Eficacia y seguridad de una nueva formulación de enjuague bucal de dexametasona para el manejo de la estomatitis en pacientes con cáncer / Effectiveness and safety of a novel dexamethasone mouthwash formulation in managing stomatitis in cancer patients

OBJETIVO: Describir una nueva formulación de enjuague bucal con dexametasona y analizar su efectividad y seguridad en pacientes que reciben agentes antineoplásicos que producen estomatitis. MÉTODO: Estudio observacional prospectivo realizado en un hospital universitario entre marzo de 2017 y noviembre de 2019. Se incluyeron los pacientes que iniciaron everolimus. El tratamiento consistió en enjuagar con solución oral de dexametasona dos veces al día hasta la interrupción del tratamiento con everolimus. Se reclutó una segunda cohorte de pacientes con estomatitis inducida por otros agentes antineoplásicos con alta probabilidad de provocar estomatitis. Se evaluó la efectividad y seguridad del enjuague bucal con dexametasona. RESULTADOS: Se reclutaron nueve pacientes en profilaxis con formulación de enjuague bucal con dexametasona; seis pacientes presentaban un diagnóstico de cáncer de mama, dos de tumor neuroendocrino y uno de carcinoma renal. Cuatro pacientes desarrollaron estomatitis leve (grado 1-2) y tres pacientes descontinuaron everolimus por otros eventos adversos relacionados con el tratamiento. Se prescribió enjuague bucal con dexametasona en cinco pacientes con estomatitis existente como tratamiento. Todos los pacientes lograron una reducción significativa de la gravedad de la estomatitis tras iniciar el enjuague bucal con dexametasona. En general, el nuevo enjuague bucal con dexametasona fue bien tolerado y no se requirieron reducción de dosis ni interrupción debido a estomatitis. CONCLUSIONES: La nueva formulación de enjuague bucal con dexametasona podría considerarse una alternativa adecuada para el manejo de la estomatitis

OBJECTIVE: To present a new dexamethasone mouthwash formulation and analyze its effectiveness and safety among patients receiving stomatitis-producing antineoplastic agents. METHOD: Prospective observational study conducted in a university hospital between March 2017 and November 2019. Consecutive patients starting everolimus were enrolled. Patients were instructed to rinse dexamethasone mouthwash formulation twice daily until discontinuation of everolimus. A second cohort of patients with existing stomatitis induced by high probability of producing stomatitis chemotherapy therapies was also recruited to assess treatment effectiveness. Effectiveness and safety of dexamethasone mouthwash formulation was assessed. RESULTS: Dexamethasone mouthwash formulation was prescribed in nine patients as prophylaxis. Six patients were diagnosed with breast cancer, two with neuroendocrine tumor and one with renal cell carcinoma. Four patients developed mild stomatitis (grade 1-2) and three patients discontinued everolimus due to other treatment-related adverse events. In addition, dexamethasone mouthwash formulation was prescribed as treatment in five patients with existing stomatitis. All patients achieved a significant reduction in the severity of stomatitis after starting the dexamethasone mouthwash formulation. In both cohorts, dexamethasone mouthwash formulation was well tolerated and neither dose reduction nor discontinuation related to stomatitis was required. CONCLUSIONS: Dexamethasone mouthwash formulation could be considered as a suitable alternative for stomatitis management

Breast density, benign breast disease, and risk of breast cancer over time.

OBJECTIVES: Assessing the combined effect of mammographic density and benign breast disease is of utmost importance to design personalized screening strategies. METHODS: We analyzed individual-level data from 294,943 women aged 50-69 years with at least one mammographic screening participation in any of four areas of the Spanish Breast Cancer Screening Program from 1995 to 2015, and followed up until 2017. We used partly conditional Cox models to assess the association between benign breast disease, breast density, and the risk of breast cancer. RESULTS: During a median follow-up of 8.0 years, 3697 (1.25%) women had a breast cancer diagnosis and 5941 (2.01%) had a benign breast disease. More than half of screened women had scattered fibroglandular density (55.0%). The risk of breast cancer independently increased with the presence of benign breast disease and with the increase in breast density (p for interaction = 0.84). Women with benign breast disease and extremely dense breasts had a threefold elevated risk of breast cancer compared with those with scattered fibroglandular density and without benign breast disease (hazard ratio [HR] = 3.07; 95%CI = 2.01-4.68). Heterogeneous density and benign breast disease was associated with nearly a 2.5 elevated risk (HR = 2.48; 95%CI = 1.66-3.70). Those with extremely dense breast without a benign breast disease had a 2.27 increased risk (95%CI = 2.07-2.49). CONCLUSIONS: Women with benign breast disease had an elevated risk for over 15 years independently of their breast density category. Women with benign breast disease and dense breasts are at high risk for future breast cancer. KEY POINTS: • Benign breast disease and breast density were independently associated with breast cancer. • Women with benign breast disease had an elevated risk for up to 15 years independently of their mammographic density category.

