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1.
ESMO Open ; 5(6)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33154022

RESUMO

BACKGROUND: In HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease ('trastuzumab-free interval', TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role. METHODS: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models. RESULTS: Out of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred <12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233). CONCLUSIONS: TFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients.

2.
J Clin Oncol ; 38(34): 4120-4129, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33052755

RESUMO

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

3.
Int J Cancer ; 147(10): 2708-2716, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32383162

RESUMO

Breast cancer risk is approximately twice as high in first-degree relatives of female breast cancer cases than in women in the general population. Less than half of this risk can be attributed to the currently known genetic risk factors. Recessive risk alleles represent a relatively underexplored explanation for the remainder of familial risk. To address this, we selected 19 non-BRCA1/2 breast cancer families in which at least three siblings were affected, while no first-degree relatives of the previous or following generation had breast cancer. Germline DNA from one of the siblings was subjected to exome sequencing, while all affected siblings were genotyped using SNP arrays to assess haplotype sharing and to calculate a polygenic risk score (PRS) based on 160 low-risk variants. We found no convincing candidate recessive alleles among exome sequencing variants in genomic regions for which all three siblings shared two haplotypes. However, we found two families in which all affected siblings carried the CHEK2*1100delC. In addition, the average normalized PRS of the "recessive" family probands (0.81) was significantly higher than that in both general population cases (0.35, P = .026) and controls (P = .0004). These findings suggest that the familial aggregation is, at least in part, explained by a polygenic effect of common low-risk variants and rarer intermediate-risk variants, while we did not find evidence of a role for novel recessive risk alleles.

4.
Br J Cancer ; 122(10): 1453-1460, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32203207

RESUMO

BACKGROUND: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. METHODS: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. RESULTS: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55-3.51]). CONCLUSIONS: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

5.
J Clin Oncol ; 38(11): 1186-1197, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32083990

RESUMO

PURPOSE: MINDACT demonstrated that 46% of patients with early breast cancer at high clinical but low genomic risk on the basis of MammaPrint may safely avoid adjuvant chemotherapy. A second random assignment (R-C) compared docetaxel-capecitabine with an anthracycline-based regimen. PATIENTS AND METHODS: R-C randomly assigned patients 1:1 between standard anthracycline-based regimens, with or without taxanes (control) and experimental docetaxel 75 mg/m2 intravenously plus oral capecitabine 825 mg/m2 two times per day for 14 days (DC) every 3 weeks for 6 cycles. The primary end point was disease-free survival (DFS). Secondary end points included overall survival and safety. RESULTS: Of 2,832 patients, 1,301 (45%) were randomly assigned, and 97% complied with R-C assignment. In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. At 5 years of median follow-up, DFS was not different between DC (n = 652) and control (n = 649; 90.7% [95% CI, 88% to 92.8%] v 88.8% [95% CI, 85.9% to 91.1%]; hazard ratio [HR], 0.83 [95% CI, 0.60 to 1.15]; P = .26). Overall survival (HR, 0.91 [95% CI, 0.54 to 1.53]) and DFS in the clinical high and genomic high-risk subgroup (86.1% v 88.1%; HR, 0.83 [95% CI, 0.58 to 1.21]) were similar in both arms. DC led to more grade 1 neuropathy (27.1% v 11.2%) and more grade 2 hand/foot syndrome (28.5% v 3.3%) and diarrhea (13.7% v 5.8%). Serious cardiac events occurred in 9 patients (control, n = 4; DC, n = 5). Fifty-three patients developed second cancers (control, n = 32; DC, n = 21; leukemia: 2 v 1). Five treatment-related deaths occurred (control, 2 [0.3%]; DC, 3 [0.5%]). CONCLUSION: Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.

6.
Int J Mol Sci ; 21(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085669

RESUMO

Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) (p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%-68%), and 44% (95%CI 22%-69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23-9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%-81%) and 0% (95%CI 0%-31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , MicroRNA Circulante/sangue , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada
7.
J Med Genet ; 56(9): 581-589, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31186341

RESUMO

BACKGROUND: The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. METHODS: 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS. RESULTS: The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively. CONCLUSION: Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Estudos de Casos e Controles , Tomada de Decisão Clínica , Gerenciamento Clínico , Genótipo , Humanos , Pessoa de Meia-Idade , Linhagem , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Adulto Jovem
8.
Cancer ; 125(2): 307-316, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30335191

RESUMO

BACKGROUND: Limited data exist on the safety of using anti-human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2-positive patients. METHODS: The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2-positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease-free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time-varying covariates to account for a guarantee-time bias. RESULTS: Ninety-two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52-2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307). CONCLUSIONS: For patients with HER2-positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Lapatinib/administração & dosagem , Lapatinib/uso terapêutico , Terapia Neoadjuvante , Gravidez , Complicações Neoplásicas na Gravidez/metabolismo , Complicações Neoplásicas na Gravidez/mortalidade , Receptor ErbB-2/metabolismo , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico
9.
Hum Mutat ; 37(9): 914-25, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27233470

