Rassegna della letteratura –  2019

Biopatologia, genetica, fattori prognostici e predittivi di risposta ai trattamenti


Qi Y, Wang X, Kong X, Zhai J  et Al. – Expression signatures and roles of microRNAs in inflammatory breast cancer. – Cancer Cell Int. 2019 Jan 31;19:23. doi: 10.1186/s12935-018-0709-6.

Inflammatory breast cancer (IBC) is an infrequent but aggressive manifestation of breast cancer, which accounts for 2-4% of all breast cancercases but responsible for 7-10% of breast cancer-related deaths, and with a 20-30% 10-year overall survival compared with 80% for patients with non-IBC with an unordinary phenotype, whose molecular mechanisms are still largely unknown to date. Discovering and identifying novel bio-markers responsible for diagnosis and therapeutic targets is a pressing need. MicroRNAs are a class of small non-coding RNAs that are capable to post-transcriptionally regulate gene expression of genes by targeting mRNAs, exerting vital and tremendous affects in numerous malignancy-related biological processes, including cell apoptosis, metabolism, proliferation and differentiation. In this study, we review present and high-quality evidences regarding the potential applications of inflammatory breast cancer associated microRNAs for diagnosis and prognosis of this lethal disease.

Wang DY, Gendoo DMA, Ben-David Y et Al. – A subgroup of microRNAs defines PTEN-deficient, triple-negative breast cancer patients with poorest prognosis and alterations in RB1, MYC, and Wnt signaling. – Breast Cancer Res. 2019 Jan 31;21(1):18. doi: 10.1186/s13058-019-1098-z.

Background: Triple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs.

Methods: Publically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy.

Results: In TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P < 0.0001), and this was validated on an independent cohort (HR = 4.42; P = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway.

Conclusion: This analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy.

Williams LA, Casbas-Hernandez P et Al. – Risk factors for Luminal A ductal carcinoma in situ (DCIS) and invasive breast cancer in the Carolina Breast Cancer Study. –  PLoS One. 2019 Jan 25;14(1):e0211488.

Background: Invasive breast cancers are thought to arise from in situ lesions, but some ductal carcinoma in situ (DCIS) are indolent with low likelihood of progressing to invasive carcinoma. Comparison of risk factor associations between DCIS and invasive disease may elucidate which factors influence early versus late stages of carcinogenesis. Therefore, we determined whether there were differences in risk factor profiles for screen-detected DCIS and invasive breast cancer among Luminal A lesions.

Methods: We conducted a case-control analysis using data from the Carolina Breast Cancer Study (1993-2001). Analyses were restricted to Luminal A tumors and screen-detected tumors among mammography-eligible women, to limit confounding by mode of detection (N = 108 DCIS; N = 203 invasive). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between risk factors and lesion type

Results: In stratified analyses, we observed qualitative differences in the direction of association for ever smoking, obese BMI, high waist-to-hip-ratio (WHR), and ≥10 years of oral contraceptive use between DCIS and invasive disease. Breastfeeding was inversely associated with invasive disease and was not associated with DCIS. Interaction tests for risk factor associations between Luminal A DCIS and invasive breast cancer were not statistically significant (p>0.05).

Conclusion: Among Luminal A tumors, established breast cancer risk factors may exert stronger effects on progression of early lesions to invasive disease, with lesser effects on risk of DCIS.

Shah NM, Scott DM, Kandagatla P – Young Women with Breast Cancer: Fertility Preservation Options and Management of Pregnancy-Associated Breast Cancer. – Ann Surg Oncol. 2019 Jan 24. doi: 10.1245/s10434-019-07156-7.

Background: Breast cancer is the most common malignancy diagnosed in women of childbearing age. A breast cancer diagnosis in this young patient population can be uniquely complex to navigate when considering the potential impact of fertility loss associated with specific gonadotoxic therapies. Another unique challenge for young breast cancer patients is pregnancy-associated breast cancer (PABC), which occurs in approximately 1 of every 3000 pregnancies. Pregnancy adds a layer of complexity to breast cancer treatment planning as many therapies can affect the developing fetus. These two clinical challenges require nuanced multidisciplinary approaches to facilitate optimal treatment outcomes. We sought to review and summarize the management strategy options for both fertility preservation and PABC.

Methods: A guideline and literature review was performed for fertility preservation, young patients with breast cancer, and pregnancy-associated breast cancer.