Thromboembolic, cardiovascular and overall mortality risks of aromatase inhibitors, compared with tamoxifen treatment: an outpatient-register-based retrospective cohort study.

BACKGROUND: Tamoxifen (TAM) and aromatase inhibitor (AI) therapies have been associated with increased risk of thromboembolic and cardiovascular events, respectively, in addition to other side effects. This study analysed the risk of these events and the overall survival (OS) benefit in breast cancer patients treated with AI, compared with TAM-treated patients, in a large population-based cohort. METHODS: This observational cohort study included women diagnosed with breast cancer and treated with TAM or AI. Data were extracted from primary care records in a population database (SIDIAP, System for the Development of Research in Primary Care). Incidence rates of study outcomes are reported. Survival analyses included Kaplan-Meier estimation and Cox proportional hazards models. Sensitivity analysis was carried out, using Fine and Gray models to account for competing risk of death. Confounding was minimized using propensity score adjustment and inverse probability weighting (IPW) adjustment. RESULTS: Data from 3082 postmenopausal women treated with TAM, and 18,455 treated with AI, were available. Adjusted hazard ratios (HRs) [95% confidence interval (CI)] for AI users, compared with TAM group, were 0.93 (95%CI 0.69-1.26) for thromboembolic events (TEEs); 1.13 (95%CI 0.79-1.63) for cardiovascular events, and 0.76 (95%CI 0.70-0.82) for mortality. Additional analyses using competing risk analysis had similar results, while IPW adjustment showed a potential risk of pulmonary embolism (PE) [2.26 (95%CI 1.02-4.97)] in AI-treated patients. CONCLUSIONS: AI users had >20% lower all-cause mortality compared with TAM users, without increasing risk to experience cardiovascular and TEEs. This would locate AI therapy on the first line in clinical practice. Thus, AI might be the most preferable option in adjuvant hormonal therapy choice.

Effectiveness and safety of a novel dexamethasone mouthwash formulation in managing stomatitis in cancer patients.

OBJECTIVE: To present a new dexamethasone mouthwash formulation and  analyze its effectiveness and safety among patients receiving stomatitis-producing antineoplastic agents. METHOD: Prospective observational study conducted in a university hospital between March 2017 and November 2019. Consecutive patients starting everolimus were enrolled. Patients were instructed to rinse dexamethasone mouthwash formulation twice daily until discontinuation of everolimus. A second cohort of patients with existing stomatitis induced by  high probability of producing stomatitis chemotherapy therapies was also  recruited to assess treatment effectiveness. Effectiveness and safety of dexamethasone mouthwash formulation was assessed. RESULTS: Dexamethasone mouthwash formulation was prescribed in nine patients as prophylaxis. Six patients were diagnosed with breast cancer, two with neuroendocrine tumor and one with renal cell carcinoma. Four patients developed mild stomatitis (grade 1-2) and three patients  discontinued everolimus due to other treatment-related adverse events. In  addition, dexamethasone mouthwash formulation was prescribed as treatment in five patients with existing stomatitis. All patients achieved a significant reduction in the severity of stomatitis after starting the  dexamethasone mouthwash formulation. In both cohorts, dexamethasone  mouthwash formulation was well tolerated and neither dose reduction nor  discontinuation related to stomatitis was required. CONCLUSIONS: Dexamethasone mouthwash formulation could be considered as a  suitable alternative for stomatitis management.

