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1.
Breast ; 76: 103761, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38880077

ABSTRACT

BACKGROUND: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. METHODS: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. RESULTS: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1-2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0-1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). CONCLUSIONS: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Fulvestrant , Letrozole , Piperazines , Proton Pump Inhibitors , Pyridines , Receptor, ErbB-2 , Receptors, Estrogen , Humans , Pyridines/administration & dosage , Pyridines/therapeutic use , Female , Piperazines/administration & dosage , Piperazines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Middle Aged , Aged , Receptor, ErbB-2/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Letrozole/administration & dosage , Proton Pump Inhibitors/administration & dosage , Adult , Receptors, Estrogen/metabolism , Receptors, Estrogen/analysis , Fulvestrant/administration & dosage , Fulvestrant/therapeutic use , Progression-Free Survival , Receptors, Progesterone/metabolism , Aged, 80 and over
2.
EClinicalMedicine ; 71: 102520, 2024 May.
Article in English | MEDLINE | ID: mdl-38638399

ABSTRACT

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

3.
J Clin Oncol ; 42(11): 1288-1300, 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38301187

ABSTRACT

PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive. RESULTS: One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status. CONCLUSION: Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.


Subject(s)
Breast Neoplasms , Phthalazines , Piperazines , Quality of Life , Receptor, ErbB-2 , Female , Humans , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Fatigue/chemically induced , Mutation , Nausea , Patient Reported Outcome Measures , Vomiting
4.
Breast ; 69: 342-348, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37011481

ABSTRACT

PURPOSE: Tamoxifen is a drug used for hormone receptor-positive breast cancers, primarily metabolised by the CYP2D6 enzyme into active metabolites such as endoxifen. CYP2D6 displays varying degrees of activity depending on its genotype. This study aims to analyse the effect of an early increase in tamoxifen dose in poor metabolisers (PM) on survival. METHODS: We enrolled 220 patients diagnosed with breast cancer who were treated with tamoxifen. CYP2D6 polymorphisms were determined, and the phenotype was estimated according to the Clinical Pharmacogenetics Implementation Consortium. Disease-free survival (DFS) and overall survival (OS) were analysed considering the entire patient group, and a subgroup of 110 patients selected by Propensity Score Matching (PSM). All women were treated with 20 mg/day of tamoxifen for 5 years, except PM, who initially received 20 mg/day for 4 months, followed by 40 mg/day for 4 months and 60 mg/day for 4 months before returning to the standard dose of 20 mg/day until completing 5 years of treatment. RESULTS: The analysis of the influence of CYP2D6 polymorphisms in the complete group and in the PSM subgroup revealed no significant differences for DFS or OS. Furthermore, DFS and OS were analysed in relation to various covariates such as age, histological grade, nodal status, tumour size, HER-2, Ki-67, chemotherapy, and radiotherapy. Only age, histological grade, nodal status, and chemotherapy treatment demonstrated statistical significance. CONCLUSION: An early increase in tamoxifen dose in PM patients is not associated with survival differences among CYP2D6 phenotypes.


Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cytochrome P-450 CYP2D6/genetics , Propensity Score , Antineoplastic Agents, Hormonal/therapeutic use , Treatment Outcome , Tamoxifen/therapeutic use , Genotype
5.
Oncologist ; 28(1): 23-32, 2023 01 18.
Article in English | MEDLINE | ID: mdl-36239405

ABSTRACT

BACKGROUND: Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. MATERIALS AND METHODS: Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant-palbociclib (FP) or letrozole-palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. RESULTS: A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P < .01). CONCLUSION: The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy. CLINICALTRIALS.GOV IDENTIFIER: NCT02491983; https://clinicaltrials.gov/ct2/show/NCT02491983).


