Triple negative breast cancer: microRNA expression profile and novel discriminators according to BRCA1 status

Triple-negative breast cancer (TNBC) represents 15% of breast carcinomas. More than 80% of women with a breast cancer associated with a breast cancer type 1 (BRCA1) mutation develop a TNBC. microRNAs (miRNAs) play critical roles in diverse biological processes and are aberrantly expressed in several human neoplasms including breast cancer, where they function as actors of tumor onset, behavior, and progression. However, an extensive microRNA profile has not yet been determined for TNBC. Taqman low-density arrays (TLDAs) were used to screen the expression level of 667 miRNAs in TNBC versus normal breast tissues. Our TLDA results revealed 20 differentially expressed miRNAs among which 14 (10 upregulated and four downregulated) were confirmed by an individual quantitative real-time polymerase chain reaction. Interestingly, a novel link between BRCA1 status and miRNA expression level was identified through miR-96 and miR-10b that were very important discriminators between TNBC with mutated BRCA1 and TNBC with wild type BRCA1. This study promises discoveries of new pathological pathways at work in this dreadful disease and clearly warrants validation in large prospective studies with the aim of identifying novel biomarkers for diagnosis and targets for clinical interventions.     

Clinical implications for BRCA gene mutation in breast cancer

To investigate the mutations of BRCA1 and BRCA2 and determine whether clinic-pathological factors related to BRCA gene mutation. Mastectomy specimens from 360 breast cancers were enrolled and examined in the study. The relationship between BRCA gene mutation and clinic-pathological factors was evaluated. Overall, 280 patients were BRCA negative and 80 got BRCA gene mutation. Triple-negative breast cancers—i.e., breast cancers that do not express estrogen receptors (ER), progesterone receptors (PR) or human epidermal growth factor receptor 2 (HER2/neu)—was observed in 53.85% of the BRCA1 mutation patients, in 28.57% of the BRCA2 mutation cases, while 14.29% of BRCA negative patients. BRCA1 mutation patients got a heavy lymph node metastasis and higher nuclear grade tumors than the others (P = 0.004, 0.007). Furthermore, BRCA mutation was also found to be significantly related to ER, PR and HER2/neu status (P < 0.05). BRCA1 expression was not associated with breast cancer-specific survival in the triple-negative breast cancers (P = 0.742). After Cox regression, BRCA1 mutation was not shown to be an independent prognostic factor for breast cancer. These findings substantiated the possibility of tumors associated with BRCA1 mutations divided into two distinct groups, triple-negative and non-triple-negative groups requires further investigation.     

Reproductive factors and breast cancer risk among BRCA1 or BRCA2 mutation carriers: Results from ten studies

Although reproductive factors are among the most well-established risk factors for breast cancer in the general population, it is still a matter for debate whether these factors act as risk modifiers among BRCA1 or BRCA2 mutation carriers. This meta-analysis is the first to be performed to determine the relationship between reproductive factors and breast cancer risk among BRCA1 and BRCA2 mutation carriers. We searched the PubMed database up to February 2013. A total of ten studies met the inclusion criteria. The results showed that the reproductive factors may be associated with breast cancer risk only among BRCA1 mutation carriers. No association was found between parity and breast cancer risk. Compared with women at the youngest age in the first-birth category, women in the oldest age category were at a 38% lower risk of breast cancer (RR = 0.62, 95%CI = 0.45–0.85). Breastfeeding for at least 1 or 2 years was associated with a 37% reduction in breast cancer risk (RR = 0.63, 95%CI = 0.46–0.86). Women at the oldest age in the menarche category were at a 34% lower risk of breast cancer (RR = 0.66, 95%CI = 0.53–0.81) than women in the youngest age category. However, none of the reproductive factors were associated with breast cancer risk among BRCA2 mutation carriers. In conclusion, late age at first birth, breastfeeding, and late age at menarche protect against breast cancer in BRCA1 mutation carriers only. Further studies are needed to explore the mechanisms.     

