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1.
Cell Death Dis ; 10(9): 666, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511498

RESUMO

Adriamycin(ADR) is still considered to be one of the most effective agents in the treatment of breast cancer (BrCa), its efficacy is compromised by intrinsic resistance or acquire characteristics of multidrug resistance. At present, there are few genetic alterations that can be exploited as biomarkers to guide targeted use of ADR in clinical. Therefore, exploring the determinants of ADR sensitivity is pertinent for their optimal clinical application. TP53 is the most frequently mutated gene in human BrCa, p53 mutation has been reported to be closely related to ADR resistance, whereas the underlying mechanisms that cause endogenous ADR resistance in p53-mutant BrCa cells are not completely understood. The aim of the present study was to investigate the potential roles of miRNA in the response to ADR in p53-mutated breast cancer. Here, we report that BrCa cells expressing mutp53 are more resistant to ADR than cells with wild-type p53 (wtp53). The DNA repair protein- Fanconi anemia complementation group F protein (FANCF) and the translesion synthesis DNA polymerase REV1 protein is frequently abundant in the context of mutant p53 of BrCa. By targeting two key factors, miR-30c increases the sensitivity of BrCa cells to ADR. Furthermore, p53 directly activates the transcription of miR-30c by binding to its promoter. Subsequent analyses revealed that p53 regulates REV1 and FANCF by modulating miR-30c expression. Mutation of the p53 abolished this response. Consistently, reduced miR-30c expression is highly correlated with human BrCa with p53 mutational status and is associated with poor survival. We propose that one of the pathways affected by mutant p53 to increase intrinsic resistance to ADR involves miR-30c downregulation and the consequent upregulation of FANCF and REV1. The novel miRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.

3.
Cancer Med ; 8(12): 5609-5618, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31407530

RESUMO

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild-type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild-type patients and among BRCA2 carriers vs matched wild-type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild-type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild-type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild-type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild-type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short-term repetitive hematopoietic stressors.

4.
BMC Res Notes ; 12(1): 403, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307552

RESUMO

OBJECTIVE: The aim of the descriptive, cross sectional, questionnaire-based study reported here was to explore the causes of low productivity in non-communicable diseases research among postgraduate scholars and early career researchers in Nigeria and identify measures that could facilitate increased research output. RESULTS: The 89 respondents were masters-level, doctoral scholars and resident doctors who attended a workshop. Majorities of the respondents (over 70%) either agreed or strongly agreed that factors contributing to poor non-communicable diseases research productivity include a dearth of in-country researchers with specialized skills, inability of Nigerian researchers to work in multidisciplinary teams, poor funding for health research, sub-optimal infrastructural facilities, and limited use of research findings by policy makers. Almost all the respondents (over 90%) agreed that potential strategies to facilitate non-communicable diseases research output would include increased funding for research, institutionalization of a sustainable, structured capacity building program for early career researchers, establishment of Regional Centers for Research Excellence, and increased use of research evidence to guide government policy actions and programs.