Subject(s)
Breast Neoplasms , Pulmonary Embolism , Venous Thromboembolism , Female , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fulvestrant/therapeutic use , Letrozole/therapeutic use , Pulmonary Embolism/etiology , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Venous Thromboembolism/etiology
6.
Cancers (Basel) ; 14(14)2022 Jul 19.
Article in English | MEDLINE | ID: mdl-35884572

ABSTRACT

BACKGROUND: Most breast cancer (BC) patients fail to achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). The aim of this study was to evaluate whether imaging features (perfusion/diffusion imaging biomarkers + radiomic features) extracted from pre-treatment multiparametric (mp)MRIs were able to predict, alone or in combination with clinical data, pCR to NAC. METHODS: Patients with stage II-III BC receiving NAC and undergoing breast mpMRI were retrospectively evaluated. Imaging features were extracted from mpMRIs performed before NAC. Three different machine learning models based on imaging features, clinical data or imaging features + clinical data were trained to predict pCR. Confusion matrices and performance metrics were obtained to assess model performance. Statistical analyses were conducted to evaluate differences between responders and non-responders. RESULTS: Fifty-eight patients (median [range] age, 52 [45-58] years) were included, of whom 12 showed pCR. The combined model improved pCR prediction compared to clinical and imaging models, yielding 91.5% of accuracy with no false positive cases and only 17% false negative results. Changes in different parameters between responders and non-responders suggested a possible increase in vascularity and reduced tumour heterogeneity in patients with pCR, with the percentile 25th of time-to-peak (TTP), a classical perfusion parameter, being able to discriminate both groups in a 75% of the cases. CONCLUSIONS: A combination of mpMRI-derived imaging features and clinical variables was able to successfully predict pCR to NAC. Specific patient profiles according to tumour vascularity and heterogeneity might explain pCR differences, where TTP could emerge as a putative surrogate marker for pCR.

7.
Arch Esp Urol ; 74(10): 941-952, 2021 Dec.
Article in Spanish | MEDLINE | ID: mdl-34851309

ABSTRACT

Urological evaluation is essential to guarantee the success of the kidney transplant. Urologists working within a multidisciplinary team have a crucial role to detect and manage certain recipient urological conditions that could jeopardize the function and survival of the graft.The critical aspects that Urologists should consider in thepre-transplant evaluation would be:- Is renal transplantation surgical technique feasible with assumable risks based on the recipient's baseline characteristics? age, life expectancy, performance status,physical examination...- Is bladder function adequate to properly ensure the urine storage and voiding?- Is there a potentially treatable urinary flow obstruction?- Are there urological pathologies in the recipient that could lead to post-transplant complications that compromise graft survival: functional, infectious, oncological comorbidities…?- Based on the patient's cardiovascular risk factors, arteriosclerosis in the aorto-iliac territory colud put at risk thearterial anastomosis? In this chapter, we will try to explain how the pre-transplant urological evaluation should be guided according to the specific recipient characteristics. We will also explain which pre-transplant surgeries are required to avoid some risky that may compromise the recipient and graft survival after renal transplantation, as well as those should be postponed after transplantation.


La evaluación urológica en el estudio pre-trasplante es una pieza clave para garantizar eléxito del mismo. El papel del urólogo dentro de un equipo multidisciplinar que lleva a cabo esta evaluación es fundamental para detectar y manejar ciertas patologías urológicas del receptor que podrían poner en riesgo la función y supervivencia del injerto. Los puntos clave que el urólogo debe tratar en la consulta pretrasplante serían:- ¿La técnica quirúrgica del trasplante renal es viable con riesgos asumibles en base a las características basales del receptor? Edad biológica, esperanza de vida ,estado basal, exploración física…- ¿La función vesical es adecuada para asegurar un correcto almacenaje de la orina y una adecuada excreción de la misma?- ¿Existe una obstrucción al flujo urinario potencialmente tratable?- ¿Existen en el receptor patologías urológicas que puedan conllevar complicaciones en el post-trasplante que comprometan la función y supervivencia del injerto?:funcionales, infecciosas, oncológicas…- ¿En base a los factores de riesgo cardiovascular del paciente, podría existir una arteriosclerosis en el territorioaorto-iliaco que impida una anastomosis arterial congarantías? En este capítulo, trataremos de exponer cómo debemos orientar la consulta pre-trasplante desde el punto de vista urológico, comenzando por el estudio básico hasta el estudio más específico en base a características concretas del receptor. Además, expondremos cuáles son las cirugías pre-trasplante requeridas para eliminar condiciones de riesgo presentes en el potencial receptor que puedan comprometer la supervivencia del mismo y del injerto tras el trasplante renal así como, aquellos procedimientos programados indicados tras el trasplante.


