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BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement.; METHODS: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n=8; cohort 1), asymptomatic untreated BMs (n=4; cohort 2), or progressing BMs after local therapy (n=9; cohort 3). Patients received 5.4mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial overall response rate (ORR-IC) for cohorts 2 and 3.; RESULTS: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P

Objective: To assess the effect of vitamin D supplementation on musculoskeletal complications related to aromatase inhibitor (AI) treatment in patients with breast cancer. Material and methods: Prospective observational study of women undergoing AI treatment, recruited in the B‐ABLE cohort. Patients with baseline serum 25 (OH) D (25‐hydroxyvitamin D) levels 0 at 3 months, was evaluated using logistic regression. Results: Vitamin D supplementation at the start of AI treatment decreased the risk of both incident arthralgia and its worsening. The effective threshold of 25 (OH) D in serum to reduce joint pain was established at 40 ng/ml. However, this threshold was not significantly related to bone changes at one year of follow‐up. However, vitamin D levels were in‐ versely correlated with lumbar spine bone loss (LS) (β=0.177% [95% CI: 0.014 to 0.340]). Conclusions: Vitamin D supplementation aimed at achieving serum 25(OH)D levels of at least 40 ng/ml is protective for arthralgia. Vitamin D levels at three months could predict the risk of bone loss in LS at one year of AI treatment. The‐ refore, high doses of vitamin D are recommended in these patients, who are more prone to musculoskeletal conditions.

Background: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes. Patients and methods: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQC30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively. Results: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs.-2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale. Conclusion: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated. Trial registration number: NCT02028507 (ClinTrials.gov). EudraCT study number: 2013-003170-27. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background: The effect of changes in mammographic density over time on the risk of breast cancer remains inconclusive. Methods: We used information from four centres of the Breast Cancer Screening Program in Spain in the period 1996-2015. We analysed individual level data from 117,388 women first screened age 50-54, with at least two screening examinations. Breast density was determined using the BI-RADS classification (A to D in increasing order) at earliest and latest screening examination. Adjusted Poisson regression models were used to estimate the relative risk (RR) and 95% confidence intervals (95% CI) of the association between changes in mammographic density and breast cancer risk over time. Results: During an average 5.8 years of follow-up, 1592 (1.36%) women had a breast cancer diagnosis. An increase in density category increased breast cancer risk, and a decrease in density decreased the risk, compared with women who remained in the same BI-RADS category. Women whose density category increased from B to C or B to D had a RR of 1.55 (95% CI = 1.24-1.94) and 2.32 (95% CI = 1.48-3.63), respectively. The RR for women whose density increased from C to D was 1.51 (95% CI = 1.03-2.22). Changes in BI-RADS density were similarly associated with the risk for invasive cancer than for ductal carcinoma in situ. Conclusions: Although a modest proportion of women changed BI-RADS density category, mammographic density changes modulated the risk of breast cancer and identified women at a differential risk. Using two longitudinal measures of BI-RADS density could help target women for risk-based screening strategies. (C) 2019 Elsevier Ltd. All rights reserved.

Objectives: To investigate how breast density affects screening performance indicators in a digital mammography context. Methods: We assessed the effect of breast density over the screen-detected and interval cancers rates, false-positives, specificity, sensitivity, recall rate, positive predictive value of recall (PPV-1), and PPV of invasive tests (PPV-2). Radiologists classified breast density using the BIRADS System. We used generalized estimating equations to account for within-woman correlation by means of the robust Huber-While variance estimator. Results: We included 177,164 women aged 50-69 years who underwent 499,251 digital mammograms from 2004 to 2015 in Spain. According to the fibroglandular tissue percentage, 24.7% of mammograms were classified as BI-RADS 1 ( < 25% glandular), 54.7% as BI-RADS 2 (25-50% glandular), 14.0% as BI-RADS 3 (51-75% glandular) and 6.6% as BI-RADS 4 ( > 75% glandular). Overall, women with BI-RADS 3 had the highest screen-detected cancer rate (5.9 per 1000) and BI-RADS 4 the highest interval cancer rate (2.4 per 1000). Sensitivity decreased from 89.2% in women with BI-RADS 1 to 67.9% in BI-RADS 4. Both PPV-1 and PPV-2 decreased from 10.4% to 5.7% and from 49.8% to 32.4% in women with BI-RADS 1 and BI-RADS 4, respectively. Women aged 60-69 years with BI-RADS 4 had the lowest sensitivity (54.9%) and the highest interval cancer rate (3.8 per 1000). Conclusions: Performance screening measures are negatively affected by breast density falling to a lower sensitivity and PPV, and higher interval cancer rate as breast density increases. Particularly women aged 60-69 years with > 75% glandular breasts had the worst results and therefore may be candidates for screening using other technologies.

