigen affinity and heterogeneity, genomic instability, melanoma dedifferentiation and phenotypic plasticity), ii) immune cell trafficking, T-cell priming, and cell death evasion, iii) melanoma neovascularization, cellular TME components(e.g., T regs , CAFs) and extracellular matrix modulation, iv) metabolic antagonism in the TME(highly glycolytic status, upregulated CD39/CD73/adenosine pathway, iDO-dependent tryptophan catabolism), v) T-cell exhaustion and negative immune checkpoints, and vi) gut microbiota. In the present overview, we discuss how these parameters compromise the efficacy of ICIs, with an emphasis on the lessons learned by the latest melanoma studies; and in parallel, we describe the main ongoing approaches to overcome the resistance to immunotherapy. Summarizing this information will improve the understanding of how these complicated dynamics contribute to immune escape and will help to develop more effective strategies on how anti-tumor immunity can surpass existing barriers of ICI-refractory melanoma., 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 © 2022 Elsevier Ltd. All rights reserved.)

Background: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF V600 -mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy., Patients and Methods: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers., Results: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

Background: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAF V600 wild-type advanced melanoma., Patients and Methods: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population., Results: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab., Conclusion: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF V600 wild-type advanced melanoma., Competing Interests: Disclosure HG reports honoraria payments from Merck Sharp & Dohme, Bristol Myers Squibb, and Novartis; consulting/advisory roles for Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Pierre Fabre, and Amgen; research funding from Merck Sharp & Dohme, Bristol Myers Squibb, and Roche; and travel/accommodations/expenses from Bristol Myers Squibb, Amgen, and Merck Sharp & Dohme. BD reports a consulting/advisory role for Roche. JL reports honoraria payments from, consulting/advisory roles for, and travel/accommodations/expenses from Achilles, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess; and research funding from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo. LD reports consulting/advisory roles for, speaker's bureau for, and travel/accommodations/expenses from Roche, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, and BIOCAD; and research funding from Roche, Novartis, Bristol Myers Squibb, BIOCAD, and Amgen. DS reports consulting/advisory roles for Bristol Myers Squibb, Roche, Merck Sharp & Dohme, and Novartis; travel/accommodations/expenses from Bristol Myers Squibb, Roche, and Merck Sharp & Dohme; and support from the NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre. ZE reports consulting/advisory roles for Array and Regeneron, and research funding from Novartis. PFF reports consulting/advisory roles for Bristol Myers Squibb, Roche, Merck Sharp & Dohme, and Novartis; and travel/accommodations/expenses from Bristol Myers Squibb, Roche, and Merck Sharp & Dohme. JP reports consulting/advisory roles for Bristol Myers Squibb and Merck Sharp & Dohme. PR reports honoraria payments from Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Pierre Fabre, Pfizer, and Eli Lilly; consulting/advisory roles for Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; travel/accommodations/expenses from Orphan Drugs; and officer/board of director's roles for the Polish Society of Surgical Oncology and the European Society of Medical Oncology. JM reports consulting/advisory roles for Bristol Myers Squibb and Merck Sharp & Dohme; speaker's bureau for Bristol Myers Squibb, GlaxoSmithKline, Roche, Merck Sharp & Dohme, and Novartis; and travel/accommodations/expenses from Bristol Myers Squibb, GlaxoSmithKline, Roche, Merck Sharp & Dohme, Novartis, and Pierre Fabre. IR reports employment with stock/stock options from, and travel/accommodations/expenses from Roche. AV reports employment with and stock/stock options from Roche. ST reports employment with Genentech. BP reports employment with Roche. YG reports employment with Genentech. YY reports employment with Genentech and stock/stock options from Roche. MC reports employment with Roche. SM reports employment with Roche and stock/stock options from Roche. KF reports consulting/advisory roles for X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Array BioPharma, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm; stock/stock options from Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals, X4 Pharmaceuticals, PIC Therapeutics, Fount, Shattuck Labs, Apricity, Oncoceutics, Fog Pharma, Tvardi, and xCures; research funding from Sanofi, Novartis, Array BioPharma, Bristol Myers Squibb, Merck, Takeda, and Debiopharm; and officer/board of directors roles for Clovis Oncology, Strata Oncology, Vivid Biosciences, and Checkmate Pharmaceuticals. AA reports consulting/advisory roles for and travel/accommodations/expenses from Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, and Merck., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript., Competing Interests: Disclosure AA consultancy to and travel support from Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Roche; PAA consultancy to Amgen, Array, Bristol-Myers Squibb, Genmab, Idera, Immunocore, Incyte, MedImmune, Merck Sharp & Dohme, NewLink Genetics, Novartis, Pierre Fabre, Roche Genentech, Sandoz, Sanofi, Sindax, Sun Pharma, Ultimovacs; contracted research for Array, Bristol-Myers Squibb, Roche; travel support from Merck Sharp & Dohme; CUB advisor to Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, Genmab, Pierre Fabre, Third Rock Ventures; research funding from Bristol-Myers Squibb, Novartis, NanoString; Stock ownership in Uniti Cars; cofounder of Immagene BV; VCS travel support from Bristol-Myers Squibb, Pierre Fabre; advisory boards for Pierre Fabre; invited speaker for Novartis, Merck-Serono, Sanofi; MD honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; travel support from Merck Sharp & Dohme, Novartis; access to virtual conference services from Merck Sharp & Dohme; RD consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, CatalYm, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Second Genome, Sun Pharma, Takeda; MBF advisory boards for Amgen, Array Bioscience, Bristol-Myers Squibb, Novartis, Pulse Bioscience, Sanofi; consultancy to Delcath Systems; CG-M travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; speaker honorarium from Bristol-Myers Squibb; HG consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme; JJG advisory relationships with Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi; JH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics; scientific advisory boards for Achilles Therapeutics, AIMM Therapeutics, Celsius Therapeutics, Immunocore, Neogene Therapeutics, Neon Therapeutics, Vaximm; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Neon Therapeutics; CH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca, Bristol-Myers Squibb, Inzyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; UK consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, Glycotope, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi; institutional research grants from AstraZeneca/Medimmune, Bayer; CL consultancy, advisory boards, speakers bureau and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; advisory board for Avantis Medical Systems; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; other honoraria from Incyte, Pierre Fabre, Pfizer; PL sponsored research for Bristol-Myers Squibb; speaker bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; paid advisor to Amgen, Bristol-Myers Squibb, MelaGenix, Merck Sharp & Dohme, Novartis, Pierre Fabre; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; IL