Objetivo: Describir una nueva formulación de enjuague bucal con dexametasona y analizar su efectividad y seguridad en pacientes que reciben agentes antineoplásicos que producen estomatitis.Método: Estudio observacional prospectivo realizado en un hospital universitario entre marzo de 2017 y noviembre de 2019. Se incluyeron los pacientes que  iniciaron everolimus. El tratamiento consistió en enjuagar con solución oral de  dexametasona dos veces al día hasta la interrupción del tratamiento con  everolimus. Se reclutó una segunda cohorte de pacientes con estomatitis  inducida por otros agentes antineoplásicos con alta probabilidad de provocar  estomatitis. Se evaluó la efectividad y seguridad del enjuague bucal con  dexametasona.Resultados: Se reclutaron nueve pacientes en profilaxis con formulación de  enjuague bucal con dexametasona; seis pacientes presentaban un diagnóstico  de cáncer de mama, dos de tumor neuroendocrino y uno de carcinoma renal.  Cuatro pacientes desarrollaron estomatitis leve (grado 1-2) y tres pacientes  descontinuaron everolimus por otros eventos adversos relacionados con el  tratamiento. Se prescribió enjuague bucal con dexametasona en cinco pacientes  con estomatitis existente como tratamiento. Todos los pacientes lograron una  reducción significativa de la gravedad de la estomatitis tras iniciar el enjuague  bucal con dexametasona. En general, el nuevo enjuague bucal con  dexametasona fue bien tolerado y no se requirieron reducción de dosis ni  interrupción debido a estomatitis.Conclusiones: La nueva formulación de enjuague bucal con dexametasona podría considerarse una alternativa adecuada para el manejo de la estomatitis.

Increased Fracture Risk in Women Treated With Aromatase Inhibitors Versus Tamoxifen: Beneficial Effect of Bisphosphonates.

Aromatase inhibitors have been associated with accelerated bone loss and an increased risk of osteoporotic fractures. Currently, bisphosphonates are recommended to reduce fracture risk in these patients. The aim of this study is to evaluate the fracture risk in breast cancer patients receiving aromatase inhibitors, compared to tamoxifen users, and to assess the effectiveness of oral bisphosphonates in reducing fracture risk. We performed an observational cohort study up to 10 years of follow-up. Data were extracted from primary care records in a population database. Women diagnosed with breast cancer between 2006 and 2015 and treated with tamoxifen or aromatase inhibitors (n = 36,472) were stratified according to low (without osteoporosis diagnosis nor bisphosphonates exposure) or high (with osteoporosis and/or treated with bisphosphonates) fracture risk. Cox models were used to calculate hazard ratios (HR [95% CI]) of fracture from the propensity score-matched patients. Sensitivity analyses account for competing risk of death were performed (subdistribution hazard ratio [SHR] [95% CI]). In postmenopausal women, fracture risk in aromatase inhibitor users showed an HR 1.40 [95% CI,1.05 to 1.87] and SHR 1.48 [95% CI, 1.11 to 1.98], compared to tamoxifen. Observing aromatase inhibitors patients at high risk of fracture, bisphosphonate-treated patients had an HR 0.73 [95% CI, 0.51 to 1.04] and SHR 0.69 [95% CI, 0.48 to 0.98] compared to nontreated. In conclusion, fracture risk in postmenopausal women during aromatase inhibitor treatment, in real-life conditions, was >40% compared to tamoxifen, corroborating previous randomized controlled trials results. In high-risk patients, bisphosphonate users had lower significant fracture incidence during aromatase inhibitor therapy than nonbisphosphonate users. Monitoring fracture risk and related risk factors in aromatase inhibitor patients is advisable. © 2019 American Society for Bone and Mineral Research.

High Numbers of Circulating CD57+ NK Cells Associate with Resistance to HER2-Specific Therapeutic Antibodies in HER2+ Primary Breast Cancer.

Natural killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathologic complete response (pCR) to HER2-specific therapeutic antibodies in patients with primary breast cancer. Here, we analyzed whether diversity in circulating NK cells might influence tumor infiltration and HER2-specific therapeutic antibody efficacy. We found that numbers of circulating CD57+ NK cells inversely correlated with pCR to HER2-specific antibody treatment in patients with primary breast cancer independently of age, traditional clinicopathologic factors, and CD16A 158F/V genotype. This association was uncoupled from the expression of other NK-cell receptors, the presence of adaptive NK cells, or changes in major T-cell subsets, reminiscent of cytomegalovirus-induced immunomodulation. NK-cell activation against trastuzumab-coated HER2+ breast cancer cells was comparable in patients with high and low proportions of CD57+ NK cells. However, circulating CD57+ NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation in vitro Presence of CD57+ NK cells was reduced in breast tumor-associated infiltrates as compared with paired peripheral blood samples, suggesting deficient homing, proliferation, and/or survival of NK cells in the tumor niche. Indeed, numbers of circulating CD57+ were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57+ NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer.