5.
Cancer Imaging ; 19(1): 48, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307537

RESUMO

BACKGROUND: Imaging techniques can provide information about the tumor non-invasively and have been shown to provide information about the underlying genetic makeup. Correlating image-based phenotypes (radiomics) with genomic analyses is an emerging area of research commonly referred to as "radiogenomics" or "imaging-genomics". The purpose of this study was to assess the potential for using an automated, quantitative radiomics platform on magnetic resonance (MR) breast imaging for inferring underlying activity of clinically relevant gene pathways derived from RNA sequencing of invasive breast cancers prior to therapy. METHODS: We performed quantitative radiomic analysis on 47 invasive breast cancers based on dynamic contrast enhanced 3 Tesla MR images acquired before surgery and obtained gene expression data by performing total RNA sequencing on corresponding fresh frozen tissue samples. We used gene set enrichment analysis to identify significant associations between the 186 gene pathways and the 38 image-based features that have previously been validated. RESULTS: All radiomic size features were positively associated with multiple replication and proliferation pathways and were negatively associated with the apoptosis pathway. Gene pathways related to immune system regulation and extracellular signaling had the highest number of significant radiomic feature associations, with an average of 18.9 and 16 features per pathway, respectively. Tumors with upregulation of immune signaling pathways such as T-cell receptor signaling and chemokine signaling as well as extracellular signaling pathways such as cell adhesion molecule and cytokine-cytokine interactions were smaller, more spherical, and had a more heterogeneous texture upon contrast enhancement. Tumors with higher expression levels of JAK/STAT and VEGF pathways had more intratumor heterogeneity in image enhancement texture. Other pathways with robust associations to image-based features include metabolic and catabolic pathways. CONCLUSIONS: We provide further evidence that MR imaging of breast tumors can infer underlying gene expression by using RNA sequencing. Size and shape features were appropriately correlated with proliferative and apoptotic pathways. Given the high number of radiomic feature associations with immune pathways, our results raise the possibility of using MR imaging to distinguish tumors that are more immunologically active, although further studies are necessary to confirm this observation.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Imagem por Ressonância Magnética/métodos , Idoso , Apoptose , Neoplasias da Mama/genética , Feminino , Humanos , Fenótipo
6.
Hum Mutat ; 40(11): e1-e23, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31209999

RESUMO

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68_69del (p.Glu23Valfs), c.5030_5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700_3704del (p.Val1234Glnfs), c.4065_4068del (p.Asn1355Lysfs), c.1504_1508del (p.Leu502Alafs), c.843_846del (p.Ser282Tyrfs), c.798_799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808_2811del (p.Ala938Profs), c.5722_5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310_1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771_775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform.

8.
Int J Cancer ; 145(12): 3321-3333, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173346

RESUMO

Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole-genome or whole-exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60-85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2 = 0.575, p = 0.010) and the combined APOBEC signatures (h2 = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21-0.45) of APOBEC signature contribution at genome-wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10-6 ). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.

9.
Hum Mutat ; 40(10): 1781-1796, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31112363

RESUMO

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.

10.
Mol Cancer Ther ; 18(5): 873-885, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30824611

RESUMO

Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumulation of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.

11.
Pharmacogenet Genomics ; 29(5): 106-113, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30882558

RESUMO

BACKGROUND: The N-acetyltransferase 2 (NAT2) enzyme has been understudied in Nigerians including genotype-phenotype association studies. OBJECTIVE: The aim of this study was NAT2 haplotype identification and genotype-phenotype investigations in HIV-positive and HIV-negative Nigerians. PATIENTS AND METHODS: Phenotypes included self-reported sulphonamide hypersensitivity survey, experimental and computational NAT2 phenotyping. The NAT2 gene was amplified by PCR. Gene sequencing used ABI 3730 and Haploview 4.2 for haplotype reconstruction. Genotype-phenotype analyses used the χ P-value and odds ratio with a 95% confidence interval. RESULTS: Self-reported sulphonamide hypersensitivity showed a prevalence of 3.1 and 12.4% in HIV-positive and HIV-negative Nigerians, respectively. NAT2 genetic variants 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G and 857G>A were not significantly different between both groups (odds ratio=0.87; 95% confidence interval: 0.54-1.38, P=0.55). Nine haplotypes: NAT2*4, NAT2*12A, NAT2*13A, NAT2*5B, NAT2*6A, NAT2*7B, NAT2*5C, NAT2*14B and NAT2*14A had frequencies more than 1%, whereas NAT2*12B had 1.1% in the HIV-positive and 0.4% in the HIV-negative group. Overall, slow acetylator haplotypes made up 68%. The NAT2*12 signature single-nucleotide polymorphism was in high linkage disequilibrium with signature single-nucleotide polymorphism for NAT2*13 (D'=0.97, r=0.61) and NAT2*5 (D'=0.98, r=0.64). Genotype-phenotype association analysis showed haplotypes NAT2*13A, NAT2*5C, NAT2*7B and NAT2*14A to be associated strongly with the slow metabolic phenotype (P=0.002, 0.029, 0.032 and 0.050, respectively). Computational phenotypes were similar, with 30.9, 66 and 3.1% for slow, intermediate and rapid acetylators, respectively, among HIV-positive Nigerians and 31.2, 66.3 and 2.5% among the HIV-negative group. Overall, slow phenotypes made up 31%. CONCLUSION: NAT2 haplotype frequencies are similar in Nigerians, irrespective of HIV status, but genotype-phenotype discordances exist.