sponsored research for Amgen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, Microgenics; travel support from Bristol-Myers Squibb, Roche; MM advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; research grants from Novartis, Roche; IM-R advisory boards for Amgen, Bioncotech, Bristol-Myers Squibb, Incyte, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi; travel and congress accommodation support from Bioncotech, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; OM honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; PN advisory boards and/or speakers bureau for AstraZeneca, Bristol-Myers Squibb, Immunocore, Ipsen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; BN advisory boards, public speaking and consultancy for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; research funding for institution from Merck-Serono, Novartis, Pfizer, Roche; ROB research grants from AstraZeneca; speaker honoraria from Pfizer, Roche; advisory boards for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme; SP grants, personal fees and nonfinancial support from Almirall, Sanofi, ISDIN, La Roche Posay; grants and personal fees from Amgen, Leo Pharma, OJER Pharma; nonfinancial support from Lilly, AbbVie; personal fees from Bristol-Myers Squibb; grants from Novartis, Sun Pharma, MELAGENICS, Castle; personal fees and nonfinancial support from Pfizer, Roche; CR consultancy to and/or advisory boards for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi; PR speakers bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; advisory boards for Amgen, Blueprint Medicines, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; BS honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre; VKS consultancy to and/or advisory boards for Bristol-Myers Squibb, Merck, Novartis, Regeneron; data safety monitoring boards for Array, Bristol-Myers Squibb, Novartis, Pfizer, Polynoma; HT advisory relationships with Bristol-Myers Squibb, Merck, Novartis, Roche/Genentech; research grants from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche/Genentech; AT travel and congress registration support from Agenus; AvA honoraria paid to institute for consultancy to and/or advisory boards for 4SC, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Pfizer, Novartis; institutional research grants from Amgen, Bristol-Myers Squibb, Novartis. All remaining authors have declared no conflict of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript., Competing Interests: Disclosure AA consultancy to and travel support from Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Roche; PAA consultancy to Amgen, Array, Bristol-Myers Squibb, Genmab, Idera, Immunocore, Incyte, MedImmune, Merck Sharp & Dohme, Newlinks Genetics, Novartis, Pierre Fabre, Roche Genentech, Sandoz, Sanofi, Sindax, Sun Pharma, Ultimovacs; contracted research for Array, Bristol-Myers Squibb, Roche; travel support from Merck Sharp & Dohme; CB adviser to Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, Genmab, Pierre Fabre, Third Rock Ventures; research funding from Bristol-Myers Squibb, Novartis, Nanostring; stock ownership in Uniti Cars; co-founder of Immagene BV; VCS travel support from Bristol-Myers Squibb, Pierre Fabre; advisory boards for Pierre Fabre; invited speaker for Novartis, Merck Serono, Sanofi; MD honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; travel support from Merck Sharp & Dohme, Novartis; access to virtual conference services from Merck Sharp & Dohme; RD consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, CatalYm, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Second Genome, Sun Pharma, Takeda; MF advisory boards for Amgen, Array Bioscience, Bristol-Myers Squibb, Novartis, Pulse Bioscience, Sanofi; consultancy to Delcath Systems; CG-M travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; speaker honorarium from Bristol-Myers Squibb; HG consultancy to and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme; J-JG advisory relationships with Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi; JH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics; scientific advisory boards for Achilles Therapeutics, AIMM Therapeutics, Celsius Therapeutics, Immunocore, Neogene Therapeutics, Neon Therapeutics, Vaximm; institutional research grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Neon Therapeutics; CH consultancy, advisory boards and/or lectures for Amgen, AstraZeneca, Bristol-Myers Squibb, Inzyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; UK consultancy, advisory boards and/or lectures for Amgen, AstraZeneca/Medimmune, Bayer, Bristol-Myers Squibb, Glycotope, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi; institutional research grants from AstraZeneca/Medimmune, Bayer; CL consultancy, advisory boards, speakers bureau and/or advisory relationships with Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; advisory board for Avantis Medical Systems; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; other honoraria from Incyte, Pierre Fabre, Pfizer; PL sponsored research for Bristol-Myers Squibb; speaker bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; paid advisor to Amgen, Bristol-Myers Squibb, MelaGenix, Merck Sharp & Dohme, Novartis, Pierre Fabre; travel support from Bristol-Myers Squibb, Merck Sharp & Dohme; IL sponsored research for Amgen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, Microgenics; travel support from Bristol-Myers Squibb, Roche; MM advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; research grants from Novartis, Roche; IM-R advisory boards for Amgen, Bioncotech, Bristol-Myers Squibb, Incyte, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi; travel and congress accommodation support from Bioncotech, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; OM honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche; PN advisory boards and/or speakers bureau for AstraZeneca, Bristol-Myers Squibb, Immunocore, Ipsen, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; BN advisory boards, public speaking and consultancy for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; research funding for institution from Merck Serono, Novartis, Pfizer, Roche; ROB research grants from AstraZeneca; speaker honoraria from Pfizer, Roche; advisory boards for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme; SP grants, personal fees and non-financial support from Almirall, Sanofi, ISDIN, La Roche Posay; grants and personal fees from Amgen, Leo Pharma, OJER Pharma; non-financial support from Lilly, AbbVie; personal fees from Bristol-Myers Squibb; grants from Novartis, Sun Pharma, Melagenics, Castle; personal fees and non-financial support from Pfizer, Roche; CR consultancy to and/or advisory boards for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi; PR speakers bureau for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; advisory boards for Amgen, Blueprint Medicines, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; BS honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche; grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre; VS consultancy to and/or advisory boards for Bristol-Myers Squibb, Merck, Novartis, Regeneron; data safety monitoring boards for Array, Bristol-Myers Squibb, Novartis, Pfizer, Polynoma; HT advisory relationships with Bristol-Myers Squibb, Merck, Novartis, Roche/Genentech; research grants from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche/Genentech; AT travel and congress registration support from Agenus; AvA honoraria paid to institute for consultancy to and/or advisory boards for 4SC, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck-Pfizer, Novartis; institutional research grants from Amgen, Bristol-Myers Squibb, Novartis; all remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAF V600 mutation-positive advanced or metastatic melanoma., Methods: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAF V600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients., Findings: Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events., Interpretation: The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAF V600 mutation-positive advanced melanoma., Funding: F Hoffmann-La Roche and Genentech., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Chemokines, cytokines in the immune microenvironment of tumors, may be associated with patient outcome. We assessed the impact of CXCL13 and CXCL9 on disease-free (DFS) and overall survival (OS), in an attempt to retrospectively evaluate both T and B cell function in the microenvironment of primary tumors from patients with breast cancer., Materials and Methods: Formalin-fixed paraffin-embedded tissue blocks from patients with intermediate/high-risk, early breast cancer, treated with sequential adjuvant epirubicin, paclitaxel, and cyclophosphamide methotrexate fluorouracil within a randomized trial, were tested for CXCL13 and CXCL9 messenger RNA expression; 557 patients with adequate tissue were eligible for the analysis., Results: CXCL13 was correlated with CXCL9 (rho = 0.52; P < .001). High-expressing CXL13 and CXCL9 tumors had higher Ki67 and tumor infiltrating lymphocyte density (P-values < .001). High CXCL9 expression was an unfavorable prognosticator for OS among all patients (hazard ratio [HR], 1.73; P = .021), whereas it showed favorable significance for both DFS and OS in patients with triple negative disease (HR, 0.29; P = .027 and HR, 0.32; P = .045). High CXCL13 conferred longer DFS and OS among patients with luminal-human epidermal growth factor receptor 2 disease (HR, 0.31; P = .013 and HR, 0.25; P = .005). Patients with low CXCL13 and high CXCL9 expression had shorter DFS and OS compared with those with high expression of both chemokines (HR, 1.63; P = .006 and HR, 1.61; P = .016)., Conclusions: Both biomarkers were associated with poor prognosis characteristics and with tumor infiltrating lymphocyte density. High CXCL9 conferred an improved prognosis in the triple negative subtype, whereas high CXCL13 was associated with improved outcome in the luminal-human epidermal growth factor receptor 2 subtype. Chemokines can be associated with breast cancer subtype and outcome. These data should be evaluated prospectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The prognostic/predictive value of aberrant MYC gene copies and protein expression is not clear in breast cancer., Patients and Methods: Early breast cancer patients were treated with anthracycline-containing chemotherapy within 2 randomized adjuvant trials. MYC gene and centromere-8 status, as well as Myc protein expression were investigated on 1060 paraffin tumors with fluorescence in situ hybridization and immunohistochemistry, respectively., Results: MYC amplification was present in 45% and polysomy-8 in 23% of the tumors. Cytoplasmic staining was observed in 60% and nuclear staining in 26% of the tumors, strongly correlating with each other but not with MYC gene status. MYC gene amplification in the absence of polysomy-8 was associated with adverse disease-free survival (DFS) and overall survival (OS), and remained as an independent unfavorable prognostic factor in multivariate analysis (Wald P = .022 for DFS; P = .032 for OS), whereas patients with MYC amplification and polysomy-8, with polysomy-8 only, and with normal MYC without polysomy-8 performed significantly better compared with those with MYC gene amplification only. Nuclear Myc protein expression benefitted patients treated with paclitaxel (interaction P = .052 for DFS; P = .049 for OS). This interaction remained independently significant in multivariate analysis for OS (overall P = .028)., Conclusion: The effect of MYC gene status on breast cancer patient outcome seems to depend on the underlying chromosomal instability and appears unfavorable for tumors with MYC amplification without polysomy. Nuclear Myc protein expression seems predictive for benefit from adjuvant paclitaxel. These data might aid in the interpretation of relevant findings from large clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients., Patients and Methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics., Results: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use., Conclusions: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Intensive chemotherapy confers benefit to patients with high-risk early breast cancer (BC). We characterized the feasibility and toxicity profile of anthracycline-containing adjuvant chemotherapy (ACAC) in older women with early BC., Patients and Methods: Available data from women who received ACAC for BC in 3 randomized trials were retrieved. We identified women aged >65 years and we examined differences in tolerability and delivery of chemotherapy, toxicity, and treatment outcome., Results: From a total of 2640 patients, we identified 453 patients (17%) as being >65 years old, 89% of whom had tumors that were node-positive, with 77% who were hormone receptor-positive. At least 90% of the planned doses were delivered in 37% of the elderly, compared with 49% in the younger patients (P < .0001). Grade 3 and 4 hematological toxicity was observed in 32% of elderly patients, compared with 21% of the younger (P < .0001). Febrile neutropenia occurred in 4.5% of the elderly patients, as opposed to 2.0% in the younger patients (P < .002). Elderly patients experienced more frequent Grade 3 and 4 fatigue, mucositis, and sensory neuropathy. Relative dose intensities were significantly lower in elderly patients. Treatment discontinuation was not different in the 2 groups. At a median follow-up of 120 months, competing risks analysis showed a significant benefit in disease-free survival for elderly patients., Conclusion: Elderly BC patients treated with ACAC derive clinical benefit comparable to that in younger patients, mainly at the cost of increased risk of hematological toxicity. This should be taken into account in decision-making and treatment individualization in high-risk BC patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Many single nucleotide polymorphisms (SNPs) have been described as putative risk factors for melanoma. The aim of our study was to validate the most prominent genetic risk loci in an independent Greek melanoma case-control dataset and to assess their cumulative effect solely or combined with established phenotypic risk factors on individualized risk prediction. We genotyped 59 SNPs in 800 patients and 800 controls and tested their association with melanoma using logistic regression analyses. We constructed a weighted genetic risk score (GRSGWS) based on SNPs that showed genome-wide significant (GWS) association with melanoma in previous studies and assessed their impact on risk prediction. Fifteen independent SNPs from 12 loci were significantly associated with melanoma (P < 0.05). Risk score analysis yielded an odds ratio of 1.36 per standard deviation increase of the GRSGWS (P = 1.1 × 10(-7)). Individuals in the highest 20% of the GRSGWS had a 1.88-fold increase in melanoma risk compared with those in the middle quintile. By adding the GRSGWS to a phenotypic risk model, the C-statistic increased from 0.764 to 0.775 (P = 0.007). In summary, the GRSGWS is associated with melanoma risk and achieves a modest improvement in risk prediction when added to a phenotypic risk model., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article., Methods: We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648., Findings: Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group., Interpretation: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing., Funding: GlaxoSmithKline., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients., Methods: Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C., Results: High UBE2C mRNA expression was associated with poor DFS (Wald's P = 0.003) and OS (Wald's P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05)., Conclusions: High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts.