Assessment of early therapy discontinuation and health-related quality of life in breast cancer patients treated with aromatase inhibitors: B-ABLE cohort study.

PURPOSE: The most frequent adverse effects of aromatase inhibitors (AI) are arthralgia and bone loss induction. These reduce the quality of life of patients and their adherence to the treatment. This study evaluates the early AI cessation caused by AI intolerance, and the evolution of joint pain and health-related quality of life (HRQoL) during AI treatment until 1-year after AI completion. METHODS: Data of 910 women diagnosed with early breast cancer and candidates for AI were recruited in B-ABLE cohort. AI discontinuation was analyzed by survival analysis, including Kaplan-Meier estimation and Cox regression. Patients were distributed in three groups of the study according to previous tamoxifen (TAM) exposure and length of AI treatment: TAM-2yAI, TAM-3yAI, and 5yAI. Evolution of joint pain and HRQoL in osteoporosis was evaluated using Visual Analog Scale (VAS) and ECOS-16 tests, respectively, from baseline to 1-year after AI completion through repeated-measures ANOVA. RESULTS: Risk of AI discontinuation was increased in patients previously exposed to tamoxifen compared to non-exposed (adjusted HR 5.30 [95% CI 2.23 to 12.57]). VAS and ECOS-16 scores of TAM-2yAI and TAM-3yAI groups increased during AI treatment, mainly during the first 3-12 months. After 1-year from AI completion, values tend to decrease to baseline levels. In 5yAI group, VAS and ECOS-16 levels increased at three months, and VAS remained significantly higher at 1-year post-treatment. CONCLUSIONS: AI therapy increased joint pain and reduced HRQoL, mainly during the first year of treatment. Patients previously treated with tamoxifen experienced greater pain when they switched to AI therapy and had an excess risk of discontinuation during the first 12 months. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03811509. Registered 28 January 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03811509 .

Alkylphenolic compounds and risk of breast and prostate cancer in the MCC-Spain study.

BACKGROUND: Alkylphenolic compounds are chemicals with endocrine disrupting properties that have been widely used in industry with important changes in their usage over time. Few epidemiologic studies have evaluated the effect of alkylphenolic compounds on human health. OBJECTIVES: We investigated whether occupational exposure to alkylphenolic compounds is associated with breast and prostate cancer. METHODS: We carried out a population-based case-control study including 1513 incident cases of breast cancer, 1095 of prostate cancer, and 3055 controls, frequency matched by sex, age and region. Occupational exposure to alkylphenolic compounds was estimated using a recently developed job-exposure matrix, which considered different scenarios of exposure and different subtypes of alkylphenolic compounds. RESULTS: History of occupational exposure to alkylphenolic compounds was modestly associated with breast cancer (OR = 1.23; 95% CI = 1.01-1.48). Within the different scenarios, the occupational use of domestic tensioactives was positively associated with breast cancer (OR = 1.28; 95% CI = 1.02-1.60), while occupational exposure in other scenarios showed mostly a suggestion of a similar positive associations. Exposure to nonylphenol ethoxylates was positively associated with breast cancer (OR = 1.21; 95% CI = 1.00-1.47), while exposure to other compounds was uncommon. In general, we did not observe associations between alkylphenolic compounds and prostate cancer, except for a positive association among men occupationally exposed to cosmetic, hair and personal hygiene products. CONCLUSIONS: Our findings suggest a modest association between breast cancer risk and occupational exposure to alkylphenolic compounds, and no associations between these compounds and prostate cancer risk. These findings warrant further corroboration in other studies.

Vitamin D levels in Mediterranean breast cancer patients compared with those in healthy women.

