Advancing HER2-low breast cancer management: enhancing diagnosis and treatment strategies.

BACKGROUND: Recent evidence brought by novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates is leading to significant changes in HER2-negative breast cancer (BC) best practices. A new targetable category termed 'HER2-low' has been identified in tumors previously classified as 'HER2-negative'. Daily practice in pathology and medical oncology is expected to align to current recommendations, but patient access to novel anticancer drugs across geographies might be impeded due to local challenges. MATERIALS AND METHODS: An expert meeting involving ten regional pathology and oncology opinion leaders experienced in BC management in four Central and Eastern Europe (CEE) countries (Bulgaria, Croatia, Serbia, Slovenia) was held. Herein we summarized the current situation of HER2-low metastatic BC (mBC), local challenges, and action plans to prevent delays in patient access to testing and treatment based on expert opinion. RESULTS: Gaps and differences at multiple levels were identified across the four countries. These included variability in the local HER2-low epidemiology data, certification of pathology laboratories and quality control, and reimbursement conditions of testing and anticancer drugs for HER2-negative mBC. While clinical decisions were aligned to international guidelines in use, optimal access to testing and innovative treatment was restricted due to significant delays in reimbursement or limitative reimbursement conditions. CONCLUSIONS: Preventing delays in HER2-low mBC patient access to diagnosis and novel treatments is crucial to optimize outcomes. Multidisciplinary joint efforts and pro-active discussions between clinicians and decision makers are needed to improve care of HER2-low mBC patients in CEE countries.

Abemaciclib for the Treatment of HR+HER2- Metastatic Breast Cancer: An Institutional Experience.

(1) Background: Abemaciclib combined with endocrine therapy is a standard first- or later-line of treatment for HR+/HER2- metastatic breast cancer (MBC). The aim of this retrospective cohort study was to describe the outcomes of patients treated in a real-world setting, with particular focus on elderly patients. (2) Patients and methods: Patients treated with abemaciclib between November 2019 and February 2022 were included in the study. Data were collected from electronic medical records. The primary objective was to determine real-world progression-free survival (rwPFS), and secondary objectives included median overall survival (mOS) and safety. (3) Results: Analysis included 134 patients, with a median follow-up of 42 months. Median age was 62 years, with 29.9% aged 70+ years. A total of 51.5% of patients received abemaciclib in first-line, predominantly with aromatase inhibitor (68.1%). Median rwPFS was 21 in first-line and 20 months in the second-line, with no significant difference between treatment lines (HR 0.96; p = 0.88). Patients treated in the third- or later-line had a significantly shorter rwPFS, at 7 months (HR 1.48, p = 0.003). mOS was not reached in the first-line setting. For second- and third- or later-lines, mOS was 29 and 19 months, respectively. There was no significant difference in mOS between first- or second-line (HR 1.37, p = 0.36). In the 70+ group, median rwPFS was 15 months and mOS was 25 months with no significant difference compared to younger patients (rwPFS HR 1.1; p = 0.65; OS HR 1.4; p = 0.21). Most common adverse events (AEs) were diarrhoea (68.7%), anaemia (64.9%), and increased serum creatinine (63.4%). Grade 3/4 AEs were reported in 21.6% of patients. Dose reductions occurred in 30.6% of patients and were more frequent in patients 70+ (40%) compared to younger patients (28%); the difference was not significant (p = 0.22). At study cut-off, 64.9% of patients discontinued abemaciclib, primarily due to disease progression (73.5%). (4) Conclusions: Our study provides valuable insights into the effectiveness and safety of abemaciclib for the treatment of MBC. We observed comparable outcomes in terms of rwPFS and OS between the first two lines, suggesting consistent effectiveness across treatment lines. In addition, our findings suggest that older age (70+) does not significantly impact the effectiveness and tolerability of abemaciclib, although the careful monitoring and management of AEs are warranted.

Complete response in the axilla and the non-triple negative subtype are favourable prognostic factors for survival outcomes in inflammatory breast cancer.