Hereditary breast cancer; Genetic penetrance and current status with BRCA

The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D. Many BC susceptibility genes can be grouped into two classes, high- and low-penetrance genes, each of which interact with multiple genes and environmental factors. However, the penetrance of genes can also be represented by a spectrum, which ranges between high and low. Two of the most common susceptibility genes are BRCA1 and BRCA2, which perform vital cellular functions for repair of homologous DNA. Loss of heterozygosity accompanied by hereditary mutations in BRCA1 or BRCA2 increases chromosomal instability and the likelihood of cancer, as well as playing a key role in stimulating malignant transformation. With regard to pathological features, familial breast cancers caused by BRCA1 mutations usually differ from those caused by BRCA2 mutations and nonfamilial BCs. It is essential to acquire an understanding of these pathological features along with the genetic history of the patient to offer an individualized treatment. Germline mutations in BRCA1 and BRCA2 genes are the main genetic and inherited factors for breast and ovarian cancer. In fact, these mutations are very important in developing early onset and increasing the risk of familial breast and ovarian cancer and responsible for 90% of hereditary BC cases. Therefore, according to the conducted studies, screening of BRCA1 and BRCA2 genes is recommended as an important marker for early detection of all patients with breast or ovarian cancer risk with family history of the disease. In this review, we summarize the role of hereditary genes, mainly BRCA1 and BRCA2, in BC.     

The effect of the Flemish breast cancer screening program on breast cancer-specific mortality: A case-referent study

BackgroundBreast cancer screening programs were introduced in many countries worldwide following randomized controlled trials in the 1980s showing a reduction in breast cancer-specific mortality. However, their effectiveness remains debated and estimates vary. A breast cancer screening program was introduced in 2001 in Flanders, Belgium where high levels of opportunistic screening practices are observed. The effectiveness of this program was estimated by measuring its effect on breast cancer-specific mortality.MethodsWe performed a case-referent study to investigate the effect of participation in the Flemish population-based mammography screening program (PMSP) on breast cancer-specific mortality from 2005 to 2017. A multiple logistic regression model assessed the association between breast cancer-specific death and screening program participation status in the four years prior to (pseudo)diagnosis (yes/no), with adjustment for potential confounders (individual socio-economic position and calendar year of diagnosis) and stratified for age. In addition, we performed different sensitivity analyses.ResultsWe identified 1571 cases and randomly selected 6284 referents. After adjustment, women who participated in PMSP had a 51 % lower risk of breast cancer-specific mortality compared to those who did not (adjusted odds ratio [aOR] =0.49, 95 % CI: 0.44–0.55). Sensitivity analyses did not markedly change the estimated associations. Correction for self-selection bias reduced the effect size, but the estimate remained significant.ConclusionOur results indicate that in a context of high opportunistic screening rates, participation in breast cancer screening program substantially reduces breast cancer-specific mortality. For policy, these results should be balanced against the potential harms of screening, including overdiagnosis and overtreatment.     

Survival after breast cancer according to participation in organised or opportunistic screening and deprivation

BackgroundMany studies have investigated the survival of women by comparing those who participated in organised screening with those who did not. However, among those who do not participate in organised screening, some women undergo opportunistic screening, but these women remain difficult to identify, particularly in France. Therefore, the aim of this study was to identify opportunistic screening, and then to study survival after breast cancer separately according to participation in organised, opportunistic or no screening, and taking into account sociodemographic inequalities.MethodsThe study population was identified from 3 French cancer registries, whose data was crossed with the screening coordination centers and the National Health Data System to identify the different type of screening. The European Deprivation Index was used to define the level of deprivation. We estimated net survival using the Pohar-Perme method.ResultsThe 5-year net survival probabilities were higher for women who attended organised screening (97.0 %) than for women with opportunistic screening (94.1 %) or non-attenders (78.1 %). According to the level of deprivation, a significant difference was observed between the groups of women screened by organised and opportunistic screening, compared to the non-attenders.ConclusionThe identification of opportunistic screening is an important element in identifying women who do not screening. It enables to us to see that women who do not attend any screening have a much higher loss-of-opportunity in terms of survival than those who participate in organised or opportunistic screening, and even more so in the most deprived areas.     