Unlabelled: The CXCL13-CXCR5 is a chemokine axis that is activated in some breast cancers. A total of 321 tissue blocks from a group of patients who received adjuvant, dose-dense chemotherapy for high-risk early breast cancer were examined. Activation of this axis was found to be associated with determinants of poor prognosis but also with improved outcome in the human epidermal growth factor receptor 2 overexpressing subpopulation., Background: Chemokines are important in cell migration and are thought to play a key role in metastasis. We explored the prognostic significance of C-X-C ligand-motif (CXCL) 12, CXCL13, and receptor (CXCR) 5 on disease-free survival (DFS) and overall survival (OS) in early breast cancer., Methods: A total of 595 patients with high risk, [corrected] early breast cancer were treated in a 2-arm trial (HE10/97) with dose-dense sequential epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without paclitaxel. RNA was extracted from 321 formalin-fixed paraffin-embedded primary tumor tissue samples and quantitative reverse-transcriptase polymerase chain reaction was used to assess messenger RNA (mRNA) expression of CXCL12, CXCL13, and CXCR5; estrogen receptor; progesterone receptor (PgR); microtubule-associated protein tau and human epidermal growth factor receptor 2 (HER2)., Results: CXCL13 and CXCR5 were found to be negatively associated with estrogen receptor and microtubule-associated protein tau mRNA expression and with dense lymphocytic infiltration, and were positively associated with nuclear grade. Only CXCL13 was positively associated with HER2. Multivariate analysis revealed an association between high CXCL13 mRNA expression and improved DFS (hazard ratio [HR] 0.48 [95% CI, 0.25-0.90]; Wald, P = .023) but not OS; whereas high CXCL12 expression was significantly associated with increased OS (HR 0.53 [95% CI, 0.33-0.85]; Wald, P = .009). In the HER2 mRNA overexpressing subgroup, high CXCL13 mRNA expression was associated with improved DFS (P < .001), whereas high CXCR5 was associated with increased DFS and OS (P = .004 and P = .049, respectively)., Conclusions: The CXCL13-CXCR5 axis is associated with classic determinants of poor prognosis, such as high grade, hormone receptor negativity, and axillary node involvement. Interestingly, this chemokine axis seems to be strongly associated with improved outcome in patients with HER2(+) disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: The objective of this retrospective study was to describe the results from five institutions' experience of using Oncotype DX(®) to identify patients who need chemotherapy despite the presence of primarily favorable characteristics., Patients and Methods: Oncotype DX was performed in 106 pre- and postmenopausal patients with estrogen receptor-positive, HER2-negative, early breast cancer with a combination of favorable prognostic factors or favorable prognostic factors with at least one unfavorable characteristic (tumor size >2 cm, tumor grading of II-III, Ki-67 ≥ 10%, presence of lymph node micrometastases) in which it was unclear whether hormonal therapy only or chemotherapy plus hormonal therapy was the optimal adjuvant treatment., Results: Sixty-four (60.4%) women had Recurrence Score (RS) values <18, 29 (27.4%) intermediate RS values of 18-30, and 13 (12.3%) high RS values of ≥31. Tumor size, grading and presence of micrometastases were not associated with the RS. There was a significant association between Recurrence Score and the number of unfavorable characteristics as a categorical but not as a continuous variable. High Recurrence Scores were predictive of high Ki-67 but the converse was not true. Overall, 29 of 106 (27.4%) patients received chemotherapy because of an intermediate or a high Recurrence Score., Conclusion: The Recurrence Score helped in treatment decision-making for estrogen receptor-positive, HER2-negative patients with favorable characteristics or an intermediate risk of recurrence due to the presence of at least one unfavorable factor. The results of the 21-gene assay increased the likelihood for patients with intermediate clinical and histopathological risk factors receiving chemotherapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Disease dissemination is the major cause of melanoma-related death. A crucial step in the metastatic process is the intravascular invasion and circulation of melanoma cells in the bloodstream with subsequent development of distant micrometastases that is initially clinically undetectable and will eventually progress into clinically apparent metastasis. Therefore, the use of molecular methods to detect circulating melanoma cells may be of value in risk stratification and clinical management of such patients. Herein, we review the currently applied techniques for the detection, isolation, enrichment and further characterization of circulating melanoma cells from peripheral blood samples in melanoma patients. Furthermore, we provide a brief overview of the various molecular markers currently being evaluated as prognostic indicators of melanoma progression., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: This phase II study sought to evaluate the efficacy of the paclitaxel-carboplatin combination as neoadjuvant chemotherapy in patients with locally advanced breast cancer (LABC)., Patients and Methods: A total of 46 patients with LABC and inflammatory breast cancer (IBC) received 6 cycles of paclitaxel 175 mg/m2, followed by carboplatin, at an area under the curve of 6, before mastectomy. The primary endpoint constituted response to chemotherapy. We studied ERCC1 protein, microtubule-associated protein-tau, estrogen receptor, progesterone receptor, epidermal growth factor receptor (EGFR), HER2, and Ki-67 immunohistochemically in tissue microarray and whole-tissue sections. In addition, EGFR and HER2 gene status was assessed by fluorescence in situ hybridization. Predictive and prognostic molecular markers were retrospectively investigated., Results: A total of 42 female patients were considered eligible. Forty percent had IBC. Twenty-five patients (60%) experienced a clinical response, and 4 patients (9.5%) experienced a pathologic complete response. Chemotherapy was well tolerated. After a median follow-up of 45 months (range, 8.8-64.8 months), the estimated 3-year progression-free survival (PFS) was 54%, and the 3-year overall survival (OS) was 66%. The overexpression of EGFR protein was associated with a lower response rate (0 vs. 67%; P = .023), whereas high Ki-67 expression, high-grade tumors, tumor stage T4, and triple-negative tumors were associated with poorer PFS. Only high-grade tumors were associated with a significantly shorter OS (P = .004)., Conclusion: The combination of paclitaxel and carboplatin is an effective and well-tolerated regimen in female patients with LABC.