12.
Br J Cancer ; 120(4): 398-403, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30723304

RESUMO

BACKGROUND: To evaluate the predictors of mortality, including ER status, in women with a BRCA2 mutation and breast cancer. METHODS: Eligible participants were identified from within two longitudinal cohorts. These patients were selected because they were diagnosed with breast cancer between 1975 and 2015 and carried a BRCA2 mutation. Data were abstracted from the medical record and pathology report. We analysed the effects of ER status and other variables on breast cancer specific survival using a Cox proportional hazards model. RESULTS: Three hundred ninety women with breast cancer and a BRCA2 mutation were included in the analysis. The mean follow-up time was 12.3 years (range 1-39 years) and 89 subjects died (22.8%). In the multivariate analysis, women with ER-positive tumours were more likely to die than women with ER-negative tumours (HR 2.08, 95% CI 0.99-4.36, p = 0.05), and this was of borderline significance. For the 233 women with ER-positive tumours the 20-year survival rate was 62.2%, compared to 83.7% for 58 women with ER-negative tumours (p = 0.03). CONCLUSIONS: The majority of women with a BRCA2 mutation present with ER-positive breast cancer, and for these women, prognosis may be worse than for BRCA2 carriers with ER-negative breast cancer.


Assuntos
Neoplasias da Mama/genética , Genes BRCA2 , Mutação , Receptores Estrogênicos/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade
13.
Cancer ; 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30387876

RESUMO

BACKGROUND: The Oncotype DX recurrence score (RS) is used as a tool for making decisions about chemotherapy for patients who have hormone receptor (estrogen receptor or progesterone receptor)-positive, HER2-negative breast cancer. There is no benefit from chemotherapy among patients aged ≥50 years who have lymph node-negative disease and an RS from 11 to 25, but the benefit of chemotherapy in the lymph node-positive group remains unknown. METHODS: On the basis of data from the National Cancer Data Base between 2010 and 2014, a nationwide, retrospective cohort study included 73,185 women who had stage I through IIIA breast cancer and an RS between 11 and 30. RESULTS: Receipt of chemotherapy was associated with a reduced risk of death among patients who had lymph node-positive breast cancer (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.45-0.74; P < .001) after adjusting for other prognostic factors in a multivariable Cox model. The 5-year survival gain ranged from 1.3% (RS 11-17 subgroup), to 3.3% (RS 18-25 subgroup), and to 6.7% (RS 26-30 subgroup). Among patients who had lymph node-negative disease, chemotherapy was associated with a reduced risk of death for those with an RS from 25 to 30 (HR, 0.68; 95% CI, 0.48-0.96; P = .03; 5-year survival gain, 1.8%), but there was no benefit from chemotherapy for patients who had an RS from 11 to 17 (HR, 0.97; 95% CI, 0.61-1.55; P = .90), and there was a marginally significant benefit for women who had an RS from 18 to 25 (HR, 0.79; 95% CI, 0.62-1.00; P = .05). Similar results were observed using propensity score-matching method. CONCLUSIONS: The benefit of chemotherapy for patients with breast cancer who have an intermediate RS is driven in a nonlinear fashion by RS: the higher the RS, the larger the absolute benefit. Findings from this study underscore the utility of real-world data to inform joint decision making in practice.

14.
Clin Genet ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30417332

RESUMO

Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.