AIM: To assess real-world outcomes and prognostic factors of non-metastatic inflammatory breast cancer according to immunohistochemistry (IHC)-based subtype and treatment regimen. METHODS: An institutional retrospective analysis of patients treated with neoadjuvant systemic treatment (NAST) for stage III inflammatory breast cancer diagnosed between 2001 and 2018 was performed. The survival outcomes in relation to patient characteristics, tumour characteristics, treatment modality and response to NAST were analyzed. RESULTS: 225 patients fulfilled the inclusion criteria, 90% of patients were node-positive. IHC-based subtypes: 39.1% were HR+/HER2-, 19.1% HR+/HER2+, 23.1% HR-/HER2+ and 18.7% HR-/HER2-. Treatment was multimodal: NAST (100%), surgery (94.2%) and radiotherapy (94.2%). 53.3% of patients received adjuvant endocrine therapy, 34.3% (neo)adjuvant trastuzumab. Tri-modality therapy was applied in 89.3% of patients. Following NAST, a pathologic complete remission (pCR) in the breast was found in 16.9%, in the axilla in 29.7% and in both the breast and axilla in 10.3% of patients. The axillary pCR rate was significantly higher in HR- subtypes. Median overall survival (OS) was 8.9, 7.2, 5.8 and 2.3 years (p < 0.001) for HR+/HER2-, HR+/HER2+, HR-/HER2+ and HR-/HER2- subtype, respectively. On multivariate analysis, IHC-based subtype, age and axillary pCR were found as independent prognostic factors for RFS and OS. pCR rate and median OS improved over time, 5.8% vs 14.7% and 4.7 vs 10.0 years (2001-2009 vs. 2010-2018), respectively. CONCLUSIONS: Axillary pCR and the non-triple-negative IHC-based subtype are favourable prognostic factors for RFS and OS in inflammatory breast cancer. Introduction of taxanes and antiHER2 drugs contributed to improved pCR rate and OS.

Intraoperative Touch Imprint Cytology in Breast Cancer Patients After Neoadjuvant Chemotherapy.

BACKGROUND: Intraoperative touch imprint cytology (ITIC) is used for intraoperative detection of sentinel lymph node (SLN) metastases with intention to spare the patients another surgery. However, ITIC prolongs surgery, and ads costs. It is less likely positive in breast cancer (BC) patients after neoadjuvant chemotherapy (NAC) due to low axillary tumor burden. We aimed to evaluate ITIC in patients after NAC and assess how often it changes the ongoing surgery. MATERIALS AND METHODS: BC patients treated with NAC followed by surgery at the Institute of Oncology Ljubljana, Slovenia, from January 2008 to July 2020 with ITIC performed were selected for analysis. Sensitivity, specificity, and the proportion of positive ITIC were calculated for different subgroups. RESULTS: Overall, 144 patients were identified. 73 of 144 (50.7%) patients were N0 before NAC and 71 of 144 (49.3%) were initially N1 and downstaged to N0 after NAC. ITIC was positive in 30 of 144 (20.8%) of patients, 7 of 73 (9.6%) in N0 group and 23 of 71 (32.4%) in N1 group. In N0 group, ITIC was positive in 1 of 20 (5%) if the tumor size was ≤ 20 mm after NAC, and 2 of 39 (5.1%) if the tumor was triple negative (TN) or Her-2+. In the N1 group ITIC was positive in > 20% in all subgroups. The sensitivity and specificity of ITIC was 50.8% and 100%, respectively and did not differ between groups. CONCLUSION: ITIC after NAC is accurate with comparable sensitivity to ITIC in upfront surgery. We suggest omission of ITIC after NAC in initially N0 patients, particularly for tumors ≤ 20 mm after NAC, and in TN or Her-2+ subtypes.

Breast cancer during pregnancy: retrospective institutional case series.

