Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade.

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.

Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial.

PURPOSE: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer. PATIENTS AND METHODS: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes. RESULTS: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003). CONCLUSIONS: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

Phase II, Multicenter, Single-arm Trial of Eribulin as First-line Therapy for Patients With Aggressive Taxane-pretreated HER2-Negative Metastatic Breast Cancer: The MERIBEL Study.

BACKGROUND: Eribulin has efficacy in patients with progression after ≥ 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors. PATIENTS AND METHODS: Eribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received ≥ 1 dose of eribulin. RESULTS: The median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia. CONCLUSION: Eribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC.

[Impact of a registry on survival in familial adenomatous polyposis]. / Mejoría de la supervivencia de la poliposis adenomatosa familiar después del establecimiento de un registro.

BACKGROUND AND OBJECTIVE: Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by hundreds of adenomatous polyps in the large intestine. Almost all affected untreated patients will die from colorectal cancer (CRC) at the age of 40-50 years. The Balearic Islands Polyposis Registry was established in 1988. The aim of the present study was to evaluate changes in the prevalence of CRC and the prognosis of FAP, before and after the establishment of the registry. PATIENTS AND METHOD: The diagnosis of FAP was defined by history, clinical examination, histopathological assessment and/or genetic testing. In this study we compare the data of probands and call-up patients. To evaluate the impact of the registry, selected variables were calculated for the periods 1970-1987 and 1988-2005. RESULTS: At the end of 2005 the registry included information of 19 families with 52 affected members (19 probands, 33 call-up). Thirty-six patients were alive and 16 had died. The cumulative 15 years survival was 82% in call-up cases compared with 47% in probands (p < 0.05). The cumulative 15 years survival was 87% for the period 1988-2005, compared with 33% for the period 1970-1987 (p < 0.001). The frequency of CRC was 72% for the period 1970-1987 and 21% for the period 1988-2005 (p < 0.005). CONCLUSIONS: The survival of the call-up patients was significantly improved as compared to the probands. Since the establishment of the registry, the frequency of CRC has decreased considerably, and the prognosis has improved substantially in FAP patients.

Burden of advanced breast cancer for patients and caregivers in Europe: comparison of two treatment forms of vinorelbine, oral and intravenous.

AIM: To assess the burden of disease associated with advanced breast cancer (ABC) treated with oral (VinO) or intravenous vinorelbine (VinIV) from the perspective of patients and caregivers in five European countries. METHODS: This was an observational, prospective, international, multicenter study. Patients were included in the study at the beginning of their second cycle of chemotherapy with vinorelbine and categorized into two groups depending on whether they received VinO or VinIV. At baseline (V0) and at the end of the second cycle of chemotherapy (V1), patients and caregivers were asked to complete self-administered questionnaires: SF-12 and burden of disease. RESULTS: At baseline, the two groups were well balanced in demographic and clinical characteristics. However, while HER2+ (human epidermal growth factor receptor 2) disease was significantly more frequent in patients receiving VinIV, patients receiving VinO were predominantly treated with single-agent therapy and were older than those treated with VinIV (67.1 years versus 57.7 years [p = 0.05]). As measured with SF-12, patients with VinO had, at end of cycle 1 and end of cycle 2, significantly more favorable outcomes in physical summary score, role physical, role emotional and mental health (all p < 0.05) than those treated with VinIV. Trends for a better caregiver mental score and social functioning were also observed with VinO (cycle 1 and 2; p < 0.10). From a patient perspective, no major difference was reported on the burden of disease between the two groups, however, a trend for a better" overall impact on daily life" was observed in VinO patients. Major significant differences, showing a lower burden of disease with VinO, were also reported from caregivers. In addition, in patients treated with VinO, mental score was almost similar to the one of the general population. CONCLUSION: VinO showed benefits over VinIV for both patients and caregivers, particularly in health related quality of life and burden of disease. Because of its observational design, results are only informative.

Factors Associated with the Selection of First-line Bevacizumab plus Chemotherapy and Clinical Response in HER2-negative Metastatic Breast Cancer: ONCOSUR AVALOX Study.