15.
Sci Rep ; 8(1): 15572, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30349062

RESUMO

Long-noncoding RNAs (lncRNAs) have been shown to participate in oncogenesis across a variety of cancers and may represent novel therapeutic targets. However, little is known about the role of lncRNAs in basal-like breast cancer (BLBC), the aggressive form of breast cancer with no molecularly defined therapeutic target. To examine whether altered lncRNA expression contributes to the aggressive phenotype characteristic of BLBC, we performed a comparative analysis of BLBC versus non-BLBC using microarray profiling and RNA sequencing of primary breast cancer. We identified RP11-19E11.1 as a significantly up-regulated lncRNA in BLBC tumors and named it Basal-Like breast cancer Associated Transcript 1 (BLAT1). Analysis of pan-cancer datasets showed the highest expression of BLAT1 in BLBC tumors compared to all other cancers. Depletion of BLAT1 in breast cancer cells led to significantly increased apoptosis, partly because of accumulation of DNA damage. Mechanistically, BLAT1 expression is regulated at the epigenetic level via DNA methylation at CpG islands in the promoter. Concordantly, patients harboring tumors with BLAT1 hypomethylation showed decreased overall survival. Our results suggest that increased expression of BLAT1 via CpG site hypomethylation may contribute to the aggressive phenotype of BLBC, raising a possibility of new biomarkers for prognosis of aggressive BLBC tumors.

16.
J Exp Clin Cancer Res ; 37(1): 256, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30340507

RESUMO

BACKGROUND: Hypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has not been elucidated. METHODS: The mRNA and protein expressions of HIF-1α, HIF-2α, Wnt and Notch pathway were determined using qRT-PCR and western blot. Cell viability and renew ability were assessed by MTT, Flow cytometric analysis and soft agar colony formation. RESULTS: In our study, acute hypoxia (6-12 h) briefly increased HIF-1α expression, while chronic hypoxia (48 h) continuously enhanced HIF-2α expression and induced the resistance of breast cancer cells to Paclitaxel (PTX). Furthermore, HIF-2α overexpression induced a stem cell phenotype, the resistance to PTX and enhanced protein expression of stem cell markers, c-Myc, OCT4 and Nanog. Most importantly, Wnt and Notch signaling, but not including Shh, pathways were both activated by HIF-2α overexpression. Dickkopf-1 (DKK-1), a Wnt pathway inhibitor, and L685,458, an inhibitor of the Notch pathway, reversed the resistance to PTX and stem phenotype conversion induced by HIF-2α overexpression. In addition, HIF-2α overexpression enhanced tumorigenicity and resistance of xenograft tumors to PTX, increased activation of the Wnt and Notch pathways and induced a stem cell phenotype in vivo. CONCLUSION: In conclusion, HIF-2α promoted stem phenotype conversion and induced resistance to PTX by activating Wnt and Notch pathways.

17.
Cancer Cell ; 34(4): 529-530, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30300575

RESUMO

In this issue of Cancer Cell, Yuan et al. compared the somatic alterations harbored by tumors from European and African ancestry individuals. They determined that the latter group has a propensity for aberrations that are consistent with genomic instability, potentially lending insight to the genomic basis of cancer health disparities.