Resumen Objetivos: Los inhibidores de la aromatasa (AI) son terapias endocrinas adyuvantes eficaces para pacientes con cáncer de mama, aunque se han asociado a un mayor riesgo de fractura osteoporótica. Previamente se ha demostrado una pérdida en el Trabecular Bone Score (TBS) que puede variar entre las pacientes tratadas con IA. El estudio pretendió identificar la base genética asociada al cambio en el TBS mediante el estudio de genes de la vía esteroidogénica. Material y métodos: La cohorte B-ABLE estudia de forma prospectiva a mujeres postmenopáusicas con cáncer de mama en tratamiento con IA. Se calculó el TBS a partir de los datos adquiridos en la densitometría mediante absorciometría radiológica dual (DXA) realizada al inicio y al final del tratamiento con IA. El cambio relativo del TBS se calculó como la variación porcentual del valor de TBS al final de tratamiento respecto al TBS basal. Para estudiar la posible asociación genética se genotiparon los polimorfismos de cambio de un nucleótido (SNPs) en los genes CYP11A1, CYP17A1, HDE3B2, HDE17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, GC, CYP27B1, VDR y CYP24A1. Se estudió mediante regresión lineal múltiple la posible relación entre genes y cambios en TBS contemplando los modelos de herencia genética dominante, recesivo y aditivo. Resultados: Se incluyeron en el estudio un total de 212 mujeres no tratadas con bisfosfonatos en las que pudo calcularse el TBS. La mitad de las pacientes habían recibido tratamiento previo con tamoxifeno. El porcentaje de cambio intra-individual del TBS fue del -0,04% [IC del 95%: -0,05 a -0,03; p

Resumen Objetivos: Identificar putativas variantes funcionales en los genes CYP11A1 y CYP17A1 asociadas a efectos musculoesqueléticos (pérdida acelerada de la masa ósea y artralgias) derivados del tratamiento con inhibidores de la aromatasa (IA). Material y métodos: La cohorte B-ABLE es un estudio prospectivo de mujeres postmenopáusicas con cáncer de mama en tratamiento con IA. La densidad mineral ósea en columna lumbar y cuello femoral se midió mediante densitometría, y el dolor articular mediante escala analógica visual. A partir de polimorfismos de cambio de un nucleótido (SNPs) en los genes CYP11A1 (rs4077581, rs11632698 y rs900798) y CYP17A1 (rs4919686, rs4919683, rs4919687, rs3781287, rs10786712, rs6163, rs743572), asociados previamente con eventos musculoesqueléticos, se construyeron los haplotipos para cada paciente de la cohorte, y se seleccionaron aquellos que mostraron mayor diferencia fenotípica (p

Resumen Objetivos: Identificar putativas variantes funcionales en los genes CYP11A1 y CYP17A1 asociadas a efectos musculoesqueléticos (pérdida acelerada de la masa ósea y artralgias) derivados del tratamiento con inhibidores de la aromatasa (IA). Material y métodos: La cohorte B-ABLE es un estudio prospectivo de mujeres postmenopáusicas con cáncer de mama en tratamiento con IA. La densidad mineral ósea en columna lumbar y cuello femoral se midió mediante densitometría, y el dolor articular mediante escala analógica visual. A partir de polimorfismos de cambio de un nucleótido (SNPs) en los genes CYP11A1 (rs4077581, rs11632698 y rs900798) y CYP17A1 (rs4919686, rs4919683, rs4919687, rs3781287, rs10786712, rs6163, rs743572), asociados previamente con eventos musculoesqueléticos, se construyeron los haplotipos para cada paciente de la cohorte, y se seleccionaron aquellos que mostraron mayor diferencia fenotípica (p

Item does not contain fulltext NF-small ka, CyrillicB has been linked to doxorubicin resistance in breast cancer patients. NF-small ka, CyrillicB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-small ka, CyrillicB-dependent genes and the biological consequences are unclear. We studied NF-small ka, CyrillicB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-small ka, CyrillicB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKbeta-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-small ka, CyrillicB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-small ka, CyrillicB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-small ka, CyrillicB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-small ka, CyrillicB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-small ka, CyrillicB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-small ka, CyrillicB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.