Subject(s)
Kidney Transplantation , Urologic Diseases , Anastomosis, Surgical , Graft Survival , Humans , Kidney
8.
Arch. esp. urol. (Ed. impr.) ; 74(10): 941-952, Dic 28, 2021. tab
Article in Spanish | IBECS | ID: ibc-219465

ABSTRACT

La evaluación urológica en el estudiopre-trasplante es una pieza clave para garantizar eléxito del mismo. El papel del urólogo dentro de un equipo multidisciplinar que lleva a cabo esta evaluación esfundamental para detectar y manejar ciertas patologíasurológicas del receptor que podrían poner en riesgo lafunción y supervivencia del injerto.Los puntos clave que el urólogo debe tratar en la consulta pretrasplante serían:- ¿La técnica quirúrgica del trasplante renal es viablecon riesgos asumibles en base a las características basales del receptor? Edad biológica, esperanza de vida,estado basal, exploración física...- ¿La función vesical es adecuada para asegurar un correcto almacenaje de la orina y una adecuada excreción de la misma? - ¿Existe una obstrucción al flujo urinario potencialmentetratable?- ¿Existen en el receptor patologías urológicas que puedan conllevar complicaciones en el post-trasplante quecomprometan la función y supervivencia del injerto?:funcionales, infecciosas, oncológicas...- ¿En base a los factores de riesgo cardiovascular delpaciente, podría existir una arteriosclerosis en el territorio aorto-iliaco que impida una anastomosis arterial congarantías?En este capítulo, trataremos de exponer cómo debemosorientar la consulta pre-trasplante desde el punto de vista urológico, comenzando por el estudio básico hasta el estudio más específico en base a característicasconcretas del receptor. Además, expondremos cuálesson las cirugías pre-trasplante requeridas para eliminarcondiciones de riesgo presentes en el potencial receptorque puedan comprometer la supervivencia del mismo ydel injerto tras el trasplante renal así como, aquellos procedimientos programados indicados tras el trasplante.(AU)


Urological evaluation is essential to guarantee the success of the kidney transplant. Urologistsworking within a multidisciplinary team have a crucialrole to detect and manage certain recipient urologicalconditions that could jeopardize the function and survival of the graft.The critical aspects that Urologists should consider in thepre-transplant evaluation would be - Is renal transplantation surgical technique feasible withassumable risks based on the recipient’s baseline characteristics? age, life expectancy, performance status,physical examination...- Is bladder function adequate to properly ensure theurine storage and voiding?- Is there a potentially treatable urinary flow obstruction?- Are there urological pathologies in the recipient thatcould lead to post-transplant complications that compromise graft survival: functional, infectious, oncologicalcomorbidities...?- Based on the patient’s cardiovascular risk factors, arteriosclerosis in the aorto-iliac territory colud put at risk thearterial anastomosis?In this chapter, we will try to explain how the pre-transplant urological evaluation should be guided accordingto the specific recipient characteristics.We will also explain which pre-transplant surgeries arerequired to avoid some risky that may compromise therecipient and graft survival after renal transplantation, aswell as those should be postponed after transplantation.(AU)


Subject(s)
Humans , Kidney Transplantation , Ureteral Obstruction , Urinary Tract , Nephrectomy , Urologic Neoplasms , Urology , Urologic Diseases
9.
JAMA Oncol ; 7(12): 1791-1799, 2021 12 01.
Article in English | MEDLINE | ID: mdl-34617955

ABSTRACT

Importance: The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. Objective: To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. Design, Setting, and Participants: In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020. Interventions: Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). Main Outcomes and Measures: The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1. Results: A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. Conclusions and Relevance: Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02491983.