18.
BMC Womens Health ; 18(1): 152, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231883

RESUMO

BACKGROUND: Breast disorders cause great anxiety for women especially when they occur in pregnancy because breast cancer is the most common cause of cancer related deaths in women. Majority of the disorders are Benign Breast Diseases (BBD) with various degrees of associated breast cancer risks. With increasing breast cancer awareness in Nigeria, we sought to determine the prevalence and characteristics of breast disorders among a cohort of pregnant women. METHODS: A longitudinal study of 1248 pregnant women recruited in their first trimester- till 26 weeks gestational age consecutively from selected antenatal clinics (ANCs), in Ibadan, Southwest Nigeria. A pretested interviewer- administered questionnaire was used to collect information at recruitment. Clinical Breast Examination (CBE) using MammaCare® technique was performed at recruitment and follow up visits at third trimester, six weeks postpartum and six months postpartum. Women with breast disorders were referred for Breast Ultrasound Scan (BUS) and those with Breast Imaging Reporting and Data System (BIRADS) ≥4 had ultrasound guided biopsy. Statistical analysis was performed using Stata version 14. RESULTS: Mean age of participants was 29.7 ± 5.2 years and mean gestational age at recruitment was 20.4 ± 4.4 weeks. Seventy-two participants (5.8%) had a past history of BBD and 345 (27.6%) were primigravidae. Overall, breast disorder was detected among 223 (17.9%) participants and 149 (11.9%) had it detected at baseline. Findings from the CBE showed that 208 (69.6%) of 299 breast disorders signs found were palpable lumps or thickenings in the breast, 28 (9.4%) were persistent pain, and 63 (21.1%) were abscesses, infection and mastitis. Twenty out of 127 (15.7%) participants who had BUS performed were classified as BIRADS ≥3. Lesions found by BUS were reactive lymph nodes (42.5%), prominent ducts (27.1%), fibroadenoma (9.6%), breast cysts (3.8%) and fibrocystic changes (2.5%). No malignant pathology was found on ultrasound guided biopsy. CONCLUSIONS: Breast lump is a major breast disorder among pregnant women attending antenatal clinics in Ibadan. Routine clinical breast examination and follow up of pregnant women found with breast disorders could facilitate early detection of pregnancy associated breast cancer in low resource settings.

19.
Clin Cancer Res ; 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154229

RESUMO

PURPOSE: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer. METHODS: We performed dynamic contrast-enhanced magnetic resonance imaging (MRI) every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥ 20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. RESULTS: Between 2004-2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: four ductal carcinoma in situ (DCIS) and thirteen early stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis and no interval invasive cancers occurred. The sensitivity of bi-annual MRI alone was 88.2% and annual MG plus bi-annual MRI was 94.1%. The cancer detection rate of bi-annual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus bi-annual MRI. The number of recalls and biopsies needed to detect one cancer by bi-annual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. CONCLUSIONS: Bi-annual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus bi-annual MRI screening.

20.
J Clin Oncol ; 36(28): 2820-2825, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130155

RESUMO

PURPOSE: Among Nigerian women, breast cancer is diagnosed at later stages, is more frequently triple-negative disease, and is far more frequently fatal than in Europe or the United States. We evaluated the contribution of an inherited predisposition to breast cancer in this population. PATIENTS AND METHODS: Cases were 1,136 women with invasive breast cancer (mean age at diagnosis, 47.5 ± 11.5 years) ascertained in Ibadan, Nigeria. Patients were selected regardless of age at diagnosis, family history, or prior genetic testing. Controls were 997 women without cancer (mean age at interview, 47.0 ± 12.4 years) from the same communities. BROCA panel sequencing was used to identify loss-of-function mutations in known and candidate breast cancer genes. RESULTS: Of 577 patients with information on tumor stage, 86.1% (497) were diagnosed at stage III (241) or IV (256). Of 290 patients with information on tumor hormone receptor status and human epidermal growth factor receptor 2, 45.9% (133) had triple-negative breast cancer. Among all cases, 14.7% (167 of 1,136) carried a loss-of-function mutation in a breast cancer gene: 7.0% in BRCA1, 4.1% in BRCA2, 1.0% in PALB2, 0.4% in TP53, and 2.1% in any of 10 other genes. Odds ratios were 23.4 (95% CI, 7.4 to 73.9) for BRCA1 and 10.3 (95% CI, 3.7 to 28.5) for BRCA2. Risks were also significantly associated with PALB2 (11 cases, zero controls; P = .002) and TP53 (five cases, zero controls; P = .036). Compared with other patients, BRCA1 mutation carriers were younger ( P < .001) and more likely to have triple-negative breast cancer ( P = .028). CONCLUSION: Among Nigerian women, one in eight cases of invasive breast cancer is a result of inherited mutations in BRCA1, BRCA2, PALB2, or TP53, and breast cancer risks associated with these genes are extremely high. Given limited resources, prevention and early detection services should be especially focused on these highest-risk women.

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