Results: Fertility preservation options, both established and experimental, are detailed. Suggested clinical practice guidelines for PABC are also presented, which delineate breast cancer treatment recommendations based on pregnancy trimester.

Conclusion: A multidisciplinary approach to patient care, including oncologists and early referral to reproductive specialists, can provide young breast cancer patients with options for fertility preservation. Under the guidance of a multidisciplinary treatment team, PABC can also be diagnosed and treated to permit the best possible outcomes for the mother and the developing fetus.

Song G, He L, Yang X et Al. – Identification of aberrant gene expression during breast ductal carcinoma in situ progression to invasive ductal carcinoma. – J Int Med Res. 2019 Feb 3:300060518815364

Background: It has been reported that 80% of all breast carcinoma cases are invasive ductal carcinoma (IDC), and 45% to 78% of invasive breast carcinoma cases are associated with ductal carcinoma in situ (DCIS). Therefore, it is important to gain insights into transcriptome changes that occur during DCIS progression to IDC.

Methods: We downloaded Gene Expression Omnibus databases GSE21422 and GSE3893, and performed differentially expressed gene (DEG) analysis and cluster analysis, followed by pathway enrichment analysis and Oncomine analysis.

Results: Twenty-six conserved DEGs were identified in both GSE21422 and GSE3893. These genes are mainly enriched in intermediate filament-based processes, immune responses, Staphylococcus aureus infection response, and phagosomes. Among them, FCGR2A, HLA-DRA, C3AR1, and FYB were reported to be involved in DCIS progression to IDC. High expression of HLA-DRA, C3AR1, and FYB in different types of breast cancer was validated using different Oncomine datasets. Moreover, elevated HLA-DRA and FYB levels were associated with breast cancer recurrence. Importantly, the overexpression of FYB was correlated with breast cancer metastasis.

Conclusion: This study revealed the molecular characteristics associated with progression from DCIS to IDC. It also identified potential biomarkers for DCIS progression to IDC, which will aid breast cancer diagnosis and prevention.

Ding YC, Steele, Warden C et Al.. – Molecular subtypes of triple-negative breast cancer in women of different race and ethnicity. – Oncotarget. 2019 Jan 4;10(2):198-208

Abstract: Molecular subtypes of triple negative breast cancer (TNBC) are associated with variation in survival and may assist in treatment selection. However, the association of patient race or ethnicity with subtypes of TNBC and clinical outcome has not been addressed. Using nCounter Gene Expression Codesets, we classified TNBCs into subtypes: basal-like immune-activated (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) in 48 Hispanic, 12 African-American, 21 Asian, and 34 White patients. Mean age at diagnosis was significantly associated with subtype, with the youngest mean age (50 years) in MES and the oldest mean age (64 years) in LAR (p < 0.0005). Subtype was significantly associated with tumor grade (p = 0.0012) and positive lymph nodes (p = 0.021), with a marginally significant association of tumor stage (p = 0.076). In multivariate Cox-proportional hazards modeling, BLIS was associated with worst survival and LAR with best survival. Hispanics had a significantly higher proportion of BLIS (53%, p = 0.03), whereas Asians had a lower proportion of BLIS (19%, p = 0.05) and a higher proportion of LAR (38%, p = 0.06) compared to the average proportion across all groups. These differences in proportions of subtype across racial and ethnic groups may explain differences in their outcomes. Determining subtypes of TNBC facilitates understanding of the heterogeneity of the TNBCs and provides a foundation for developing subtype-specific therapies and better predictors of TNBC prognosis for all races and ethnicities.

Akbulut H, Ersoy YE et Al. – The role of miRNAs as a predictor of multicentricity in breast cancer.  – Mol Biol Rep. 2019 Feb 1.