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques--DNA and RNA microarrays--have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers--lactate dehydrogenase, S100B and melanoma-inhibiting activity--as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the future.

The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing.

Background: The Greek substudy of the Tamoxifen and Exemestane Adjuvant Multicenter International trial compared the effect of exemestane on the lipid profile of postmenopausal, breast cancer patients to that of tamoxifen in the adjuvant setting., Patients and Methods: Lipidemic profile changes were studied in 142 postmenopausal patients randomized to receive either adjuvant exemestane (n=77) or tamoxifen (n=65). Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and serum triglyceride (TRG) levels were measured at baseline and then every 3 months for the first 12 months of treatment and at 18 and 24 months., Results: A trend for a reduction in TC was found in both treatment arms; however, TC and LDL levels were consistently and significantly decreased in tamoxifen arm only. The mean HDL level was higher for the tamoxifen arm compared with the exemestane arm across time. No significant trend was detected throughout the study period on TRG levels on either arm., Conclusions: Unlike tamoxifen's beneficial effect on TC and LDL levels, exemestane appears to have a neutral effect on lipidemic profile of postmenopausal, breast cancer patients. These data offer additional information with regard to the safety and tolerability of exemestane treatment in the adjuvant setting.

Background: A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented., Patients and Methods: From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments., Results: Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low., Conclusion: Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen.

Background: Solar radiation has been identified as a principal factor for the causation of melanoma, whereas changing lifestyle patterns associated with obesity and diabetes might also contribute to the increasing incidence of the malignancy. No study has investigated the role of leptin, a hormone whose levels increase in obesity and which has also been related to cancer., Patients and Methods: Fifty-five patients with incident melanomas and 165 age- and gender-matched healthy controls were interviewed on the basis of a questionnaire that covers phenotypic features, sociodemographic and medical history variables, lifestyle habits and frequency of consumption of major food groups. Anthropometrical measures were also recorded and blood samples were obtained for determination of serum leptin levels. Adjusted odds ratios (ORs) for melanoma risk were derived through multiple logistic regression analyses., Results: An excess melanoma risk was observed for sun sensitive individuals and those with high circulating levels of leptin (OR: 1.56, 95% confidence interval 1.07-2.28, P = 0.02), after controlling for obesity indices, diabetes mellitus and education. Increased physical exercise, lower alcohol consumption and plant food consumption seem to play a protective role against melanoma development., Conclusions: Melanoma risk was found to be positively associated with serum leptin levels and inversely with healthy lifestyle factors. The findings need to be confirmed in prospective studies.

Background: There is now increasing evidence that a constitutive expression of cyclooxygenase (COX)-2 plays a role in the development and progression of malignant epithelial tumors. Expression of COX-2 is seen in 93% of melanomas, as determined by immunohistochemistry. Temozolomide (TMZ) has demonstrated activity against melanoma and has been investigated as single agent or in combination. We designed a phase II study to assess the efficacy and toxicity of the combination of TMZ and celecoxib (a COX-2 inhibitor) in patients with advanced melanoma., Patients and Methods: From January 2003 to July 2004, 52 patients were enrolled in the study. Nineteen patients were M1a, six M1b and 27 M1c. Patients received TMZ 200 mg/m(2) per day p.o. for 5 consecutive days every 4 weeks and celecoxib 400 mg b.i.d. p.o. for a maximum of six cycles. Celecoxib was continued until progression., Results: The median age was 63 years. There were 29 males and 23 females. Among 50 assessable patients, there were 11 (21.5%) objective responses including five complete responses and six partial responses. Twenty patients (38.5%) had stabilization of their disease, and 19 (36.5%) progressed. The median time to progression was 4.6 months and the median survival 9.5 months. Twenty-two patients (41.5%) completed all cycles of treatment. Median relative dose intensity of TMZ was 0.99 (range 0.6-1.2). Most commonly seen toxic effects included anemia (27.5%), neutropenia (17.5%), thrombocytopenia (33%), nausea/vomiting (75%), gastrointestinal (52%) and fatigue (46.5%). One patient discontinued due to severe toxicity. COX-2 was determined by immunohistochemistry and was expressed in all cases., Conclusion: The combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma. Randomized studies are needed to explore the role of celecoxib in combination with chemotherapy or as maintenance treatment in these patients.