BACKGROUND: Pregnancy associated breast cancer is a rare disease. It presents a unique entity of breast cancer with aggressive phenotype. The main aim was to evaluate how the international guidelines were followed in daily practice. PATIENTS AND METHODS: Data concerning patients' and tumours' characteristics, management, delivery and maternal outcome were recorded from institutional electronic database. In this paper a case series of pregnant breast cancer patients treated at single tertiary institution between 2007 and 2019 are presented and the key recommendations on managing such patients are summarized. RESULTS: Fourteen patients met the search criteria. The majority of tumours were high grade, triple negative or HER2 positive, two patients were de novo metastatic. Treatment plan was made for each patient by multidisciplinary team. Eight patients were treated with systemic chemotherapy with no excess toxicity or severe maternal/fetal adverse effects. In all but two patients, delivery was on term and without major complications. Only one event, which was not in whole accordance with international guidelines, was identified. It was the use of blue dye in one patient. CONCLUSIONS: Women with pregnancy associated breast cancer should be managed like non-pregnant breast cancer patients and should expect a similar outcome, without causing harm to the unborn child. To achieve a good outcome in pregnancy associated breast cancer, a multidisciplinary approach is mandatory.

Candidaemia in Central Slovenia: A 12-year retrospective survey.

BACKGROUND: Candida bloodstream infections (BSI) became an important invasive disease in the late 20th century, in particular among immunocompromised patients. Although considerable progress has been made in the management of patients with invasive mycoses, Candida BSI are still widespread among hospitalised patients and are associated with relatively high mortality. OBJECTIVES: We conducted a retrospective study to evaluate patient characteristics, incidence, species distribution and antifungal susceptibility of BSI isolates of Candida spp. as well as outcomes of Candida BSI from 2001 to 2012, before the widespread use of echinocandins. This is the first epidemiological study of Candida BSI in Slovenia so far. METHODS: All documented candidaemia cases from 2001 to 2012 in two major hospitals-University Medical Centre and Institute of Oncology in Ljubljana, Slovenia-were taken into consideration. Candida BSI were identified in 422 patients (250 male, 172 female). Laboratory and clinical data of these patients were retrospectively analysed. Mann-Whitney U test was used to compare continuous variables and Fisher's exact test or chi-squared test for categorical variables. RESULTS AND CONCLUSIONS: The average incidence of Candida BSI was 0.524/10.000 patient-days (0,317/1000 admissions); 16/422 were younger than 1 year and 251/422 patients were over 60 years old. The most commonly isolated species were Candida albicans and Candida glabrata, followed by Candida parapsilosis. Majority of the patients had a single episode of Candida BSI, multiple episodes of Candida BSI occurred in 18/434 patients (4.1%); in 25/434 patients (5.8%) mixed Candida BSI were observed. Crude 30-day case-fatality rate was 55.4%.

70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age.

BACKGROUND: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age. METHODS: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing. FINDINGS: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]). INTERPRETATION: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy. FUNDING: European Commission Sixth Framework Programme.

Efficacy and safety of selective cyclin-dependent kinases 4/6 inhibitors in hormone-receptor-positive, HER2-negative advanced breast cancer - results from a real-world setting.

BACKGROUND: Selective cyclin-dependent kinases 4/6 inhibitors (CDKi) have become the standard of care in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer (ABC). We performed retrospective analysis in patients treated with CDKi in the first year of their routine clinical use in Slovenia. METHODS: The primary goals were time-to-treatment failure (TTF) and overall survival (OS), analysed via Kaplan-Meier method, the secondary goals were clinical benefit rate (CBR) and safety. RESULTS: Overall, 218 patients' data were evaluated. The median age was 61.8 years (30.6-84.6). The median number of previous ET lines for ABC was 2 (range 0-5). At the time of inclusion, 128 patients (58.7%) had visceral metastases, 45 patients (20.6%) had bone-only disease. At the median follow-up of 15.2 months, disease progressed in 74 patients and 60 patients died. The median TTF was 8.3 months for the whole group, 19.3, 10.3 and 5.5 months for patients treated in the first-, second- and further lines of systemic therapy, respectively. The median OS from the start of CDKi treatment was not reached in any of the groups. CBR was 59.6% for the whole group, 42.7% for further lines of therapy. The most common grade 3/4 adverse event was neutropaenia in 108 patients (49.5%), followed by an increase of hepatic aminotransferases in 13 patients (6.0%). CONCLUSIONS: Even in the diverse real-world population treatment with CDKi in combination with ET showed clinical benefit, most prominently in the first- and second lines of systemic therapy.

