Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

Clinical utility of a molecular test in adjuvant treatment decision making in women with endocrine-sensitive early stage breast cancer: a retrospective, single center one year experience

Background. Molecular tests for breast cancer (BC) risk assessment are reimbursed by health insurances in Switzerland since the beginning of year 2015. The main current role of these tests is to help oncologists to decide about the usefulness of adjuvant chemotherapy in patients with early stage endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-negative BC. These gene expression signatures aim at predicting the risk of recurrence in this subgroup. One of them (OncotypeDx/OT) also predicts distant metastases rate with or without the addition of cytotoxic chemotherapy to endocrine therapy. The clinical utility of these tests -in addition to existing so-called "clinico-pathological" prognostic and predictive criteria (e.g. stage, grade, biomarkers status)-is still debated. We report a single center one year experience of the use of one molecular test (OT) in clinical decision making. Methods. We extracted from the CHUV Breast Cancer Center data base the total number of BC cases with estrogen-receptor positive (ER+), HER2-negative early breast cancer (node negative (pN0) disease or micrometastases in up to 3 lymph nodes) operated between September 2014 and August 2015. For the cases from this group in which a molecular test had been decided by the tumor board, we collected the clinicopathologic parameters, the initial tumor board decision, and the final adjuvant systemic therapy decision. Results. A molecular test (OT) was done in 12.2% of patients with ER + HER2 negative early BC. The median age was 57.4 years and the median invasive tumor size was 1.7 cm. These patients were classified by ODX testing (Recurrence Score) into low-, intermediate-, and high risk groups, respectively in 27.2%, 63.6% and 9% of cases. Treatment recommendations changed in 18.2%, predominantly from chemotherapyendocrine therapy to endocrine treatment alone. Of 8 patients originally recommended chemotherapy, 25% were recommended endocrine treatment alone after receiving the Recurrence Score result. Conclusions. Though reimbursed by health insurances since January 2015, molecular tests are used moderately in our institution as per the decision of the multidisciplinary tumor board. It's mainly used to obtain a complementary confirmation supporting the decision of no chemotherapy. The OncotypeDx Recurrence Score results were in the intermediate group in 66% of the 9 tested cases but contributed to avoid chemotherapy in 2 patients during the last 12 months.

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Development of a population-based cost-effectiveness model of chronic graft versus host disease in Spain

Chronic graft-versus-host disease (cGvHD) is the leading cause of late nonrelapse mortality (transplant-related mortality) after hematopoietic stem cell transplant. Given that there are a wide range of treatment options for cGvHD, assessment of the associated costs and efficacy can help clinicians and health care providers allocate health care resources more efficiently. OBJECTIVE: The purpose of this study was to assess the cost-effectiveness of extracorporeal photopheresis (ECP) compared with rituximab (Rmb) and with imatinib (Imt) in patients with cGvHD at 5 years from the perspective of the Spanish National Health System. METHODS: The model assessed the incremental cost-effectiveness/utility ratio of ECP versus Rmb or Imt for 1000 hypothetical patients by using microsimulation cost-effectiveness techniques. Model probabilities were obtained from the literature. Treatment pathways and adverse events were evaluated taking clinical opinion and published reports into consideration. Local data on costs (2010 Euros) and health care resources utilization were validated by the clinical authors. Probabilistic sensitivity analyses were used to assess the robustness of the model. RESULTS: The greater efficacy of ECP resulted in a gain of 0.011 to 0.024 quality-adjusted life-year in the first year and 0.062 to 0.094 at year 5 compared with Rmb or Imt. The results showed that the higher acquisition cost of ECP versus Imt was compensated for at 9 months by greater efficacy; this higher cost was partially compensated for ( 517) by year 5 versus Rmb. After 9 months, ECP was dominant (cheaper and more effective) compared with Imt. The incremental cost-effectiveness ratio of ECP versus Rmb was 29,646 per life-year gained and 24,442 per quality-adjusted life-year gained at year 2.5. Probabilistic sensitivity analysis confirmed the results. The main study limitation was that to assess relative treatment effects, only small studies were available for indirect comparison. CONCLUSION: ECP as a third-line therapy for cGvHD is a more cost-effective strategy than Rmb or Imt.