OBJECTIVES: To evaluate the vitamin D status of postmenopausal women with early estrogen-receptor-positive breast cancer and to compare it with that of healthy postmenopausal women from the same Mediterranean region. STUDY DESIGN AND OUTCOME MEASURES: Data from 691 breast cancer (BC) patients in the B-ABLE cohort were analyzed after recent cancer intervention (recent-BC) or after a minimum of two years since this intervention (long-term-BC). Patients were also stratified by previous chemotherapy exposure (ChT+ and ChT-). Plasma levels of 25-hydroxyvitamin D [25(OH)D] (25(OH)D) were compared with data from 294 healthy women (non-BC) by linear regression to estimate ß-coefficients using non-BC participants as the reference group. Age, body mass index and season of blood extraction were selected as potential confounders. RESULTS: Of the recent-BC patients, 23.7% had 25(OH)D deficiency, compared with 17.7% of the long-term-BC group, and just 1.4% of the non-BC participants. Most of the women were located in the insufficient 25(OH)D category regardless of study group. BC patients had significantly lower 25(OH)D levels than non-BC participants (adjusted ß-coefficients: -4.84 [95%CI -6.56 to -3.12] in recent-BC, and -2.05 [95%CI -4.96 to -0.14] in long-term-BC). Among BC patients, the lowest 25(OH)D levels were found in the recent-BC (ChT+) group (p < 0.001). No differences were found between the long-term-BC (ChT-), long-term-BC (ChT+) and recent-BC (ChT-) groups. Among the BC ChT+ patients, the recent-BC group had significantly lower 25(OH)D levels than the long-term-BC group (p < 0.001). CONCLUSION: Severely reduced 25(OH)D levels were detected in patients with breast cancer, particularly after recent chemotherapy. These 25(OH)D levels had partially recovered over the long term, but still remained much lower than in the healthy population.

Bone health evaluation one year after aromatase inhibitors completion.

INTRODUCTION: Breast cancer patients treated with aromatase inhibitors (AIs) experience increased bone loss during their treatment. However, there is little information about bone mineral density (BMD) after completing AI-treatment. The present study aimed to assess BMD changes one year after AI-therapy completion. METHODS: Data were collected from 864 postmenopausal women treated with AI during 5 years (5y-AI group), or during 2-3 years after taking tamoxifen therapy (pTAM-AI group). Participants with osteoporosis were treated with oral bisphosphonates (BP). BMD changes in lumbar spine (LS), femoral neck (FN) and total hip (TH) between baseline, end of treatment, and at one year post-treatment were assessed using repeated-measures ANOVA. RESULTS: At the end of AI-treatment, 382 patients had available BMD values and 316 also had post-treatment BMD values. As expected, BMD levels were decreased at AI-completion in non-BP treated patients. After one year, LS BMD increased in both groups (5y-AI: +2.11% [95%CI: 1.55 to 2.68], p < 0.001; pTAM-AI: +1.00% [95%CI: 0.49 to 1.51], p < 0.001) compared with the end of AI-therapy, while values at FN and TH remained stable. On the other hand, BMD values of BP-treated patients were increased or maintained at the end of AI-treatment and also at post-treatment. CONCLUSIONS: At one year after AI-completion, FN and TH BMD remained reduced in non-BP treated women, while LS BMD was recovered in the 5y-AI group and partially recovered in the pTAM-AI group. BP treatment increased or maintained BMD values at the end of therapy and at one year post-treatment.

Changes in metabolic risk, insulin resistance, leptin and adiponectin following a lifestyle intervention in overweight and obese breast cancer survivors.

Adiposity and physical activity are modifiable factors that could be important determinants of breast cancer (BC) prognosis through their effects on endogenous reproductive hormones, chronic inflammation and metabolic changes. Therefore, it is necessary to evaluate whether offering lifestyle interventions to BC survivors could affect the levels of certain biomarkers involved in these mechanisms. We designed a pre-post intervention study offering diet and exercise sessions over 12 weeks to 42 overweight/obese BC survivors. Before and after the intervention, we obtained dietary information, anthropometry and cardiorespiratory fitness (CRF) measurements and blood samples to measure metabolic risk, insulin resistance and adipokines biomarkers. Wilcoxon signed-rank tests and Spearman partial correlation coefficients were used to compare pre- and post-measurements and assess the correlations between changes in biomarkers and changes in anthropometry and CRF. Breast cancer survivors showed significant improvements in metabolic risk biomarkers and insulin resistance indicators along with a non-significant leptin decrease and a significant adiponectin decrease. The improvements in metabolic risk biomarkers, insulin resistance indicators and leptin were moderately correlated (0.32 ≤ |r| ≤ 0.55) with the decrease in body mass index and the increase in CRF. Diet and exercise interventions implemented in overweight/obese BC survivors may improve metabolic risk, insulin resistance and leptin biomarkers.

Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations.

While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Here we present the Cancer Genome Interpreter, a versatile platform that automates the interpretation of newly sequenced cancer genomes, annotating the potential of alterations detected in tumors to act as drivers and their possible effect on treatment response. The results are organized in different levels of evidence according to current knowledge, which we envision can support a broad range of oncology use cases. The resource is publicly available at http://www.cancergenomeinterpreter.org .