Subject(s)
Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Female , Fulvestrant , Humans , Letrozole/therapeutic use , Middle Aged , Piperazines , Pyridines , Receptor, ErbB-2
10.
J Pers Med ; 11(6)2021 Jun 12.
Article in English | MEDLINE | ID: mdl-34204722

ABSTRACT

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

12.
J Clin Invest ; 130(9): 4871-4887, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32573490

ABSTRACT

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.


Subject(s)
Breast Neoplasms , Cell Differentiation , Gene Expression Regulation, Neoplastic , Neoplasm Proteins/metabolism , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Animals , Breast Neoplasms/classification , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , MCF-7 Cells , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Metastasis , Neoplasm Proteins/genetics , Receptor, Fibroblast Growth Factor, Type 4/genetics
13.
J Clin Oncol ; 38(3): 203-213, 2020 01 20.
Article in English | MEDLINE | ID: mdl-31804894

ABSTRACT

PURPOSE: Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS: Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS: Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION: This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Capecitabine/therapeutic use , Chemotherapy, Adjuvant/methods , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Disease-Free Survival , Female , Humans , Middle Aged , Neoadjuvant Therapy , Young Adult
14.
Eur J Cancer ; 120: 54-64, 2019 10.
Article in English | MEDLINE | ID: mdl-31491604

ABSTRACT

BACKGROUND: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples. METHODS: A total of 57 paired primary and metastatic tumours from GEICAM/2009-03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion. FINDINGS: CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3-29) and 9 (range, 1-38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptor-positive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006). CONCLUSIONS: Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution.


Subject(s)
Biomarkers, Tumor/genetics , Bone Neoplasms/secondary , Brain Neoplasms/secondary , Breast Neoplasms/classification , Breast Neoplasms/pathology , Mutation , Skin Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Bone Neoplasms/genetics , Brain Neoplasms/genetics , Breast Neoplasms/genetics , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , High-Throughput Nucleotide Sequencing , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Prospective Studies , Skin Neoplasms/genetics
15.
Breast Cancer Res Treat ; 178(2): 251-261, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31388936

ABSTRACT

PURPOSE: Limited knowledge exists on the detection of breast cancer stem cell (BCSC)-related mutations in circulating free DNA (cfDNA) from patients with advanced cancers. Identification of new cancer biomarkers may allow for earlier detection of disease progression and treatment strategy modifications. METHODS: We conducted a prospective study to determine the feasibility and prognostic utility of droplet digital polymerase chain reaction (ddPCR)-based BCSC gene mutation analysis of cfDNA in patients with breast cancer. RESULTS: Detection of quantitative BCSC gene mutation in cfDNA by ddPCR mirrors disease progression and thus may represent a valuable and cost-effective measure of tumor burden. We have previously shown that hematological and neurological expressed 1-like (HN1L), ribosomal protein L39 (RPL39), and myeloid leukemia factor 2 (MLF2) are novel targets for BCSC self-renewal, and targeting these genetic alterations could be useful for personalized genomic-based therapy. CONCLUSION: BCSC mutation detection in cfDNA may have important implications for diagnosis, prognosis, and serial monitoring.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Transformation, Neoplastic/genetics , Circulating Tumor DNA , Mutation , Neoplastic Stem Cells/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/blood , Breast Neoplasms/mortality , DNA Mutational Analysis , Disease Progression , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Prognosis
16.
J Drug Assess ; 8(1): 62-69, 2019.
Article in English | MEDLINE | ID: mdl-31069129