Cost-effectiveness analysis of cardiac resynchronization therapy in patients with NYHA I and NYHA II heart failure in Spain

Objectives: The aim of the study was to combine clinical results from the European Cohort of the REVERSE study and costs associated with the addition of cardiac resynchronization therapy (CRT) to optimal medical therapy (OMT) in patients with mild symptomatic (NYHA I-II) or asymptomatic left ventricular dysfunction and markers of cardiac dyssynchrony in Spain. Methods: A Markov model was developed with CRT + OMT (CRT-ON) versus OMT only (CRT-OFF) based on a retrospective cost-effectiveness analysis. Raw data was derived from literature and expert opinion, reflecting clinical and economic consequences of patient"s management in Spain. Time horizon was 10 years. Both costs (euro 2010) and effects were discounted at 3 percent per annum. Results: CRT-ON showed higher total costs than CRT-OFF; however, CRT reduced the length of hospitalization in ICU by 94 percent (0.006 versus 0.091 days) and general ward in by 34 percent (0.705 versus 1.076 days). Surviving CRT-ON patients (88.2 percent versus 77.5 percent) remained in better functional class longer, and they achieved an improvement of 0.9 life years (LYGs) and 0.77 years quality-adjusted life years (QALYs). CRT-ON proved to be cost-effective after 6 years, except for the 7th year due to battery depletion. At 10 years, the results were 18,431 per LYG and 21,500 per QALY gained. Probabilistic sensitivity analysis showed CRT-ON was cost-effective in 75.4 percent of the cases at 10 years. Conclusions: The use of CRT added to OMT represents an efficient use of resources in patients suffering from heart failure in NYHA functional classes I and II.

Cost-effectiveness of Tenofovir / Emtricitabine / Efavirenz versus Zidovudine / Lamivudine / Efavirenz as fist-line regimens for the treatment of HIV-infected patients in low-income settings

The Highly Active Antiretroviral Therapy (HAART) is the combination of at least three antiretroviral compounds. The combination purpose is to reduce the likelihood of drug resistance. However in the long-term the resistance to the first-line combination occurs and leads to treatment failure. Thus, a second-line and even a third-line regimen are recommended in the long run. [...] [P. 5] The two treatment alternatives under comparison: Tenofovir (300 mg) CO-formulated with Emtricitabine (200 mg) and Efavirenz (600 mg) currently known under the brand name Atripla (R) was introduced in July 2006 in the United States market. The excellent safety profile and ease of use make this combination a perfect first-line regimen in low-income settings. Therefore, this treatment option was recommended in WHO 2006 reviewed guidelines. Unfortunately, Tenofovir and Emtricitabine compounds are still costly and not yet widely available. For a matter of simplification this regimen is referred in this report as "the recent" therapy. Initially, we had in mind to consider the most frequently used first-line regimen in low-income countries (Stavudine / Larnivudme / Nevirapine) as a comparator for this economic evaluation. Unfortunately, according to the literature review results (see Annex 3); there was no data available comparing head to head the effectiveness of this regimen with the recent one. Instead, we selected a less frequently but commonly used first-line regimen in low-income countries as a comparator: Zidovudine, Lamivudine, Efavirenz. This combination has extensive experience in durability, safety and toxicity and seems to be an optimal choice for a first-line regimen according to the clinical trial group 384 team. Furthermore, Zidovudine, one of the compounds of this combination is now recommended as one of the preferred NNRTI [Non Nucleoside Reverse Transcriptase Inhibitors] options to be considered by countries instead of Stavudine (the most used NNRTI in limited-income countries). As this combination has been included in the WHO guidelines as a first-line therapy since 2003 when WHO launched the "3 by 5" scaling-up initiative, this combination of drugs is referred in this report as the "old" therapy. Objectives: The primary objective of this economic evaluation is to compare the two first-line HAARTs introduced above, in a low-income setting context. Both of these combinations are recommended by the 2006 WHO guidelines as potential first-line regimens. The secondary objective is to provide a simplified and comprehensible cost-effectiveness modeling tool in order to help policy makers, in resource-limited settings, make decisions about which first-line HAART to fund using the scarce resources available. [P. 6-7]

L'échographie dans le dépistage du cancer du sein: un outil efficace dans un dépistage personnalisé [Ultrasound for Breast Cancer Screening: an Effective Tool in a Personalized Screening].