Purpose: To assess the prognostic and predictive significance of p53 and Bcl-2 protein expression in high risk patients with breast cancer treated with dose-dense sequential chemotherapy., Patients and Methods: From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (P) 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. p53 and Bcl-2 expression was investigated by immunohistochemistry in 392 and 397 patients respectively., Results: Positive expression of p53 was detected in 104 (26.5%) patients and was significantly associated with negative hormonal status, worse histologic grade, higher incidence of disease relapse and higher rate of death. p53 positive expression was a significant negative predictor of overall survival (OS) (P = 0.002) and disease-free survival (DFS) (P = 0.001). Negative expression of Bcl-2 was detected in 203 (51%) patients and was significantly associated with negative hormonal status. Multivariate analysis revealed that, positive p53 expression, higher number of positive nodes and worse tumor grade were related to significantly poorer OS and DFS., Conclusions: For both treatments, p53 positive expression was a significant negative prognostic factor for OS and DFS while Bcl-2 was not. No predictive ability of p53 status or Bcl-2 status for paclitaxel treatment was evident.

Individuals with melanocortin 1 receptor (MC1R) gene variants have been shown to carry an increased risk for the development of melanoma. In this study, we investigated the relationship of MC1R gene variants and the risk of melanoma in 123 melanoma patients and 155 control subjects from Greece. The entire MC1R gene was sequenced for polymorphisms and the results were correlated with host factors and pigmentary characteristics. MC1R polymorphisms were present in 59.4% of melanoma patients compared to 37.5% of controls, yielding an odds ratio (OR) of 2.43 (95% confidence interval (CI) = 1.50-3.96, P < 0.001) for melanoma among MC1R carriers. The risk of melanoma was enhanced in individuals carrying multiple variant alleles (OR = 6.97; 95% CI = 1.86-26.12, P = 0.004). Only the Val60Leu, Arg142His, and Arg151Cys variants were significantly associated with melanoma risk. In stratified analysis, the risk of melanoma among MC1R carriers was not influenced by skin phototype, skin color, or hair color. No association was found between MC1R genotype and the age of onset of melanoma, the tumor location, or the tumor thickness. In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.

Epidemiological, experimental and clinical data strongly support the possibility that breast cancer can be prevented by using anti-estrogenic interventions in healthy women. Four trials involving over 25,000 women have so far been reported using tamoxifen 20 mg/day or placebo in healthy women to chemoprevent breast cancer, and several trials utilizing raloxifene or aromatase inhibitors are underway. Interim analyses of the Royal Marsden tamoxifen trial and the Italian national trial showed no effect on the early incidence of breast cancer. The NSABP-P1 showed a 49% reduction in early incidence of breast cancer. This was associated with a reduction in osteoporotic fractures but increases in the risks of endometrial cancer, cataract and thromboembolism. The IBIS trial showed a 32% reduction with a two-fold increase in endometrial cancer and in thromboembolic events. Mortality rates of breast cancer in women receiving tamoxifen prophylactically should be monitored and further follow-up of these trials is needed to determine whether tamoxifen provides an overall health benefit or increase specific or overall survival of breast cancer. High-risk women should not be advised to take anti-estrogens outside of a clinical trial setting.

Purpose: The aim of this study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival (DFS) and secondarily on overall survival (OS) in patients with high-risk operable breast cancer., Patients and Methods: From June 1997 until November 2000, 604 patients with T1-3N1M0 or T3N0M0 tumors were randomized to three cycles of epirubicin 110 mg/m2 followed by three cycles of paclitaxel 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) (group A), or to four cycles of epirubicin followed by four cycles of CMF, as in group A (group B). All cycles were given every 2 weeks with granulocyte colony-stimulating factor support., Results: A total of 595 patients were eligible. Median follow-up was 61.7 months for group A and 62 months for group B. The 3-year DFS was 80% in group A and 77% in group B. Survival rates were 93% and 90%, respectively. The effect of treatment on the hazard of death was different according to hormonal receptor status. More specifically, in patients with negative receptor status the hazard of death was significantly higher for group B (hazard ratio 2.42). Both regimens were well tolerated and severe acute side-effects were infrequent. No cases of severe cardiotoxicity or acute leukemia were recorded., Conclusions: The present study failed to demonstrate a significant difference in DFS or OS between the two treatment groups. However, our study has shown clearly that high-dose paclitaxel can be safely incorporated to dose-dense sequential chemotherapy.

Purpose: Temozolomide (TMZ) is an oral alkylating agent that produces methyl adducts at the 0.6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (CDDP) is able to down-regulate the AGAT activity, suggesting that CDDP could enhance the antitumor activity of TMZ. We designed a randomized phase II study to evaluate and compare the activity and safety profile of the combination versus single-agent TMZ in patients with advanced melanoma., Patients and Methods: From January 2000 to April 2002, 132 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the two arms. Patients with cerebral metastases were included. Patients received TMZ 200 mg/m(2)/day orally for five consecutive days every 4 weeks or TMZ + CDDP 200 mg/m(2) daily on days 1-5 and 75 mg/m(2) of CDDP on day 1., Results: Tumor responses (complete and partial responses) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.8 months in arm A and 5.8 months in arm B. The median overall survival (OS) was 11.5 months in arm A and 12 months in arm B. The difference between treatment arms regarding objective response rates, TTP and OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralgias/myalgias. There was significantly more grade 3 and 4 emesis in the combination arm., Conclusions: No clear benefit in terms of response rates, median TTP or OS was shown with the combination of TMZ + CDDP. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis.