Assessment of surveillance versus etiologic factors in the reciprocal association between papillary thyroid cancer and breast cancer

BackgroundMutually increased risks for thyroid and breast cancer have been reported, but the contribution of etiologic factors versus increased medical surveillance to these associations is unknown.MethodsLeveraging large-scale US population-based cancer registry data, we used standardized incidence ratios (SIRs) to investigate the reciprocal risks of thyroid and breast cancers among adult females diagnosed with a first primary invasive, non-metastatic breast cancer (N = 652,627) or papillary thyroid cancer (PTC) (N = 92,318) during 2000–2017 who survived ≥1-year.ResultsPTC risk was increased 1.3-fold [N = 1434; SIR = 1.32; 95 % confidence interval (CI) = 1.25–1.39] after breast cancer compared to the general population. PTC risk declined significantly with time since breast cancer (Poisson regression = P_trend <0.001) and was evident only for tumors ≤2 cm in size. The SIRs for PTC were higher after hormone-receptor (HR)+ (versus HR-) and stage II or III (versus stage 0-I) breast tumors. Breast cancer risk was increased 1.2-fold (N = 2038; SIR = 1.21; CI = 1.16–1.26) after PTC and was constant over time since PTC but was only increased for stage 0-II and HR + breast cancers.ConclusionAlthough some of the patterns by latency, stage and size are consistent with heightened surveillance contributing to the breast-thyroid association, we cannot exclude a role of shared etiology or treatment effects.     

Provider delay in treatment initiation and its influence on survival outcomes in women with operable breast cancer

AimThe goal of this study was to determine whether a delay in starting treatment via surgery or neoadjuvant chemotherapy is related to a decrease in cancer-specific survival (CSS) in women with operable breast cancer (BrCr).BackgroundLimited medical infrastructure and a lack of cancer prevention awareness in low- and middle-income countries have caused high BrCr incidence and mortality rates.MethodsWe analyzed a retrospective cohort of 720 women treated at a single center from 2005 to 2012. CSS estimates were obtained by the Kaplan-Meier method. A Cox model of proportional risks was performed to obtain the risk of dying from BrCr. We also obtained the risk according to the category of treatment initiation.ResultsWomen with locally advanced stages and without hormone receptor expression were more likely to initiate treatment after 45 days. Patients in Stage IIIA had a 78.1% survival if treatment was initiated before 45 days (95% CI, 0.70–0.84) and 63.6% survival if treatment was started after 45 days (95% CI, 0.44–0.78; p < 0.001). Patients in Stage IIIB had a 62.9% survival if treatment was initiated before 45 days (95% CI, 0.53–0.72) and 57.4% survival if treatment started after 45 days (95% CI, 0.31-0.89; p < 0.001). Prognostic factors in which lower survival was recognized were Stage IIIA, Stage IIIB, treatment initiation after 45 days, and triple-negative tumors.ConclusionsThe initiation of treatment within the first 45 days of diagnosis of BrCr in women portends better survival compared with those who began treatment longer than 45 days from diagnosis.     

Racial and socio-economic disparities in breast cancer hospitalization outcomes by insurance status