Interplay between Natural Killer Cells and Anti-HER2 Antibodies: Perspectives for Breast Cancer Immunotherapy.

Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. The addition of HER2-targeted antibodies (i.e., trastuzumab, pertuzumab) to chemotherapy significantly improves relapse-free and overall survival in patients with early-stage and advanced disease. Nonetheless, considerable proportions of patients develop resistance to treatment, highlighting the need for additional and co-adjuvant therapeutic strategies. HER2-specific antibodies can trigger natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models. Antibody-dependent NK cell activation results in the release of cytotoxic granules as well as the secretion of pro-inflammatory cytokines (i.e., IFNγ and TNFα) and chemokines. Hence, NK cell tumor suppressive functions include direct cytolytic killing of tumor cells as well as the regulation of subsequent antitumor adaptive immunity. Albeit tumors with gene expression signatures associated to the presence of cytotoxic lymphocyte infiltrates benefit from trastuzumab-based treatment, NK cell-related biomarkers of response/resistance to HER2-specific therapeutic antibodies in breast cancer patients remain elusive. Several variables, including (i) the configuration of the patient NK cell repertoire; (ii) tumor molecular features (i.e., estrogen receptor expression); (iii) concomitant therapeutic regimens (i.e., chemotherapeutic agents, tyrosine kinase inhibitors); and (iv) evasion mechanisms developed by progressive breast tumors, have been shown to quantitatively and qualitatively influence antibody-triggered NK cell responses. In this review, we discuss possible interventions for restoring/enhancing the therapeutic activity of HER2 therapeutic antibodies by harnessing NK cell antitumor potential through combinatorial approaches, including immune checkpoint blocking/stimulatory antibodies, cytokines and toll-like receptor agonists.

Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer.

Purpose: Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.Experimental Design: HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate cyclin B1 were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human HER2-positive breast cancer explants.Results: We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells. Cyclin B1 knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing cdc20 partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation.Conclusions: Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer. Clin Cancer Res; 23(22); 7006-19. ©2017 AACR.

The Use of Antihypertensive Medication and the Risk of Breast Cancer in a Case-Control Study in a Spanish Population: The MCC-Spain Study.

INTRODUCTION: The evidence on the relationship between breast cancer and different types of antihypertensive drugs taken for at least 5 years is limited and inconsistent. Furthermore, the debate has recently been fueled again with new data reporting an increased risk of breast cancer among women with a long history of use of antihypertensive drugs compared with nonusers. METHODS: In this case-control study, we report the antihypertensive drugs-breast cancer relationship in 1,736 breast cancer cases and 1,895 healthy controls; results are reported stratifying by the women's characteristics (i.e., menopausal status or body mass index category) tumor characteristics and length of use of antihypertensive drugs. RESULTS: The relationship among breast cancer and use of calcium channel blockers (CCB) for 5 or more years had odds ratio (OR) = 1.77 (95% CI, 0.99 to 3.17). Stratifying by BMI, the OR increased significantly in the group with BMI ≥ 25 (OR 2.54, 95% CI, 1.24 to 5.22). CCBs were even more strongly associated with more aggressive tumors, (OR for invasive tumors = 1.96, 95% CI = 1.09 to 3.53; OR for non ductal cancers = 3.97, 95% CI = 1.73 to 9.05; OR for Erbb2+ cancer = 2.97, 95% CI: 1.20 to 7.32). On the other hand, premenopausal women were the only group in which angiotensin II receptor blockers may be associated with breast cancer (OR = 4.27, 95% CI = 1.32 to 13.84) but this could not be identified with any type or stage. Use of angiotensin-converting-enzyme inhibitors, beta blockers and diuretics were not associated with risk. CONCLUSIONS: In this large population-based study we found that long term use of calcium channel blockers is associated with some subtypes of breast cancer (and with breast cancer in overweight women).

Non-canonical NF-κB pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma.