Background: NF-kappa B signalling appears deregulated in breast tumours. The purpose of this study was to determine whether the non-canonical NF-kappa B 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-kappa B2 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-kappa B2 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-kappa B2 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-kappa B2 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-kappa B2 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-kappa B2 and RelB nuclear expression in tumour cells. Interestingly, NF-kappa B2 and RelB mRNA expression was inversely correlated with ER gene (ESR1) levels (P

Objetivos: El objetivo del estudio fue analizar los cambios en la densidad mineral ósea (DMO) a lo largo del tratamiento con inhibidores de aromatasa (IA) en la práctica clínica y evaluar la asociación entre el gen CYP11A1 y la variación de DMO al final del tratamiento. Material y métodos: La cohorte B-ABLE es un estudio prospectivo de mujeres postmenopáusicas con cáncer de mama, en tratamiento con IA. Se analizó la variación de DMO durante todo el tratamiento con IA, así como las diferencias entre las pacientes tratadas y no-tratadas previamente con tamoxifeno (TMX). Tres polimorfismos (rs4077581, rs11632698 y rs900798) del gen CYP11A1, fueron genotipados para su asociación con la variación de DMO. Resultados: Las pacientes tratadas con TMX mostraron pérdidas más aceleradas de DMO que las no tratadas previamente con TMX (60% menos en columna y 46% en fémur a los 2 años y 70% menos en columna y 63% en fémur a los 3 años). No obstante, al final del tratamiento no se detectaron diferencias significativas en la pérdida de DMO entre ambos grupos de pacientes. Los 3 polimorfismos del gen CYP11A1 resultaron significativamente asociados a la variación de DMO en fémur al final del tratamiento. Conclusiones: La DMO disminuyó de forma más acelerada en las pacientes con tratamiento previo con TMX que en las que solo recibieron AI, a pesar de que no se detectaron diferencias significativas al final de tratamiento. Polimorfismos en el gen CYP11A1 están relacionados con la variación de la DMO en respuesta al tratamiento con IA. Objectives: The aim of this study was to analyze bone mineral density (BMD) changes throughout aromatase inhibitor (AI) treatment in clinical cases and also consider its association with the CYP11A1 gene and the BMD variation after treatment. Material and methods: The B-ABLE cohort is a prospective study of postmenopausal women with breast cancer, in AI treatment. BMD variation was analyzed during AI treatment, as well as the differences those patients who were treated and not treated previously with tamoxifen (TMX). Three polymorphisms (rs4077581, rs11632698 and rs900798) of the CYP11A1 gene were genotyped for their association with BMD variation. Results: TMX-treated patients presented more rapid BMD loss than those who did not undergo prior TMX treatment (60% less in spine and 46% in femur at 2 years and 70% less in the spine and 63% in the femur at 3 years). However, no significant BMD loss was detected after treatment in either group. The 3 CYP11A1 gene polymorphisms were significantly associated with BMD variation in the femur at the end of the treatment. Conclusions: BMD was reduced more rapidly in patients with prior TMX treatment than in those who only received AI, although no significant differences were detected after treatment. The 3 CYP11A1 gene polymorphisms were associated with BMD variation in response to AI treatment.

NF-?B has been linked to doxorubicin resistance in breast cancer patients. NF-?B nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-?B-dependent genes and the biological consequences are unclear. We studied NF-?B-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-?B-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKß-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-?B activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-?B driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-?B-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-?B driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-?B/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-?B-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.

Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly unselected patient populations. Two lines of research in this field are needed: the identification of novel subsets of patients that could potentially benefit from PARP inhibitors and the discovery of suitable targeted therapies for combination strategies.