Multigene expression signatures in early hormone receptor positive HER 2 negative breast cancer.

Background The standard treatment of hormone receptor positive, HER2 negative early breast cancer (BC) is surgery followed by adjuvant systemic therapy either with endocrine therapy alone or with the addition of chemotherapy followed by endocrine therapy. Adjuvant systemic therapy reduces the risk of recurrence and death from BC. Whether an individual patient will benefit from adjuvant chemotherapy is an important clinical decision. Decisions that rely solely on clinical-pathological factors can often lead to overtreatment. Multigene signatures represent an important progress in optimal selection of high risk patients that might benefit from the addition of chemotherapy to adjuvant endocrine therapy. Conclusions Several signatures are already commercially available and also accepted by international guidelines. Oncotype DX and MammaPrint have been most extensively validated and supported by level IA evidence.

Cardiac monitoring in patients on trastuzumab: correlation of ultrasound and radionuclide ventriculography.

BACKGROUND: Guidance on cardiac surveillance during adjuvant trastuzumab therapy remains elusive. The recommended methods are two-dimensional echocardiography (2D-ECHO) and electrocardiography gated equilibrium radionuclide ventriculography (RNV). We assessed the correlation and possible specific merits of these two methods. METHODS: In a prospective cohort study in patients undergoing post-anthracycline adjuvant trastuzumab therapy, clinical assessment, 2D-ECHO and RNV were performed at baseline, 4, 8 and 12 months. The correlation between used methods was estimated with Pearson's correlation coefficient and Bland-Altman analysis. RESULTS: Ninety-two patients (mean age 53.6±9.0 years) were included. The correlation of LVEF measured by ECHO and RNV at each time point was statistically insignificant. Values obtained by ECHO were on average higher (3.7% to 4.5%). A decline in LVEF of ≥10% from baseline was noticed in 19 (24.4%) and 13 (14.9%) patients with ECHO and RNV, respectively, however in only one patient by both methods simultaneously. A decline in LVEF of ≥10% to below 50% was found in three and none patients according to RNV and ECHO measurements, respectively. CONCLUSIONS: There is a weak correlation of ECHO and RNV measurements in individual patient, the results obtained by the methods are not interchangeable. LVEF values determined by 2D-ECHO were on average higher compared to RNV determined ones. When in an asymptomatic patient a decline in LVEF requiring treatment interruption is detected by RNV ECHO re-evaluation and referral to a cardiologist is advised.

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. RESULTS: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

A Prospective Cohort Study on Cardiotoxicity of Adjuvant Trastuzumab Therapy in Breast Cancer Patients / Estudo Prospectivo de Coorte sobre Cardiotoxicidade na Terapia Adjuvante com Trastuzumabe em Pacientes com Câncer de Mama

Abstract Background: Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. Objectives: The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. Methods: In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). Results: 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. Conclusions: Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant.

Resumo Fundamento: Cardiotoxicidade é um importante efeito colateral da terapia com trastuzumabe, recomendando-se vigilância cardíaca. Objetivos: Avaliar prospectivamente as características basais de pacientes, nível de fração N-terminal do pró-peptídeo natriurético cerebral (NT-proBNP) e parâmetros ecocardiográficos como possíveis preditores de disfunção cardíaca relacionada ao trastuzumabe. Métodos: Em um estudo clínico prospectivo de coorte, realizou-se avaliação ecocardiográfica e neuro-humoral basal, aos 4, 8 e 12 meses em pacientes com câncer de mama submetidas a terapia adjuvante com trastuzumabe após antraciclina (3-4 ciclos). Definiu-se disfunção cardíaca relacionada ao trastuzumabe como uma redução na fração de ejeção ventricular esquerda (FEVE) ≥ 10%. Resultados: Este estudo incluiu 92 pacientes (idade média, 53,6 ± 9,0 anos). Pacientes que desenvolveram redução na FEVE ≥ 10% (20,6%) relacionada ao trastuzumabe durante tratamento tinham FEVE basal significativamente maior (70,7 ± 4,4%) do que aqueles sem (64,8 ± 5,5%) (p = 0,0035). Todos os demais parâmetros basais medidos (idade, índice de massa corporal, hipertensão arterial, nível de NT-proBNP e outros parâmetros ecocardiográficos) não foram identificados como significativos. Conclusões: Nossos achados sugerem que as características basais das pacientes, nível de NT-proBNP e parâmetros ecocardiográficos, contanto que dentro da variação normal, não são ferramentas confiáveis para predição precoce de disfunção cardíaca relacionada ao trastuzumabe em pacientes submetidas a terapia adjuvante com trastuzumabe após baixa dose de antraciclina. Uma redução na FEVE em pacientes com FEVE basal alta-normal, ainda que estatisticamente significativa, não é clinicamente relevante.