BACKGROUND: NF-κB signalling appears deregulated in breast tumours. The purpose of this study was to determine whether the non-canonical NF-κB pathway, is activated in oestrogen receptor positive (ER+) breast cancer, to identify any correlation between its activity and the clinico-pathological phenotype and to explore whether NF-κB2 and RelB subunits and/or any of their target genes might be used as a predictive marker. METHODS: Two independent cohorts of ER+ early breast cancer patients treated with adjuvant endocrine therapy were included in the study. Activation of RelB and NF-κB2 subunits was determined in a training set of 121 patients by measuring DNA-binding activities in nuclear extracts from fresh frozen specimens by an ELISA-based assay. Samples of 15 ER- breast cancer patients were also included in the study. In a large validation cohort of 207 patients, nuclear immunostaining of RelB and NF-κB2 on formalin-fixed paraffin-embedded specimens was performed. Statistical correlation within clinico-pathological factors, disease-free survival (DFS) and overall survival (OS) was evaluated. Publicly available gene expression and survival data have been interrogated aimed to identify target genes. RESULTS: Activation of NF-κB2 and RelB was found in 53.7 and 49.2% of the 121 ER+ tumours analysed, with similar levels to ER- breast tumours analysed in parallel for comparisons. In the validation cohort, we obtained a similar proportion of cases with activation of NF-κB2 and RelB (59.9 and 32.4%), with a 39.6% of co-activation. Multiplexing immunofluorescence in breast cancer tissue confirmed an inverse spatial distribution of ER with NF-κB2 and RelB nuclear expression in tumour cells. Interestingly, NF-κB2 and RelB mRNA expression was inversely correlated with ER gene (ESR1) levels (P<0.001, both) and its activation was significantly associated with worse DFS (P=0.005 and P=0.035, respectively) in ER+ breast cancer. Moreover, the co-activation of both subunits showed a stronger association with early relapse (P=0.002) and OS (P=0.001). Finally, higher expression of the non-canonical NF-κB target gene myoglobin was associated with a poor outcome in ER+ breast cancer (DFS, P<0.05). CONCLUSIONS: The non-canonical NF-κB pathway activation is inversely associated with oestrogen receptor expression in ER+ breast cancer and predicts poor survival in this subgroup. The myoglobin gene expression has been identified as a possible surrogate marker of the non-canonical NF-κB pathway activation in these tumours.

Total Effective Xenoestrogen Burden in Serum Samples and Risk for Breast Cancer in a Population-Based Multicase-Control Study in Spain.

BACKGROUND: Most studies on endocrine-disrupting chemicals and breast cancer have focused on single compounds and have produced inconclusive findings. OBJECTIVES: We assessed the combined estrogenic effects of mixtures of xenoestrogens in serum and their relationship to breast cancer risk. METHODS: A total of 186 incident pretreatment breast cancer cases and 196 frequency-matched controls were randomly sampled from a large population-based multicase-control study in Spain. The total effective xenoestrogen burden attributable to organohalogenated xenoestrogens (TEXB-α) and endogenous hormones and more polar xenoestrogens (TEXB-ß) was determined in serum samples using high-performance liquid chromatography and E-Screen bioassay. Odds ratios for breast cancer comparing tertiles of serum TEXB-α and TEXB-ß were estimated using logistic models, and smooth risk trends were obtained using spline models. RESULTS: Cases had higher geometric mean TEXB-α and TEXB-ß levels (8.32 and 9.94 Eeq pM/mL, respectively) than controls (2.99 and 5.96 Eeq pM/mL, respectively). The fully adjusted odds ratios for breast cancer (95% confidence intervals) comparing the second and third tertiles of TEXB-α with the first tertile were 1.77 (0.76, 4.10) and 3.45 (1.50, 7.97), respectively, and those for TEXB-ß were 2.35 (1.10, 5.03) and 4.01 (1.88, 8.56), respectively. A steady increase in risk was evident across all detected TEXB-α levels and a sigmoidal trend was observed for TEXB-ß. Individual xenoestrogens showed weak and opposing associations with breast cancer risk. CONCLUSIONS: This is the first study to show a strong positive association between serum total xenoestrogen burden and breast cancer risk, highlighting the importance of evaluating xenoestrogen mixtures, rather than single compounds, when studying hormone-related cancers. CITATION: Pastor-Barriuso R, Fernández MF, Castaño-Vinyals G, Whelan D, Pérez-Gómez B, Llorca J, Villanueva CM, Guevara M, Molina-Molina JM, Artacho-Cordón F, Barriuso-Lapresa L, Tusquets I, Dierssen-Sotos T, Aragonés N, Olea N, Kogevinas M, Pollán M. 2016. Total effective xenoestrogen burden in serum samples and risk for breast cancer in a population-based multicase-control study in Spain. Environ Health Perspect 124:1575-1582; http://dx.doi.org/10.1289/EHP157.

AI-related BMD variation in actual practice conditions: A prospective cohort study.