AIM: To evaluate factors associated with the selection of first-line bevacizumab plus chemotherapy and clinical response in HER2-negative metastatic breast cancer (MBC) in clinical practice in Spain. PATIENTS AND METHODS: All consecutive adult female patients with HER2-negative MBC who had received first-line bevacizumab plus chemotherapy for at least 3 months were enrolled in the present study. RESULTS: A total of 292 evaluable patients were included; 25% had triple-negative breast cancer (TNBC) and 75% had hormone receptor-positive breast cancer (HRPBC). Nearly 40% of patients had ≥3 metastatic sites, mainly located in the bone (48%) and liver (40%). Bevacizumab was mostly combined with paclitaxel (67.1%). ER-positive tumors were only identified as an independent factor associated with the choice of treatment (odds ratio (OR): 0.538; p=0.02). The overall response rate (ORR) was 63.7% (TNBC: 57.5%; HRPBC: 65.9%). Patients aged 36-50 years (OR: 3.03; p=0.028) and those with metastases at sites other than the bone (OR: 0.38; p=0.001) and ≥3 metastatic sites (OR: 1.41; p=0.018) were more likely to achieve objective responses. CONCLUSION: First-line bevacizumab plus chemotherapy, mainly paclitaxel, is an effective and well-tolerated treatment option for HER2-negative MBC, particularly in more aggressive disease.

The oxidative stress in breast tumors of postmenopausal women is ERα/ERß ratio dependent.

Estrogen receptor status is a diagnostic parameter in breast cancer treatment. Estrogen receptor presence is related to a better prognosis because the principal treatments attacking breast cancer tumors have their action site directed at the estrogen receptor. However, the two different subtypes of estrogen receptor, ERα and ERß, have different functions. In this work an alternative point of view focusing on oxidative stress is shown, given that estrogen receptors regulate several proteins related to this oxidative stress, such as antioxidant enzymes, sirtuins, and uncoupling proteins. Postmenopausal human breast tumors with different ERα/ERß ratios were analyzed to characterize the amount of oxidative stress, mitochondrial function, and proliferation-related and oxidative stress-activated signaling pathways. Results showed that tumors with a low ERα/ERß ratio have greater oxidative damage and higher antioxidant enzyme protein levels, as well as uncoupling protein (UCP) and sirtuin 3 (SIRT3), and have high studied signaling pathway activation. Glutathione peroxidase, Complex V, Complex III, Complex II, Complex IV, AKT, SAPK, and ERα were significantly and positively correlated with ERα/ERß ratio. However, carbonyl groups, catalase, CuZn-superoxide dismutase, UCP5, SIRT3, and ERß were significantly and negatively correlated with ERα/ERß ratio. From the independent variables included in the step-by-step stepwise multiple linear regression analysis, only the ERα/ERß ratio was independently associated with carbonyl groups. Surprisingly, these low ERα/ERß ratio tumors have poor prognosis for the patient, and these results and those of other authors suggest that these tumors are adapted to conditions of increased oxidative stress.

Estrogen down-regulates uncoupling proteins and increases oxidative stress in breast cancer.

Oxidative stress has been postulated as one of the mechanisms underlying the estrogen carcinogenic effect in breast cancer. Estrogens are known to increase mitochondrial-derived reactive oxygen species (ROS) by an unknown mechanism. Given that uncoupling proteins (UCPs) are key regulators of mitochondrial energy efficiency and ROS production, our aim was to check the presence and activity of UCPs in estrogen receptor (ER)-positive and ER-negative breast cancer cells and tumors, as well as their relation to oxidative stress. Estrogen (1 nM) induced higher oxidative stress in the ER-positive MCF-7 cell line, showing increased mitochondrial membrane potential, H(2)O(2) levels, and DNA and protein damage compared to ER-negative MDA-MB-231 cells. All isoforms of uncoupling proteins were highly expressed in ER-positive breast cancer cells and tumors compared to negative ones. ROS production in mitochondria isolated from MCF-7 was increased by inhibition of UCPs with GDP, but not in mitochondria from MDA-MB-231. Estrogen treatment decreased uncoupling protein and catalase levels in MCF-7 and decreased GDP-dependent ROS production in isolated mitochondria. On the whole, these results suggest that estrogens, through an ER-dependent mechanism, may increase mitochondrial ROS production by repressing uncoupling proteins, which offers a new perspective on the understanding of why estrogens are a risk factor for breast cancer.

Variation in 'standard care' for breast cancer across Europe: a EUROCARE-3 high resolution study.

On a population-based sample of 13,500 European breast cancer patients mostly diagnosed in 1996-1998 and archived by 26 cancer registries, we used logistic regression to estimate odds of conservative surgery plus radiotherapy (BCS+RT) versus other surgery, in T1N0M0 cases by country, adjusted for age and tumour size. We also examined: BCS+RT in relation to total national expenditure on health (TNEH); chemotherapy use in N+ patients; tamoxifen use in oestrogen-positive patients; and whether 10 nodes were examined in lymphadenectomies. Stage, diagnostic examinations and treatments were obtained from clinical records. T1N0M0 cases were 33.0% of the total. 55.0% of T1N0M0 received BCS+RT, range 9.0% (Estonia) to 78.0% (France). Compared to France, odds of BCS+RT were lower in all other countries, even after adjusting for covariates. Women of 70-99 years had 67% lower odds of BCS+RT than women of 15-39 years. BCS+RT was 20% in low TNEH, 58% in medium TNEH, and 64% in high TNEH countries. Chemotherapy was given to 63.0% of N+ and 90.7% of premenopausal N+ (15-49 years), with marked variation by country, mainly in post-menopause (50-99 years). Hormonal therapy was given to 55.5% of oestrogen-positive cases, 44.6% at 15-49 years and 58.8% at 50-99 years; with marked variation across countries especially in premenopause. The variation in breast cancer care across Europe prior to the development of European guidelines was striking; older women received BCS+RT much less than younger women; and adherence to 'standard care' varied even among countries with medium/high TNEH, suggesting sub-optimal resource allocation.

