Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial

<p>Abstract</p> <p>Background</p> <p>Adjuvant trastuzumab (Herceptin) treatment of breast cancer patients significantly improves their clinical outcome. Vaccination is an attractive alternative approach to provide HER-2/neu (Her2)-specific antibodies and may in addition concomitantly stimulate Her2-reactive T-cells. Here we report the first administration of a Her2-plasmid DNA (pDNA) vaccine in humans.</p> <p>Patients and Methods</p> <p>The vaccine, encoding a full-length signaling-deficient version of the oncogene Her2, was administered together with low doses of GM-CSF and IL-2 to patients with metastatic Her2-expressing breast carcinoma who were also treated with trastuzumab. Six of eight enrolled patients completed all three vaccine cycles. In the remaining two patients treatment was discontinued after one vaccine cycle due to rapid tumor progression or disease-related complications. The primary objective was the evaluation of safety and tolerability of the vaccine regimen. As a secondary objective, treatment-induced Her2-specific immunity was monitored by measuring antibody production as well as T-cell proliferation and cytokine production in response to Her2-derived antigens.</p> <p>Results</p> <p>No clinical manifestations of acute toxicity, autoimmunity or cardiotoxicity were observed after administration of Her2-pDNA in combination with GM-CSF, IL-2 and trastuzumab. No specific T-cell proliferation following <it>in vitro </it>stimulation of freshly isolated PBMC with recombinant human Her2 protein was induced by the vaccination. Immediately after all three cycles of vaccination no or even decreased CD4⁺T-cell responses towards Her2-derived peptide epitopes were observed, but a significant increase of MHC class II restricted T-cell responses to Her2 was detected at long term follow-up. Since concurrent trastuzumab therapy was permitted, λ-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab. Her2-pDNA vaccination induced and boosted Her2-specific antibodies that could be detected for several years after the last vaccine administration in a subgroup of patients.</p> <p>Conclusion</p> <p>This pilot clinical trial demonstrates that Her2-pDNA vaccination in conjunction with GM-CSF and IL-2 administration is safe, well tolerated and can induce long-lasting cellular and humoral immune responses against Her2 in patients with advanced breast cancer.</p> <p>Trial registration</p> <p>The trial registration number at the Swedish Medical Products Agency for this trial is Dnr151:785/2001.</p

Transcriptional profiling of breast cancer metastases identifies liver metastasis-selective genes associated with adverse outcome in luminal A primary breast cancer.

The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis

Mammography-based screening program: preliminary results from a first 2-year round in a Brazilian region using mobile and fixed units

RLH, TBS and ALF made substantial contributions to the conception and design of the article, the acquisition, analysis and interpretation of the data, and drafting of the article. ECM, JSCM and NB made substantial contributions to the conception and design of the study.Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths among women worldwide. The use of mobile mammography units to offer screening to women living in remote areas is a rational strategy to increase the number of women examined. This study aimed to evaluate results from the first 2 years of a government-organized mammography screening program implemented with a mobile unit (MU) and a fixed unit (FU) in a rural county in Brazil. The program offered breast cancer screening to women living in Barretos and the surrounding area. Methods: Based on epidemiologic data, 54 238 women, aged 40 to 69 years, were eligible for breast cancer screening. The study included women examined from April 1, 2003 to March 31, 2005. The chi-square test and Bonferroni correction analyses were used to evaluate the frequencies of tumors and the importance of clinical parameters and tumor characteristics. Significance was set at p < 0.05. Results: Overall, 17 964 women underwent mammography. This represented 33.1% of eligible women in the area. A mean of 18.6 and 26.3 women per day were examined in the FU and MU, respectively. Seventy six patients were diagnosed with breast cancer (41 (54%) in the MU). This represented 4.2 cases of breast cancer per 1000 examinations. The number of cancers detected was significantly higher in women aged 60 to 69 years than in those aged 50 to 59 years (p < 0.001) or 40 to 49 years (p < 0.001). No difference was observed between women aged 40 to 49 years and those aged 50 to 59 years (p = 0.164). The proportion of tumors in the early (EC 0 and EC I) and advanced (CS III and CS IV) stages of development were 43.4% and 15.8%, respectively. Conclusions: Preliminary results indicate that this mammography screening program is feasible for implementation in a rural Brazilian territory and favor program continuation

Prognosis of screen-detected breast cancers: results of a population based study

BACKGROUND: The reduced mortality rate from breast carcinoma among women offered screening mammography is demonstrated after 15–20 years of follow-up. However, the assessment of 5-year overall and event-free survival could represent an earlier measure of the efficacy of mammography screening program (MSP). METHODS: All cases of breast cancer diagnosed in the Province of Modena between years 1996 and 2000 in women aged 50 to 69 years, were identified through the Modena Cancer Registry (MCR). Stage of disease and treatment information were obtained from clinical records. All the events occurring up to June 30, 2003 were retrieved by experienced monitors. Five-year overall and event-free survival were the principal end-points of the study. RESULTS: During a 5-year period, 587 primary breast cancers were detected by the MSP and 471 primary breast cancers were diagnosed out of the MSP. The screen-detected breast cancers were smaller, more likely node negative, with low histological grade, low proliferative activity and positive receptors status. Furthermore, the breast cancer diagnosed through the MSP more frequently received a conservative surgery. The 5-year survival rate was 94% in the screen-detected group, versus 84% in the other group (p = 0.0001). The rate of 5-year event-free survival was 89% and 75% for the MSP participants and not participants, respectively (p = 0.0001). CONCLUSIONS: Our data confirm a favourable outcome of screen-detected breast cancers in terms of five-year overall and event-free survival, which reflect the good quality assurance parameters of the MSP. Finally, a cancer registry should be implemented in every area covered by screening programs

Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas

BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.Peer reviewe

Should women under 50 be screened for breast cancer?

Should women under 50 be screened for breast cancer? Despite some controversy in recent years, the majority of experts agree on the evidence for effectiveness of breast screening by mammography for women aged 50 years and above, but for those under 50 years, the picture is much less clear. However, the issue remains of importance both to policy makers and to individual women; although the incidence of breast cancer is lower at younger ages, the life years lost due to cancers diagnosed below 50 years amount to a third of all those lost due to the disease