The aim of the study was to evaluate the progression of bone mineral density (BMD) during 3 years of aromatase inhibitors (AI) therapy in actual practice conditions. This prospective, clinical cohort study of Barcelona-Aromatase induced Bone Loss in Early breast cancer (B-ABLE) assessed BMD changes during 3 years of AI treatment in women with breast cancer. Patients with osteoporosis (T score < -2.5 or T score ≤ -2.0) and a major risk factor and/or prevalent fragility fractures were treated with oral bisphosphonates (BPs). Of 685 women recruited, 179 (26.1%) received BP treatment. By the third year of AI therapy, this group exhibited increased BMD in the lumbar spine (LS; 2.59%) and femoral neck (FN; 2.50%), although the increase was significant only within the first year (LS: 1.99% and FN: 2.04%). Despite BP therapy, however, approximately 15% of these patients lost more than 3% of their baseline bone mass. At 3 years, patients without BP experienced BMD decreases in the LS (-3.10%) and FN (-2.79%). In this group, BMD changes occurred during the first (LS: -1.33% and FN: -1.25%), second (LS: -1.19% and FN: -0.82%), and third (LS: -0.57% and FN: -0.65%) years of AI treatment. Increased BMD (>3%) was observed in just 7.6% and 10.8% of these patients at the LS and FN, respectively. Our data confirm a clinically relevant bone loss associated with AI therapy amongst nonusers of preventative BPs. We further report on the importance of BMD monitoring as well as calcium and 25-hydroxy vitamin D supplementation in these patients.

Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile.

Around 40% of patients with breast cancer will present with a recurrence of the disease. Chemotherapy is recommended for patients with recurrent hormone-independent or hormone-refractory breast cancer and almost all patients with metastatic breast cancer (MBC) receive chemotherapy during their medical history. Nanoparticle albuminbound (nab)-paclitaxel is a solvent-free, 130-nanometer particle formulation of paclitaxel. Nab-paclitaxel can be administered to all patients for whom the treatment choice is a taxane. In this review, 6 patient profiles for which nabpaclitaxel may be particularly useful are described and analyzed: (i) as first-line treatment of MBC, (ii) as second-line treatment of MBC after oral chemotherapy, (iii) after a standard taxane, (iv) as third-line treatment after a standard taxane and oral chemotherapy, (v) for patients with HER2-positive MBC and (vi) for patients with intolerance to standard taxanes. Nab-paclitaxel is a rational treatment choice for patients with MBC in different settings, as well as for those with prior exposure to a standard taxane.

Perinatal and childhood factors and risk of breast cancer subtypes in adulthood.

BACKGROUND: Accumulated exposure to hormones and growth factors during early life may influence the future risk of breast cancer (BC). This study examines the influence of childhood-related, socio-demographic and anthropometric variables on BC risk, overall and by specific pathologic subtypes. METHODS: This is a case-control study where 1539 histologically-confirmed BC cases (23-85 years) and 1621 population controls, frequency matched by age, were recruited in 10 Spanish provinces. Perinatal and childhood-related characteristics were directly surveyed by trained staff. The association with BC risk, globally and according to menopausal status and pathologic subtypes, was evaluated using logistic and multinomial regression models, adjusting for tumor specific risk factors. RESULTS: Birth characteristics were not related with BC risk. However, women with high socioeconomic level at birth presented a decreased BC risk (OR=0.45; 95% CI=0.29-0.70), while those whose mothers were aged over 39 years at their birth showed an almost significant excess risk of hormone receptor positive tumors (HR+) (OR=1.35; 95% CI=0.99-1.84). Women who were taller than their girl mates before puberty showed increased postmenopausal BC risk (OR=1.26; 95% CI=1.03-1.54) and increased HR+ BC risk (OR=1.26; 95% CI=1.04-1.52). Regarding prepubertal weight, while those women who were thinner than average showed higher postmenopausal BC risk (OR=1.46; 95% CI=1.20-1.78), associated with HR+ tumors (OR=1.34; 95% CI=1.12-1.61) and with triple negative tumors (OR=1.56; 95% CI=1.03-2.35), those who were heavier than average presented lower premenopausal BC risk (OR=0.64; 95% CI=0.46-0.90) and lower risk of epidermal growth factor receptor positive tumors (OR=0.61; 95% CI=0.40-0.93). CONCLUSION: These data reflect the importance of hormones and growth factors in the early stages of life, when the mammary gland is in development and therefore more vulnerable to proliferative stimuli.