BackgroundBreast cancer remains a major cause of morbidity and mortality among women in the US, and despite numerous studies documenting racial disparities in outcomes, the survival difference between Black and White women diagnosed with breast cancer continues to widen. Few studies have assessed whether observed racial disparities in outcomes vary by insurance type e.g. Medicare/Medicaid versus private insurance. Differences in coverage, availability of networked physicians, or cost-sharing policies may influence choice of treatment and treatment outcomes, even after patients have been hospitalized, effects of which may be differential by race.PurposeThe aim of this analysis was to examine hospitalization outcomes among patients with a primary diagnosis of breast cancer and assess whether differences in outcome exist by insurance status after adjusting for age, race/ethnicity and socio-economic status.MethodsWe obtained data on over 67,000 breast cancer patients with a primary diagnosis of breast cancer for this cross-sectional study from the 2007–2011 Healthcare Cost and Utilization project Nationwide Inpatient Sample (HCUP-NIS), and examined breast cancer surgery type (mastectomy vs. breast conserving surgery or BCS), post-surgical complications and in-hospital mortality. Multivariable regression models were used to compute estimates, odds ratios and 95% confidence intervals.ResultsBlack patients were less likely to receive mastectomies compared with White women (OR: 0.80, 95% CI: 0.71–0.90), regardless of whether they had Medicare/Medicaid or Private insurance. Black patients were also more likely to experience post-surgical complications (OR: 1.41, 95% CI: 1.12–1.78) and higher in-hospital mortality (OR: 1.57, 95%: 1.21–2.03) compared with White patients, associations that were strongest among women with Private insurance. Women residing outside of large metropolitan areas were significantly more likely to receive mastectomies (OR: 1.89, 95% CI: 1.54–2.31) and experience higher in-hospital mortality (OR: 1.74, 95% CI: 1.40–2.16) compared with those in metropolitan areas, regardless of insurance type.ConclusionAmong hospitalized patients with breast cancer, racial differences in hospitalization outcomes existed and worse outcomes were observed among Black women with private insurance. Future studies are needed to determine factors associated with poor outcomes in this group of women, as well as to examine contributors to low BCS adoption in non-metropolitan areas.     

Parity and risk of developing breast cancer according to tumor subtype: A systematic review and meta-analysis

BackgroundClinical breast cancer subtypes are categorized basing on the expression of hormone receptors and overexpression of the human epidermal growth factor receptor 2 (HER2). It is still unclear whether parity impact the risk of different breast cancer subtypes.MethodsWe searched eight mainstream databases for published epidemiologic studies that assessed the relationship between parity and risk of breast cancer subtypes up to January 12, 2021. Parity number were unified into nulliparity and ever parity. The random-effects or fixed-effect models were used to calculate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) among different subtypes. Restricted cubic spline analysis with four knots was applied to determine the relationship of parity number and risk of breast cancer subtypes.ResultsWe pooled sixteen case-control and four cohort studies, and performed an analysis including 7795 luminal A, 3576 luminal B, 1794 HER2-overexpressing, and 5192 triple-negative breast cancer cases among 1135131 participants. The combined ORs for ever parity versus nulliparity indicated a 34% reduction in luminal A risk (OR=0.66, 95% CI: 0.56–0.78), and a 29% reduction in luminal B risk (OR=0.71, 95% CI: 0.63–0.81), there was no significant association in HER2-overexpressing or TNBC risk. In the dose-response analysis, we observed a potentially non-linear and gradually increasing protective relationship between the number of parity and luminal breast cancer risk.ConclusionsThe effect of parity on breast cancer seems to vary among breast tumor subtypes, and it plays a protective role in luminal breast cancer.     

Clinical and technological transition in breast cancer

This article is a summary of the conference “Clinical and technological transition in breast cancer” that took place in the Congress of the Spanish Society of Radiation Oncology, placed in Vigo (Spain) on June 21, 2013. Hugo Marsiglia and Philip Poortmanns were the speakers, the first discussed about “Clinical and technological transition” and the second about “EORTC clinical trials and protocols”.     