A Prospective Cohort Study on Cardiotoxicity of Adjuvant Trastuzumab Therapy in Breast Cancer Patients.

BACKGROUND: Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. OBJECTIVES: The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. METHODS: In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). RESULTS: 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. CONCLUSIONS: Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant.

Effectiveness of adjuvant trastuzumab in daily clinical practice.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) positive breast cancer is an entity with aggressive behaviour. One year of adjuvant trastuzumab significantly improves the disease free survival in the range of 40-50% and reduces the risk of dying from HER2 positive breast cancer by one third. Adjuvant treatment with trastuzumab became available in Slovenia in 2005 and the aim of this study is to explore, if the exceptional results reported in adjuvant clinical trials are achieved also in daily clinical practice. PATIENTS AND METHODS: An analysis of tumour and patient characteristics, type of treatment and outcome (relapse free and overall survival) of 313 patients (median age 52 years) treated at the Institute of Oncology Ljubljana in years 2005-2009 was performed. RESULTS: Median follow-up was 4.4 years. Sixty-one patients relapsed and 24 died. Three and four years relapse free survival was 84.2% and 80.8% and the overall survival was 94.4% and 92.5%, respectively. Independent prognostic factors for relapse were tumour grade (HR 2.10; 95% CI 1.07-4.14; p = 0.031) and nodal stage (HR 1.35; 1.16-1.56; p < 0.0001) and for the overall survival nodal stage only (HR 1.36; 1.05-1.78; p = 0.021). CONCLUSIONS: The outcome in patients with adjuvant trastuzumab in daily clinical practice, treated by medical oncologists, is comparable to results obtained in international adjuvant studies.

Human epidermal growth factor receptor 2-positive microinvasive breast carcinoma with a highly aggressive course: a case report.

BACKGROUND: Microinvasive ductal carcinoma in situ of the breast is a rare entity defined as ductal carcinoma in situ with invasive foci measuring no more than 1 mm. In general, the outcome is excellent, similar to ductal carcinoma in situ. We report a patient with breast ductal carcinoma in situ with microinvasion who died eight months after diagnosis due to progression of the disease - liver metastases. This is the first report in the literature of such an aggressive course. CASE PRESENTATION: A 47-year-old Caucasian woman presented with mammographic-detected suspicious microcalcinations in an area of 8.6 x 6 cm. A radical mastectomy with a sentinel lymph node biopsy and immediate breast reconstruction with implant was performed. A histopathological report showed a massive high grade ductal carcinoma in situ, of the solid and comedo type. In one quadrant, some foci of microinvasions of less than 1 mm were present. Tumour margins were free. Isolated tumour cells were found in the sentinel lymph node. Hormone receptors were negative and human epidermal growth factor receptor-2 status was not performed. The patient received no adjuvant systemic therapy. Eight months after the surgery, she died from hepatic failure without known breast cancer progression before. An autopsy revealed diffuse liver metastases with human epidermal growth factor receptor 2-positive, hormone receptor negative breast cancer. Dissemination to other organs was not proven. CONCLUSION: Our patient is a rare case of ductal carcinoma in situ with microinvasion that developed distant metastases very early. In case of multiple foci of microinvasion, besides radical local treatment we suggest considering adjuvant systemic treatment based on biological characteristics since tumour size alone does not predict the prognosis well.