Recent changes in breast cancer incidence in Spain, 1980-2004.

BACKGROUND: Since the 1980s, Spain experienced two decades of sharply increasing breast cancer incidence. Declines in breast cancer incidence have recently been reported in many developed countries. We examined whether a similar downturn might have taken place in Spain in recent years. METHODS: Cases of invasive female breast cancer were drawn from all population-based Spanish cancer registries that had at least 10 years of uninterrupted registration over the period 1980-2004. Overall and age-specific changes in incidence rates were evaluated using change-point Poisson models, which allow for accurate detection and estimation of trend changes. All statistical tests were two-sided. RESULTS: A total of 80,453 incident cases of invasive breast cancer were identified. Overall age- and registry-adjusted incidence rates rose by 2.9% (95% confidence interval [CI] = 2.7% to 3.1%) annually during the 1980s and 1990s; there was a statistically significant change in this trend in 2001 (95% CI = 1998 to 2004; P value for the existence of a change point <.001), after which incidence declined annually by 3.0% (95% CI = 1.8% to 4.1%). This trend differed by age group: There was a steady increase in incidence for women younger than 45 years, an abrupt downturn in 2001 for women aged 45-64 years, and a gradual leveling off in 1995 for women aged 65 years or older. Separate analyses for registries that had at least 15 years of uninterrupted registration detected a statistically significant interruption of the previous upward trend in breast cancer incidence in provinces that had aggressive breast cancer screening programs and high screening participation rates, including Navarra (change point = 1991, P < .001), Granada (change point = 2002, P = .003), Bizkaia (change point = 1998, P < .001), Gipuzkoa (change point = 1998, P = .001), and Araba (change point = 1997, P = .002). CONCLUSIONS: The recent downturn in breast cancer incidence among Spanish women older than 45 years is best explained by a period effect linked to screening saturation.

Treatment of medical databases and their graphical representation on the internet.

The use of new information technologies could facilitate enormously work to process and spread knowledge from medical data and, in particular, epidemiological data from cancer registries. Cancer registries are official institutions that collect information on the occurrence and outcome of cancer in defined population groups (city, region, or country). The aim of the present project was to design and develop a graphical web system to offer clear information about medical information, in this case cancer incidence, using Internet technology. A protocol and a system to process, manipulate, and represent medical data, epidemiological cancer data, from the Epidemiology Unit and Cancer Registry of the Balearic Islands, has been developed. All the steps to change the data format to obtain a medical data graphical representation database have been described. The result of the project is an application built in graphical web format that can be accessed at the following URL: http://gmein.uib.es/registro/resultados/resultados2.htm

Assessment of feasibility of workplace health promotion.

BACKGROUND: A simple empirically based method for assessment of the feasibility of workplace health promotion programs is described, focusing on cancer hazards (lifestyles, workplace hazards, deficient early detection). The basic components of feasibility are addressed: extent of hazards; needs of employees for hazard reduction and acceptability of WHP; and social context. METHODS: The procedure consists of six modules: guidelines on feasibility assessment; employee questionnaire; interview checklists for probing attitudes of management and partners (social context); data form; debriefing; and assessment of feasibility. Pretesting was completed in 16 workplace communities representing industry, construction, transport, telecommunications, health care, lodging and catering, teaching, and municipality jobs in five countries; a total of 1,085 subjects completed the employee questionnaire on health hazards, needs, and acceptability. RESULTS: The method demonstrated its utility in obtaining and summarizing the necessary data. Feasibility was assessed for the 16 test communities. CONCLUSION: The procedure can be customized; it has a high degree of face validity or understandability, and it is applicable in a wide variety of settings.

Pleural mesothelioma incidence in Europe: evidence of some deceleration in the increasing trends.