Evolutionary dynamics of BRCA1 alterations in breast tumorigenesis

Cancer results from the accumulation of alterations in oncogenes and tumor suppressor genes. Tumor suppressors are classically defined as genes which contribute to tumorigenesis if their function is lost. Genetic or epigenetic alterations inactivating such genes may arise during somatic cell divisions or alternatively may be inherited from a parent. One notable exception to this rule is the BRCA1 tumor suppressor that predisposes to hereditary breast cancer when lost. Genetic alterations of this gene are hardly ever observed in sporadic breast cancer, while individuals harboring a germline mutation readily accumulate a second alteration inactivating the remaining allele—a finding which represents a conundrum in cancer genetics. In this paper, we present a novel mathematical framework of sporadic and hereditary breast tumorigenesis. We study the dynamics of genetic alterations driving breast tumorigenesis and explore those scenarios which can explain the absence of somatic BRCA1 alterations while replicating all other disease statistics. Our results support the existence of a heterozygous phenotype of BRCA1 and suggest that the loss of one BRCA1 allele may suppress the fitness advantage caused by the inactivation of other tumor suppressor genes. This paper contributes to the mathematical investigation of breast tumorigenesis.     

BRCA1、PTEN、Rb、C-myc和C-myb在乳腺癌中的异常表达及临床意义探讨

目的 探讨BRCA1、PTEN、Rb、C-myc、C-myb蛋白异常表达在乳腺癌发生、发展中的作用及其临床意义.方法应用免疫组织化学S-P法检测150例乳腺癌、20例不典型增生和30例良性增生性病变组织中BRCA1、PTEN、Rb、C-myc、C-myb蛋白的表达;结合临床病理指标进行分析.结果 乳腺癌组织和不典型增生组织中 BRCA1、PTEN、Rb、C-myc、C-myb蛋白表达与良性增生性病变组织中表达均具有显著性差异(P<0.05).BRCA1蛋白失表达率随乳腺癌组织学分级的增高而增高,在年龄<50岁和ER(雌激素受体)阴性时BRCA1蛋白失表达率增高.PTEN蛋白的失表达与淋巴结转移、ER失表达有关(P<0.05).Rb蛋白在乳腺癌Ⅲ级中失表达率较高,但无统计学差异(P＞0.05).C-myc蛋白的过表达与组织学分级、淋巴结转移及病理类型有关(P<0.05).C-myb蛋白的过表达与乳腺癌组织学分级有关(P<0.05).结论 BRCA1、PTEN、Rb、C-myc、C-myb蛋白异常表达均在乳腺癌的发生过程中起作用;PTEN、C-myc、C-myb 蛋白的异常表达参与了乳腺癌的浸润和转移.     

Naturally occurring B-cell responses to breast cancer

As demonstrated by the effectiveness of trastuzumab, antibodies against breast cancer antigens are a potentially potent mechanism of tumor control. While trastuzumab is administered exogenously, its efficacy suggests that induction of very high titer antibody responses in vivo might also be therapeutic. Both naturally occurring and vaccine-induced antibody responses to some breast cancer antigens are associated with improved survival in some cases. However, the improvement in survival associated with antibody responses to breast cancer is modest, and tumor regression is not known to be associated with the natural antitumor antibody response, indicating a need for improved understanding of the natural antitumor antibody response. Naturally occurring B-cell responses in the form of serum antibody, tumor reactive lymph node B cells, and tumor-infiltrating B cells have been described, and a variety of breast tumor–associated antigens have been identified based on reactivity of patient antibodies. This review discusses current knowledge of humoral immunity to breast cancer with regard to specific antigens and the basis for their immunogenicity, and the contexts (tumor, lymph node, serum) in which responses are observed. With few exceptions, "tumor-associated antigens" identified with naturally occurring antibodies may be overexpressed on tumor but are in fact nonspecific autoantigens. This suggests that while overexpression or aberrant processing can increase immunogenicity in some cases, the immunogenicity of many or even most tumor-associated antigens is a function of expression in tumor or the result of ancillary tumor factors.     