Screening mammography is the only imaging modality with proved decrease in breast cancer mortality. Ultrasound has been proposed as additional tool for screening. Controversies remain about the real value of sonography in this setting. In Caucasian women with dense breast, sonography improves significantly breast cancer detection, but also increases the false positive cases, biopsies and costs. A careful selection of women who may benefit from additional screening with sonography is mandatory.

Axillary ultrasound and fine-needle aspiration in preoperative staging of axillary lymph nodes in patients with invasive breast cancer

Abstract Objective: To propose an algorithm to determine the necessity for ultrasonography-guided fine-needle aspiration (US-FNA) in preoperative axillary lymph node staging of patients with invasive breast cancer. Materials and Methods: Prospective study developed at National Cancer Institute. The study sample included 100 female patients with breast cancer referred for axillary staging by US-FNA. Results: The overall US-FNA sensitivity was set at 79.4%. The positive predictive value was calculated to be 100%, and the negative predictive value, 69.5%. The US-FNA sensitivity for lymph nodes with normal sonographic features was 0%, while for indeterminate lymph nodes it was 80% and, for suspicious lymph nodes, 90.5%. In the assessment of invasive breast tumors stages T1, T2 and T3, the sensitivity was respectively 69.6%, 83.7% and 100%. US-FNA could avoid sentinel node biopsy in 54% of cases. Conclusion: Axillary ultrasonography should be included in the preoperative staging of all patients with invasive breast cancer. The addition of US-FNA in cases of lymph nodes suspicious for malignancy may prevent more than 50% of sentinel lymphadenectomies, significantly shortening the time interval to definitive therapy.

Balloon-based adjuvant radiotherapy in breast cancer: comparison between 99mTc and HDR 192Ir

Abstract Objective: To perform a comparative dosimetric analysis, based on computer simulations, of temporary balloon implants with 99mTc and balloon brachytherapy with high-dose-rate (HDR) 192Ir, as boosts to radiotherapy. We hypothesized that the two techniques would produce equivalent doses under pre-established conditions of activity and exposure time. Materials and Methods: Simulations of implants with 99mTc-filled and HDR 192Ir-filled balloons were performed with the Siscodes/MCNP5, modeling in voxels a magnetic resonance imaging set related to a young female. Spatial dose rate distributions were determined. In the dosimetric analysis of the protocols, the exposure time and the level of activity required were specified. Results: The 99mTc balloon presented a weighted dose rate in the tumor bed of 0.428 cGy.h-1.mCi-1 and 0.190 cGyh-1.mCi-1 at the balloon surface and at 8-10 mm from the surface, respectively, compared with 0.499 and 0.150 cGyh-1.mCi-1, respectively, for the HDR 192Ir balloon. An exposure time of 24 hours was required for the 99mTc balloon to produce a boost of 10.14 Gy with 1.0 Ci, whereas only 24 minutes with 10.0 Ci segments were required for the HDR 192Ir balloon to produce a boost of 5.14 Gy at the same reference point, or 10.28 Gy in two 24-minutes fractions. Conclusion: Temporary 99mTc balloon implantation is an attractive option for adjuvant radiotherapy in breast cancer, because of its availability, economic viability, and similar dosimetry in comparison with the use of HDR 192Ir balloon implantation, which is the current standard in clinical practice.

Identification of molecular subtypes and gene expression patterns of breast cancer analysing RNA-seq data

Breast cancer is the most common diagnosed cancer and the leading cause of cancer death among females worldwide. It is considered a highly heterogeneous disease and it must be classified into more homogeneous groups. Hence, the purpose of this study was to classify breast tumors based on variations in gene expression patterns derived from RNA sequencing by using different class discovery methods. 42 breast tumors paired-samples were sequenced by Illumine Genome Analyzer and the data was analyzed and prepared by TopHat2 and htseq-count. As reported previously, breast cancer could be grouped into five main groups known as basal epithelial-like group, HER2 group, normal breast-like group and two Luminal groups with a distinctive expression profile. Classifying breast tumor samples by using PAM50 method, the most common subtype was Luminal B and was significantly associated with ESR1 and ERBB2 high expression. Luminal A subtype had ESR1 and SLC39A6 significant high expression, whereas HER2 subtype had a high expression of ERBB2 and CNNE1 genes and low luminal epithelial gene expression. Basal-like and normal-like subtypes were associated with low expression of ESR1, PgR and HER2, and had significant high expression of cytokeratins 5 and 17. Our results were similar compared with TGCA breast cancer data results and with known studies related with breast cancer classification. Classifying breast tumors could add significant prognostic and predictive information to standard parameters, and moreover, identify marker genes for each subtype to find a better therapy for patients with breast cancer.