Background: In the present phase II multicenter study, we assessed the efficacy and tolerability of the combination of gemcitabine and carboplatin in patients with advanced pancreatic cancer., Patients and Methods: Patients with previously untreated, locally advanced or metastatic pancreatic cancer were treated with gemcitabine 800 mg/m(2) on days 1 and 8 and carboplatin at an AUC of 4 on day 8 of a 3-week cycle, for a total of six cycles. Primary end points were response rate and clinical benefit; secondary end points were, survival, time to progression (TTP) and toxicity., Results: A total of 50 patients were enrolled in the study, 47 of whom were eligible for treatment. The median age was 63 years (range 34-76) and the median Karnofsky performance status (PS) was 80%. Patients received a median of six cycles (range 1-11). Among 35 patients evaluable for response, eight (17%) achieved partial response; 15 (32%) and 12 (25%) patients had stable and progressive disease, respectively. The median overall survival was 7.4 months; the median TTP was 4.4 months and the 1-year survival was 28%. The observed clinical benefit response was remarkable. After the second cycle of chemotherapy, 21 of 31 (68%) patients experienced pain improvement and reduced analgesic consumption. At the same time, 35% and 56% of our patients significantly improved their Karnofsky PS and weight, respectively. Overall, the treatment was well tolerated. The most common grade 3-4 toxicities were hematological, including 8% anemia, 6% neutropenia and 13% thrombocytopenia., Conclusions: The combination of gemcitabine plus carboplatin is a moderately active treatment for patients with locally advanced and metastatic pancreatic cancer. This regimen has an acceptable toxicity profile and provides a significant clinical benefit, and hence warrants further investigation.

Background: To compare survival between patients with advanced breast cancer (ABC) treated with epirubicin/paclitaxel (Taxol) or paclitaxel/carboplatin (Cp) chemotherapy., Patients and Methods: From January 1999 to April 2002, 327 eligible patients with ABC were randomized to receive either paclitaxel 175 mg/m(2) in a 3-h infusion followed by epirubicin (EPI) 80 mg/m(2) (group A) or paclitaxel, as in group A, followed by Cp at an AUC of 6 mg x min/ml (group B) every 3 weeks for six cycles., Results: After a median follow-up of 23.5 months, median survival was not significantly different between the two groups (22.4 months versus 27.8 months, P=0.25), whereas median time to treatment failure was significantly longer in patients treated with paclitaxel/Cp (8.1 months in group A versus 10.8 months in group B, P=0.04). Both regimens were well tolerated. In total, 39 patients (24%) in group A and 46 (29%) in group B suffered at least one severe side-effect. Quality-of-life assessment and cost analysis did not reveal any significant differences between the two groups., Conclusion: Our study suggests that the paclitaxel/Cp combination is an effective therapeutic alternative for patients with ABC in which anthracycline administration has the potential of being harmful.

The incidence of central nervous system (CNS) metastases in patients with melanoma ranges from 10% to 40% in clinical studies and is even higher in autopsy series with as many as two-thirds of patients with metastatic melanoma having CNS involvement. Treatment options for patients with cerebral metastases are limited and depend largely on the number and the size of the lesions and on the extracranial extension of metastatic disease. This report gives the results of different treatment modalities in patients with melanoma metastases to the brain. As data from prospective randomized studies are lacking, the general recommendations based on clinical series reports are: (i) the combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. (ii) Radio surgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that the lesion's diameter does not exceed 3 cm. With the use of WBRT after surgery or radio surgery the local control seems better (with the combined approach), but the overall survival does not improve. (iii) WBRT alone or in combination with chemotherapy is the treatment of choice in patients with single brain metastasis not amenable to surgery or radio surgery, with an active systemic disease, and in patients with multiple brain metastases. Chemotherapy may be also offered to patients with a good performance status, or after recurrence to local therapy.

Background: This multicenter, prospective phase II study evaluated the safety and efficacy of the combination of docetaxel and vinorelbine in patients with platinum-resistant, paclitaxel-pretreated recurrent ovarian cancer., Patients and Methods: Treatment consisted of vinorelbine 25 mg/m(2) as a 20-min i.v. infusion (days 1 and 8), and docetaxel 70 mg/m(2), as a 1-h i.v. infusion (day 8). Granulocyte colony-stimulating factor support was administered prophylactically on days 12-16. Treatment was repeated every 21 days., Results: Forty-six patients were enrolled. The median number of previous chemotherapeutic regimens was one (range 1-3) with a median treatment-free interval of 4.3 months. Four chemotherapy cycles per patient were administered. Almost 75% of the planned doses for both drugs were given. Forty-one patients are evaluable for response. Three patients (6.5% of all patients; 7.3% of evaluable patients) achieved complete response and eight (17.4% and 19.5%, respectively) a partial response to chemotherapy, leading to overall response rates of 23.9% and 26.8%, respectively. Another 34.8% (39.0%) had stable disease. At a median follow-up of 30 months, the median disease-free survival was 13 months, relapse-free survival was 5 months, time to progression was 4.5 months, and overall survival was 9.3 months. Severe toxicities included leukopenia (31%), neutropenia (35%) and febrile neutropenia (20%)., Conclusions: The combination of docetaxel/vinorelbine is an effective regimen with manageable toxicity for the treatment of platinum-resistant, paclitaxel-pretreated ovarian cancer.