Triple negative breast cancer - prognostic factors and survival.

BACKGROUND: Triple negative breast cancer (TNBC) is defined by a lack of expression of both estrogen (ER) and progesteron (PgR) receptors as well as human epidermal growth factor receptor 2 (HER2). Our retrospective analysis addressed prognostic factors for short- and long-term outcomes of patients (pts) with TNBC pts treated in routine clinical practice. PATIENT AND METHODS.: Our retrospective study included 269 TNBC treated at Institute of Oncology Ljubljana between March 2000 and December 2006. The collected data included patients', tumours' and treatments' characteristics. The survival analyses were performed using the Kaplan-Meier method. The Cox proportional hazard model was used in the multivariate analysis. RESULTS: The median age of our patients was 55.3 yrs (23-88.5) and the median follow-up was 5.9 yrs (0.3-9.6). Six (2%) pts experienced local only, 79 (92%) pts distal recurrence and 66 (24%) died. The predominant localisation of the first relapse was in visceral organs (70.4%). The 5-year disease-free survival (DFS) for the entire group was 68.2% and the 5-year overall survival (OS) was 74.5%. We found a pattern of high recurrence rate in the first 3 years following the diagnosis and a clear decline in recurrence rate over the next 3 years. In the univariate analysis age, nodal status, size and lymphovascular invasion (LVI) were found to have a significant impact on DFS as well as on OS. In the multivariate analysis only age (HR=1.79; 95%CI=1.14-2.82; p=0.012) and nodal status (HR=2.71; 95%CI=1.64-4.46; p<0.001) retained their independent prognostic value for DFS and for OS only the nodal status (HR=2.96; 95%CI=1.51-5.82; p=0.002). CONCLUSIONS: In our series of TNBC pts nodal status and age (older than 65 yrs) were found to be independent prognostic factors for DFS, whereas for OS only the nodal status. We found a pattern of a high recurrence rate in the first 3 years following the diagnosis and a decline in the recurrence rate over the next 3 yrs with higher rate of distal versus local recurrence and a predominant localization of distal metastases in visceral organs.

Report on isoelectric focusing trial of erythropoietin profiling in two cancer patients during chemotherapy and darbepoetin treatment.

The level of erythropoietin, main regulator of erythropoiesis, is affected by hypoxia, anaemia, application of recombinant erythropoietin, chemotherapy and others. Isoelectric focusing (IEF) combined with double immunobloting is a method that enables distinct analysis of endogenous and recombinant erythropoietin isoforms. Aim of our study was to set up analysis of treatment effects on the pattern of endogenous erythropoietin in anaemic breast cancer patient. Urine and blood samples were collected during and after termination of the treatment and analysed by isoelectric focusing. Endogenous erythropoietin was found lower, but still detectable during darbepoetin treatment. Normal shift of erythropoietin isoforms between serum vs. urine, ordinary seen in healthy volunteers, was not observed indicating kidney damage. The patient was suffering from heavy proteinuria and had low Glomerular filtration rate indicating acute renal failure, probably caused by clinical status or cisplatin chemotherapy. IEF has not yet been used for follow up of erythropoietin profile in cancer patients. It enables to monitor the effects of treatment on the level of endogenous erythropoietin and indirectly indicates kidney function.

Fertility in patients treated for testicular cancer.