RESUMO

XRCC2 genetic variants have been associated with breast cancer susceptibility. However, association studies have been complicated because XRCC2 variants are extremely rare and consist mainly of amino acid substitutions whose grouping is sensitive to misclassification by the predictive algorithms. We therefore functionally characterized variants in XRCC2 by testing their ability to restore XRCC2-DNA repair deficient phenotypes using a cDNA-based complementation approach. While the protein-truncating variants p.Leu117fs, p.Arg215*, and p.Cys217* were unable to restore XRCC2 deficiency, 19 out of 23 missense variants showed no or just a minor (<25%) reduction in XRCC2 function. The remaining four (p.Cys120Tyr, p.Arg91Trp, p.Leu133Pro, and p.Ile95Leu) had a moderate effect. Overall, measured functional effects correlated poorly with those predicted by in silico analysis. After regrouping variants from published case-control studies based on the functional effect found in this study and reanalysis of the prevalence data, there was no longer evidence for an association with breast cancer. This suggests that if breast cancer susceptibility alleles of XRCC2 exist, they are likely restricted to protein-truncating variants and a minority of missense changes. Our study emphasizes the use of functional analyses of missense variants to support variant classification in association studies.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mutação de Sentido Incorreto , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Reparo do DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos
10.
PLoS One ; 8(1): e55734, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23383274

RESUMO

The bulk of familial breast cancer risk (∼70%) cannot be explained by mutations in the known predisposition genes, primarily BRCA1 and BRCA2. Underlying genetic heterogeneity in these cases is the probable explanation for the failure of all attempts to identify further high-risk alleles. While exome sequencing of non-BRCA1/2 breast cancer cases is a promising strategy to detect new high-risk genes, rational approaches to the rigorous pre-selection of cases are needed to reduce heterogeneity. We selected six families in which the tumours of multiple cases showed a specific genomic profile on array comparative genomic hybridization (aCGH). Linkage analysis in these families revealed a region on chromosome 4 with a LOD score of 2.49 under homogeneity. We then analysed the germline DNA of two patients from each family using exome sequencing. Initially focusing on the linkage region, no potentially pathogenic variants could be identified in more than one family. Variants outside the linkage region were then analysed, and we detected multiple possibly pathogenic variants in genes that encode DNA integrity maintenance proteins. However, further analysis led to the rejection of all variants due to poor co-segregation or a relatively high allele frequency in a control population. We concluded that using CGH results to focus on a sub-set of families for sequencing analysis did not enable us to identify a common genetic change responsible for the aggregation of breast cancer in these families. Our data also support the emerging view that non-BRCA1/2 hereditary breast cancer families have a very heterogeneous genetic basis.


Assuntos
Neoplasias da Mama/genética , Hibridização Genômica Comparativa , Exoma , Mutação em Linhagem Germinativa , Cromossomos Humanos Par 4 , Família , Feminino , Genes BRCA1 , Genes BRCA2 , Ligação Genética , Humanos , Escore Lod , Fases de Leitura Aberta , Linhagem , Análise de Sequência de DNA
11.
PLoS One ; 8(2): e55681, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23409019

RESUMO

The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.


Assuntos
Alelos , Neoplasias da Mama/genética , Exoma , Genes BRCA1 , Genes BRCA2 , Feminino , Humanos
12.
J Med Genet ; 49(10): 618-20, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23054243

RESUMO

BACKGROUND: Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation. METHODS: The coding regions and exon-intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms. RESULTS: The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls. CONCLUSIONS: Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer.


Assuntos
Alelos , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , Feminino , Humanos , Fases de Leitura Aberta
13.
Radiother Oncol ; 102(1): 115-21, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22100658

RESUMO

BACKGROUND AND PURPOSE: It has been established that radiotherapy can increase cardiovascular disease (CVD) risk. Genetic variants, which play a role in the tissue, damage response and angiogenesis regulating TGFß pathway might give us insight into the mechanisms underlying radiation-induced CVD. We examined the effects of two polymorphisms, TGFß1 29C>T and PAI-1 5G>4G, on CVD incidence. MATERIALS AND METHODS: This retrospective cohort study included 422 10-year breast cancer survivors, aged <50 years at diagnosis, treated between 1977 and 1995. We collected information on treatment, oncological follow-up, CVD, CVD risk factors and genotypes. RESULTS: During a mean follow-up of 19.4 years, 61 patients developed CVD. Internal mammary chain (IMC) irradiation, exposing a part of the heart to radiation, was associated with a hazard ratio of 2.36 (95% CI: 1.27-4.37, p=0.01) compared to no IMC irradiation. Compared to the C/C+C/T genotype, the T/T genotype of the TGFß1 polymorphism was associated with hazard ratios of 1.79 (0.99-3.26, p=0.06) and 1.74 (0.90-3.34, p=0.10) in the total and IMC-irradiated group, respectively. We found no evidence for an association between PAI-1 5G>4G and CVD risk. CONCLUSION: Our study suggests there might be an association between the TGFß1 29C>T polymorphism and CVD risk in long-term breast cancer survivors.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Sistema Cardiovascular/efeitos da radiação , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Fator de Crescimento Transformador beta1/genética , Idoso , Feminino , Seguimentos , Variação Genética , Genótipo , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
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