Despite the widespread use of trastuzumab in the management of patients with HER2-overexpressing metastatic breast cancer, its optimal duration of administration is unknown. We retrospectively reviewed the medical records of 80 such patients who received trastuzumab monotherapy or combination chemotherapy beyond disease progression in order to register their clinical course. Median age of the patients was 54 years. Ninety-one percent had 3+ HER2 overexpression and 9% had 2+ HER2 overexpression. Fifty-six percent of patients had previously been treated with chemotherapy for advanced disease. The most commonly used combinations in first- and second-line treatments were trastuzumab with paclitaxel and trastuzumab with vinorelbine, respectively. In total, 32 responses were observed, most of them during the second or third line of treatment. Severe toxicities frequently seen (in = 5% of patients) were neutropenia (25%), thrombocytopenia (11.5%), infection (10%), peripheral neuropathy (9%), nausea/vomiting (6%), stomatitis (6%), diarrhea (6%), constipation (6%), edema (6%), and myalgias/arthralgias (5%). Median survival from diagnosis of advanced disease was 43.4 months (range, 6.4-91.7+), whereas median survival from disease progression after trastuzumab administration was 22.2 months (range, 0.01-32.9+). In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic breast cancer is feasible and safe. Randomized studies are warranted.

Background: To determine the activity and safety of the combination of paclitaxel and pegylated liposomal doxorubicin (Caelyx) in patients with locally advanced breast cancer., Patients and Methods: This was a multicenter phase II study. Thirty-five newly diagnosed patients with locally advanced breast cancer were included in the study. Histological or cytological diagnosis was necessary for inclusion. Median age was 54 years (range 26-73 years). Fifteen patients were premenopausal and 20 postmenopausal. Paclitaxel was administered at a dose of 175 mg/m(2) and pegylated liposomal doxorubicin 35 mg/m(2) every 3 weeks for six cycles., Results: Twenty-five patients (71%) responded. Six (17%) had a complete response, 19 (54%) had a partial response, four remained stable, two progressed and four were not evaluated for response due to discontinuation of chemotherapy. Three patients had a pathologically complete response. A total of 173 cycles were administered. The primary toxicity observed was skin toxicity. Grade 3 skin toxicity was noted in four patients (11%). Palmar-plantar erythrodysesthesia (PPE) grade 3 was experienced by three (9%). Two patients presented with PPE and skin toxicity. Hematological toxicities included grade 3 leukopenia in four patients (3%). Other grade 3 toxicities were uncommon and included only alopecia in 29 patients (83%). Grade 3 or 4 neurotoxicity was not observed in any patient. Dose reduction was necessary in seven patients; in six due to skin toxicity and in one due to neutropenia. Four patients discontinued treatment due to skin toxicity. There were no treatment-related deaths., Conclusions: The combination of pegylated liposomal doxorubicin and paclitaxel was active in locally advanced breast cancer. The primary toxicity was cutaneous toxicity and it was manageable.

Aim: To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC)., Background: Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC., Patients and Methods: From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells., Results: Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached, Conclusions: The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.

Background: Adenocarcinoma of unknown primary comprises up to 10% of metastatic malignant disease. With few exceptions this diagnosis carries a very poor prognosis of a few months with minimal survival advantage to chemotherapy. However there is the possibility that chemotherapy can improve symptom control and quality of life., Patients and Methods: Forty-four patients with adenocarcinoma of unknown primary received CFTam chemotherapy regimen (5-FU 750 mg/m2/day by protracted infusion for five days, cisplatin 60 mg/m2 once and tamoxifen 20 mg daily on a 21-day cycle). Disease response and toxicity were collected and survival compared to patients who were not treated or who received different chemotherapy regimens., Results: Overall response to CFTam was 27% with a median duration of 10 months (range 4-26 months). The chemotherapy was well tolerated with no grade 4 non-haematological toxicity and only three patients (7%) grade 4 neutropaenia with only two (5%) patients developing sepsis. There were no toxic deaths. Performance status was maintained or improved in responders., Conclusions: CFTam is a well tolerated chemotherapy regimen with similar efficacy to other regimens described in the treatment of adenocarcinoma of unknown primary. In the absence of a significant survival advantage there is a need to conduct randomised trials of chemotherapy versus best supportive care to quantify any improvement in quality of life or symptom control.

Background: Bone-marrow micrometastases have been found in patients with primary breast cancer. We report long-term follow-up of women with primary breast cancer, diagnosed between 1981 and 1986, who had multiple aspirates taken at the time of initial surgery., Methods: 350 women with primary breast cancer were examined immunocytochemically with antibody to epithelial membrane antigen. We investigated associations with various prognostic factors as well as the effect of micrometastases on relapse-free survival and overall survival., Findings: At median follow-up of 12.5 years, 151 patients had metastatic disease and 136 patients had died from breast cancer. 10-year relapse-free and overall survival were 43.9% (95% CI 33.4-54.7) and 44.9% (34.2-55.9) in patients with micrometastases, and 62.7% (56.5-68.6) and 65.7% (59.4-71.5) in patients without micrometastases at presentation (p<0.001). For relapse-free survival and overall survival, allowing for tumour size, lymph-node status, and vascular invasion, the effect of micrometastases decreased and was no longer significant, with a hazard ratio of 1.09 (0.74-1.61) for relapse-free survival and 1.21 (0.84-1.75) for overall survival., Interpretation: The presence of bone-marrow micrometastases in patients with primary breast cancer is associated with a shorter relapse-free survival and overall survival, but is not an independent prognostic factor. This immunocytochemical technique may be of value in patients for whom pathological tumour size and lymph-node status are unavailable (ie, patients receiving primary medical treatment).

We report a case of meningioma subsequently developed in a patient with bilateral breast carcinoma, which was originally thought to be single brain metastases. A brief review of the literature is presented with emphasis on the unique association between the two neoplasms, which suggests a possible hormonal relationship. The knowledge of this association is important in the differential diagnosis of patients with breast cancer who develop central nervous system manifestations.