INTRODUCTION: Testicular cancer affects men mostly in their reproductive age with a cure rate over 90% and fertility is one of the main concerns of survivors. To further elucidate the question of fertility after treatment for testicular cancer, we performed a survey in patients treated in our institution. PATIENTS AND METHODS: We sent a questionnaire to patients treated for testicular cancer at our institute from 1976 to 2002 (n = 490) of whom 297 (60.6%) responded. We considered the patients to have conserved fertility if they had children after treatment without assisted reproductive technologies. RESULTS: Before treatment 119/297 (40.1%) of patients and after treatment 150/297 (50.5%) of patients tried to have children (p = 0.019). Of 119 patients who tried to have children before treatment for testicular cancer 98 (82.4%) succeeded and 74/150 (49.3%) were successful after treatment (p < 0.001). After treatment patients had 1-3 (median 1) children. The median time to birth of first child from diagnosis was 12 years. The post-treatment fatherhood in patients treated with surgery only (orchidectomy +/- retroperitoneal lymphnode dissection-RPLND) was 59%, in those with additional radiotherapy 68%, and chemotherapy 50% (p = 0.233). Fertility rate in patients where a non nerve sparing RPLND was performed was only 37%, 62% in patients with nerve sapring RPLND, and 77% in patients where RPLND was not performed (p < 0.0001). CONCLUSION: Fertility rate after treatment for testicular cancer is reduced. From our data, the most important treatment modality that influences fertility is non nerve sparing RPLND that should be avoided whenever possible in order improve the quality of life our patients.

Current standards in the treatment of metastatic breast cancer with focus on Lapatinib: a review by a Central European Consensus Panel.

In breast cancer, early detection as well as new developments in therapeutic options has resulted in less patients presenting with metastatic disease. However, about one-third of women with early stage breast cancer will eventually develop metastatic disease. Furthermore, approximately 20-30% of patients with breast cancer have tumors that overexpress human epidermal growth factor receptor (HER-2), which is associated with an aggressive tumor phenotype and poor prognosis. The identification of the HER-2 protein led to the development of highly effective therapeutics directed at this receptor. Trastuzumab, a recombinant, humanized, monoclonal antibody that binds to the extracellular domain of the HER-2 protein, has shown significant clinical benefit in metastatic and early-stage HER-2-positive breast cancer. Since the cancer recurs after adjuvant therapy in some women, and metastatic breast cancer eventually develops resistance to trastuzumab, there is a need for alternative treatment modalities to block HER-2 signaling. One of these treatment options is lapatinib, an orally active small molecule that inhibits the tyrosine kinases of HER-2 and the epidermal growth factor receptor type 1 (EGFR). In this consensus statement current treatment options in metastatic and locally advanced disease are discussed with a special focus on lapatinib.

Modalidades de hemodiálise ambulatorial: breve revisão / Types of ambulatory hemodialysis: a brief review / Modalidades de hemodiálisis ambulatoria: breve revision

Objetivou-se estudar as modalidades de hemodiálise utilizadas, assim como suas vantagens e desvantagens a fim de contribuir com o bem-estar do cliente com insuficiência renal crônica, durante o tratamento. O estudo é uma revisão bibliográfica conduzida nas bases de dados LILACS e SciElo. Foi constatado que a hemodiálise convencional é a mais utilizada no mundo, mas apresenta muitas intercorrências. A diária e noturna, oferecem benefícios ao coração, mas a primeira tem elevado custo e a segunda, possui estudos limitados. A domiciliar é cômoda ao cliente, mas, requer alterações no domicilio.

The objectives of this brief review were to discuss the types of ambulatory hemodialysis and to describe their advantages and disadvantages regarding well-being of individuals with chronic renal insufficiency during the treatment. A search of the literature was conducted using LILACS and Scielo databases. Findings suggest that although having many complications, the conventional hemodialysis is the type of hemodialysis most used worldwide. Both the daily and nocturnal types of hemodialysis offer cardiovascular benefits. However, daily hemodialysis is costly and nocturnal hemodialysis is not well studied. Home hemodialysis may be more comfortable to the individual, but requires modification of the home environment.

En la presente investigación se tuvo como objetivo estudiar las modalidades de hemodiálisis utilizadas, así como sus ventajas y desventajas a fin de contribuir con el bienestar del cliente con insuficiencia renal crónica, durante el tratamiento. El estudio es una revisión bibliográfica realizada en las bases de datos LILACS y SciElo. Fue constatado que la hemodiálisis convencional es la más utilizada en el mundo, pero presenta muchas intercurrencias. La diurna y la nocturna, ofrecen beneficios al corazón, sin embargo la primera ha elevado el costo y la segunda, posee estudios limitados. La domiciliaria es cómoda para el cliente, no obstante, requiere de alteraciones en el domicilio.