ABSTRACT

Objective: The aim of this survey conducted by 20 leading Spanish oncologists was to analyze the concurrence between Spanish clinical practice and the recently published definition of the optimal sequence for the systemic treatment of metastatic breast cancer (MBC) according to patient profiles. Methods: A self-administered questionnaire was developed, divided into five sections comprising 34 specific questions related to sequential treatments, plus three additional general questions. Respondents were asked to justify negative answers. Participants were recruited randomly by invitation out of a total of 619 oncologists. The questionnaire was sent and collected via e-mail between October 2015 and May 2016. A total of 191 completed questionnaires were received. Results: Overall, 70% of oncologists would keep the three patient profiles exactly as proposed (hormone receptor-positive and HER2-negative, HER2-positive, and triple negative breast cancer). Affirmative answers to questions regarding treatment sequences for these patient profiles (1-34) ranged from 77.8-99.5%, with an average of 90.9% of oncologists being in agreement with the recommended sequential treatments. The lowest degree of consensus was observed for endocrine treatments in pre-menopausal women and for chemotherapy options in hormone-resistant patients, whilst the highest degree of consensus was reached for targeted therapies in HER2-positive patients and for endocrine therapy in post-menopausal women. In their comments, participants revealed a number of economic constraints that prevented them from implementing some of the best treatment options. Conclusions: In conclusion, despite the complexity of MBC treatment, there is general agreement on the optimal treatment sequences.

17.
Cancer Res ; 77(9): 2213-2221, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28249905

ABSTRACT

Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment. Cancer Res; 77(9); 2213-21. ©2017 AACR.


Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Neoplasm Proteins/genetics , Neoplasm Recurrence, Local/genetics , Receptor, ErbB-2/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/biosynthesis , Breast Neoplasms/classification , Breast Neoplasms/pathology , Estrogens/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Proteins/biosynthesis , Neoplasm Recurrence, Local/pathology , Prognosis , Transcriptome
18.
Curr Cancer Drug Targets ; 16(5): 415-28, 2016.
Article in English | MEDLINE | ID: mdl-26278712

ABSTRACT

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.


Subject(s)
Albumins/pharmacology , Albumins/therapeutic use , Breast Neoplasms/drug therapy , Nanoparticles/administration & dosage , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Animals , Bridged-Ring Compounds/pharmacology , Bridged-Ring Compounds/therapeutic use , Female , Humans , Taxoids/pharmacology , Taxoids/therapeutic use
19.
J Clin Oncol ; 33(32): 3788-95, 2015 Nov 10.
Article in English | MEDLINE | ID: mdl-26416999

ABSTRACT

PURPOSE: Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. PATIENTS AND METHODS: Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m(2), respectively, × four cycles), followed by docetaxel (100 mg/m(2) × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m(2), respectively, × four cycles), followed by capecitabine (1,250 mg/m(2) twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). RESULTS: After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). CONCLUSION: Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Lymph Nodes/pathology , Adult , Aged , Breast Neoplasms/surgery , Capecitabine/administration & dosage , Capecitabine/adverse effects , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Docetaxel , Drug Administration Schedule , Epirubicin/administration & dosage , Epirubicin/adverse effects , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Follow-Up Studies , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Staging , Odds Ratio , Taxoids/administration & dosage , Taxoids/adverse effects , Treatment Outcome
20.
J Med Genet ; 52(7): 498-502, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25908759

ABSTRACT

BACKGROUND: The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). METHODS: Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. RESULTS: Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004). CONCLUSIONS: Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Methylation/genetics , Epigenesis, Genetic/genetics , Mutation/genetics , Nuclear Proteins/genetics , Base Sequence , DNA Mismatch Repair/genetics , Genetic Testing/standards , Humans , Microsatellite Repeats/genetics , Molecular Sequence Data , MutL Protein Homolog 1 , Prevalence , Promoter Regions, Genetic/genetics , Sequence Analysis, DNA , Statistics, Nonparametric
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