OBJECTIVE: To summarize the geographical and temporal variations in incidence of pleural mesothelioma in Europe, using the extensive data available from European general cancer registries, and consider these in light of recent trends in asbestos extraction, use and import in European countries. MATERIAL AND METHODS: The data were extracted from the European Cancer Incidence and Mortality database (EUROCIM). The inclusion criteria was acceptance in Volume VII of Cancer Incidence in Five Continents. Truncated age-standardized rates per 100,000 for the ages 40-74 were used to summarise recent geographical variations. Standardized rate ratios and 95% confidence intervals for the periods 1986-1990 and 1991-1995 were compared to assess geographical variations in risk. To investigate changes in the magnitude of most recent trends, regression models fitted to the latest available 10-year period (1988-1997) were compared with trends in the previous decade. Fitted rates in younger (40-64) and older adults (65-74) in the most recent period were also compared. RESULTS: There was a great deal of geographical variation in the risk of mesothelioma, annual rates ranging from around 8 per 100,000 in Scotland, England and The Netherlands, to lower than 1 per 100,000 in Spain (0.96), Estonia (0.85), Poland (0.85) and Yugoslavia, Vojvodina (0.56) among men. The rank of the rates for women was similar to that observed for men, although rates were considerably lower. Between 1978 and 1987, rates in men significantly increased in all countries (excepting Denmark). In the following 10 years, there was a deceleration in trend, and a significant increase was detectable only in England and France. In addition, the magnitude of recent trends in younger men was generally lower than those estimated for older men, in both national and regional cancer registry settings. CONCLUSIONS: While mesothelioma incidence rates are still rising in Europe, a deceleration has started in some countries. A decrease may begin in the next few years in certain European populations considering the deceleration of observed trends in mesothelioma and asbestos exposure, as well as the recent ban on its use.

Mejoría de la supervivencia de la poliposis adenomatosa familiar después del establecimiento de un registro / Impact of a registry on the survival familial adenomatous polyposis

Fundamento y objetivo: La poliposis adenomatosa familiar (PAF) es una enfermedad hereditaria, autosómica dominante, que se caracteriza por el desarrollo de centenares de pólipos adenomatosos en el colon. La mayoría de los afectados no tratados desarrollan cáncer colorrectal (CCR) a edades tempranas. El Registro de PAF de las Islas Baleares se estableció en 1988. El objetivo de este estudio es evaluar los cambios en la incidencia de CCR y en la supervivencia de los pacientes con PAF tras la creación del registro. Pacientes y método: El diagnóstico de PAF se establece a partir de la historia clínica, la exploración física, los datos histopatológicos y/o los resultados de los análisis genéticos. En el presente estudio se comparan los datos de los casos índice y de los casos secundarios. Asimismo, se han recogido los datos de los pacientes diagnosticados antes del establecimiento del registro (1970-1987) a fin de poder compararlos con los recabados durante su funcionamiento (1988-2005). Resultados: En 2005 el registro incluía información de 19 familias con 52 miembros afectados (19 casos índice y 33 casos secundarios). Del total, 36 pacientes siguen vivos y 16 han fallecido. La supervivencia acumulada a los 15 años es del 82% en los casos secundarios y del 47% en los casos índice (p < 0,05). La supervivencia a los 15 años fue del 87% en el período 1988-2005 y del 33% para el período 1970-1987 (p < 0,001). La frecuencia de CCR fue del 72% para el período 1970-1987 y del 21% para el período 1988-2005 (p < 0,005). Conclusiones: La supervivencia de los casos secundarios es significativamente mejor que la de los casos índice. Los pacientes con PAF han presentado una mejoría en la supervivencia y una disminución de la frecuencia de CCR tras el establecimiento del registro

Background and objective: Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by hundreds of adenomatous polyps in the large intestine. Almost all afected untreated patients will die from colorectal cancer (CRC) at the age of 40-50 years. The Balearic Islands Polyposis Registry was established in 1988. The aim of the present study was to evaluate changes in the prevalence of CRC and the prognosis of FAP, before and after the establishment of the registry. Patients and method: The diagnosis of FAP was defined by history, clinical examination, histopathological assessment and/or genetic testing. In this study we compare the data of probands and call-up patients. To evaluate the impact of the registry, selected variables were calculated for the periods 1970-1987 and 1988-2005. Results: At the end of 2005 the registry included information of 19 families with 52 affected members (19 probands, 33 call-up). Thirty-six patients were alive and 16 had died. The cumulative 15 years survival was 82% in call-up cases compared with 47% in probands (p < 0.05). The cumulative 15 years survival was 87% for the period 1988-2005, compared with 33% for the period 1970-1987 (p < 0.001). The frecuency of CRC was 72% for the period 1970-1987 and 21% for the period 1988-2005 (p < 0.005). Conclusions: The survival of the call-up patients was significantly improved as compared to the probands. Since the establishment of the registry, the frequency of CRC has decreased considerably, and the prognosis has improved substantially in FAP patients