The contribution of SIPA1 and RRP1B germline polymorphisms to breast cancer phenotype,lymph node status and survival in a group of Lithuanian young breast cancer patients

The germline polymorphisms in signal-inducing proliferation-associated protein 1 (SIPA1) and ribosomal RNR processing 1B (RRP1B) might be involved in breast cancer metastasis. The aim of this study was to analyze how SIPA1 and RRP1B polymorphisms contribute to breast cancer phenotype, lymph node status and survival. A group of 100 young, I–II stage breast cancer patients were analyzed for SIPA1 and RRP1B polymorphisms with PCR-RFLP assay. SIPA1 c.2760G?>?A, c.545C?>?T and RRP1B c.436T?>?C polymorphisms were associated with lymph node status, survival and tumor grade, respectively. Our results suggest that SIPA1 and RRP1B germline polymorphisms are important for breast cancer prognosis.     

Mathematical modelling of radiotherapy strategies for early breast cancer

Targeted intraoperative radiotherapy (Targit) is a new concept of partial breast irradiation where single fraction radiotherapy is delivered directly to the tumour bed. Apart from logistic advantages, this strategy minimizes the risk of missing the tumour bed and avoids delay between surgery and radiotherapy. It is presently being compared with the standard fractionated external beam radiotherapy (EBRT) in randomized trials. In this paper we present a mathematical model for the growth and invasion of a solid tumour into a domain of tissue (in this case breast tissue), and then a model for surgery and radiation treatment of this tumour. We use the established linear-quadratic (LQ) model to compute the survival probabilities for both tumour cells and irradiated breast tissue and then simulate the effects of conventional EBRT and Targit. True local recurrence of the tumour could arise either from stray tumour cells, or the tumour bed that harbours morphologically normal cells having a predisposition to genetic changes, such as a loss of heterozygosity (LOH) in genes that are crucial for tumourigenesis, e.g. tumour suppressor genes (TSGs). Our mathematical model predicts that the single high dose of radiotherapy delivered by Targit would result in eliminating all these sources of recurrence, whereas the fractionated EBRT would eliminate stray tumour cells, but allow (by virtue of its very schedule) the cells with LOH in TSGs or cell-cycle checkpoint genes to pass on low-dose radiation-induced DNA damage and consequently mutations that may favour the development of a new tumour. The mathematical model presented here is an initial attempt to model a biologically complex phenomenon that has until now received little attention in the literature and provides a 'proof of principle' that it is possible to produce clinically testable hypotheses on the effects of different approaches of radiotherapy for breast cancer.     

Influence of ABCB1 genetic variants in breast cancer treatment outcomes

BackgroundTransportation of anticancer drugs such as anthracyclines across the membrane is regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 (ABCB1). Polymorphisms in the ABCB1 gene (1236C > T, 2677G > T/A, 3435C > T) have been found to be associated with intrinsic and acquired cross resistance to these anticancer drugs. Therefore, the aim of this study is to evaluate the influence of ABCB1 gene polymorphisms in breast cancer treatment outcomes in terms of response and toxicity.MethodResponse to neo-adjuvant chemotherapy was evaluated in 100 patients while grade 2–4 toxicity was followed in 207 patients, who had undergone FEC/FAC chemotherapy. Genotyping for ABCB1 polymorphisms was done by PCR-RFLP. Chi square and logistic regression analyses were used to calculate Odd's ratio using SPSS ver 17.0. A meta analysis was also performed using Comprehensive Meta Analysis Ver 2.ResultsIn response evaluation, 1236C > T polymorphism was significantly associated with treatment response for CT genotype [OR = 5.17(1.3–20.2), P = 0.018] and in dominant model (CC vs CT + TT) [OR = 4.63(1.25–17.0), P = 0.021]. In the toxicity group, the T allele of 1236C>T was associated with grade 2–4 tocxicity [OR 1.48(1.00–2.20), P = 0.049] and the association was also significant in the recessive model [OR 1.88(1.05–3.39), P = 0.033]. For other two SNPs 2677G>T/A and 3435C>T no association was seen with either treatment response or grade 2–4 toxicity. In meta analysis, no overall association was found.ConclusionIn our study, significant association was seen for ABCB1 1236C>T polymorphism with treatment response. The meta analysis did not show overall association with treatment outcomes.