Core communication components along the cancer care process: the perspective of breast cancer patients

This study sought to assess the impact of health care professional (HCP) communication on breast cancer patients across the acute care process as perceived by patients. Methodological approach was based on eight focus groups conducted with a sample of patients (n ¼ 37) drawn from 15 Spanish Regions; thematic analysis was undertaken using the National Cancer Institute (NCI) framework of HCP communication as the theoretical basis. Relevant results of this study were the identification of four main communication components: (1) reassurance in coping with uncertainty after symptom detection and prompt access until confirmed diagnosis; (2) fostering involvement before delivering treatments, by anticipating information on practical and emotional illness-related issues; (3) guidance on the different therapeutic options, through use of clinical scenarios; and, (4) eliciting the feeling of emotional exhaustion after ending treatments and addressing the management of potential treatment-related effects. These communication-related components highlighted the need for a comprehensive approach in this area of cancer care

Synergism between dipyridamole and cisplatin in human breast cancer cells in vitro

Cisplatin is very effective in the treatment of metastatic breast cancer. However, the development of cellular resistance is a serious problem in cisplatin chemotherapy. In the present work, the effects of dipyridamole (DPM) on the cellular accumulation and cytotoxicity of cisplatin was studied in cisplatinsensitive (MDA/S) and cisplatinresistant (MDA/R) human breast cancer cells. In the presence of 30 µM DPM, the IC50 of cisplatin was reduced by 39% for both cell lines. Combination index analysis revealed that cisplatin and dipyridamole interact synergistically in MDA/R cells. In the MDA/S cells, the cellular accumulation of cisplatin increased by 57 ± 8% in the presence of 30 µM DPM. In the MDA/R cells, the cellular accumulation of cisplatin remained the same with or without 30 µM DPM. The results suggest that the enhancement of cisplatin cytotoxicity by DPM in MDA/S cells may be related to a DPM-induced increase in cisplatin accumulation, but the enhanced cytotoxicity in MDA/R cells employs a mechanism that does not involve an increase in the cellular accumulation of cisplatin.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia

Estimation of lung cancer diagnosis and treatment costs based on a patient-level analysis in Catalonia (Spain)

Background: Assessing of the costs of treating disease is necessary to demonstrate cost-effectiveness and to estimate the budget impact of new interventions and therapeutic innovations. However, there are few comprehensive studies on resource use and costs associated with lung cancer patients in clinical practice in Spain or internationally. The aim of this paper was to assess the hospital cost associated with lung cancer diagnosis and treatment by histology, type of cost and stage at diagnosis in the Spanish National Health Service. Methods: A retrospective, descriptive analysis on resource use and a direct medical cost analysis were performed. Resource utilisation data were collected by means of patient files from nine teaching hospitals. From a hospital budget impact perspective, the aggregate and mean costs per patient were calculated over the first three years following diagnosis or up to death. Both aggregate and mean costs per patient were analysed by histology, stage at diagnosis and cost type. Results: A total of 232 cases of lung cancer were analysed, of which 74.1% corresponded to non-small cell lung cancer (NSCLC) and 11.2% to small cell lung cancer (SCLC); 14.7% had no cytohistologic confirmation. The mean cost per patient in NSCLC ranged from 13,218 Euros in Stage III to 16,120 Euros in Stage II. The main cost components were chemotherapy (29.5%) and surgery (22.8%). Advanced disease stages were associated with a decrease in the relative weight of surgical and inpatient care costs but an increase in chemotherapy costs. In SCLC patients, the mean cost per patient was 15,418 Euros for limited disease and 12,482 Euros for extensive disease. The main cost components were chemotherapy (36.1%) and other inpatient costs (28.7%). In both groups, the Kruskall-Wallis test did not show statistically significant differences in mean cost per patient between stages. Conclusions: This study provides the costs of lung cancer treatment based on patient file reviews, with chemotherapy and surgery accounting for the major components of costs. This cost analysis is a baseline study that will provide a useful source of information for future studies on cost-effectiveness and on the budget impact of different therapeutic innovations in Spain.