Abstract: Expression profiles of miRNAs are shown to be different in various cancers to regulate expression of mRNA or to have a role in inhibition of translation, thus it shows the possible effect in progression, invasion and metastasis of breast cancer cells. The effect of breast conserving treatment in local recurrence and survival rates for the patients who have multicentric breast cancer is still controversial. In our study, we intended to evaluate the foresight of 84 miRNAs which are identified in breast cancer for having differentiated expressions. Thirty-one patients with unifocal and 26 patients with multicentric breast cancer were included in this study. These tissue samples of both malignant and normal breast tissues were kept in RNA later solution at - 80 °C. Eighty-four miRNAs were studied with miScript miRNA PCR Array Human Breast Cancer kit. Fold change, cut off value was accepted as four. In unifocal group, there were 13 upregulated and five downregulated miRNAs and in multicentric group, there were three upregulated and seven downregulated miRNAs. To reach better results for breast cancer diagnosis and treatment, it is important to enlighten tumor biology, and pay attention to target and individual therapy. Thus, miRNAs have potential role in identifying tumor characteristics in supporting diagnosis and resulting with better evaluated disease for better treatment results with individual strategies.

Silva LCFF, Arruda LSM, David Filho WJ et Al. – Hormone receptor-negative as a predictive factor for pathologic complete response to neoadjuvant therapy in breast cancer.- Einstein (Sao Paulo). 2019 Jan 21;17(1)

Objective: To define a predictive factor for pathologic complete response, compare the oncologic outcomes associated with the degree of pathologic response after neoadjuvant chemotherapy, and to analyze pathologic complete response as a prognostic factor for overall survival and progression-free survival.

Methods: A retrospective study of patients admitted to Hospital Estadual Mário Covas and Hospital Anchieta from 2008 to 2012, with locally advanced breast cancer. Hormone receptor status, HER2 status, histologic and nuclear grade, age upon diagnosis and histological type of the tumor were analyzed. Pathologic evaluation of the tumor was subdivided into pathologic complete response, defined by the absence of tumor; intermediate response, considered as a favorable stage; and poor response, considering low-responder patients. Data obtained were submitted to statistical analysis.

Results: The study included 243 patients. There was an association of pathologic complete response with HER-2 negative, histological grade 3, stage III, hormone receptor negative, positive lymph node, older age and more advanced tumors. However, after multivariate analysis the only predictor of pathologic complete response was the presence of negative hormone receptor. By analyzing the prognostic factors, hormone receptor negative was considered as an independent risk factor, and pathologic complete response was considered as an independent protective factor.

Conclusion: Hormone receptor negative is predictive of pathologic complete response and is an isolated risk factor for lower progression-free survival and overall survival. Pathologic complete response is a protective factor for these same survival analyses.

Okamoto T, Ito A. – Association between alcohol consumption and mammographic density: a hospital-based cross-sectional study – Breast Cancer. 2019 Jan 24.

Background: Mammographic density (MD), the proportion of radiological dense breast, has been reported to be a strong risk factor for breast cancer in many studies. Epidemiological evidence indicates that alcohol consumption increases the risk of breast cancer. In Western countries, a positive association between alcohol consumption and MD has been reported.

Methods: To investigate the effect of alcohol consumption on MD, we conducted a cross-sectional analysis of healthy women enrolled in a breast cancer screening program at the Ebina Health Service Center, Japan, in 2012, comprising 477 premenopausal women and 308 postmenopausal women. Alcohol consumption was assessed using a self-report questionnaire. Unconditional logistic regression was applied to calculate the odds ratio (OR) and 95% confidence intervals (CI) while adjusting for confounders.

Results: The study included 497 women with high breast density (HD group) and 288 women with low breast density (LD group). In all women, multivariate analysis revealed that the OR for HD was significantly increased among women with the highest alcohol intake (≥ 140 g/week of ethanol) compared with abstainers (OR 2.1, 95% CI 1.2-3.9 p = 0.01). The linear trend with increasing alcohol consumption was statistically significant (p = 0.009).

Conclusion:  MD was positively associated with alcohol consumption in Japanese women.

Kim HY, Choi HJ et Al – Cancer Target Gene Screening: a web application for breast cancer target gene screening using multi-omics data analysis. – Brief Bioinform. 2019 Jan 29. doi: 10.1093

Abstract: Breast cancer comprises several molecular subtypes with distinct clinical features and treatment responses, and a substantial portion of each subtype remains incurable. A comprehensive analysis of multi-omics data and clinical profiles is required in order to better understand the biological complexity of this cancer type and to identify new prognostic and therapeutic markers. Thus, there arises a need for useful analytical tools to assist in the investigation and clinical management of the disease. We developed Cancer Target Gene Screening (CTGS), a web application that provides rapid and user-friendly analysis of multi-omics data sets from a large number of primary breast tumors. It allows the investigation of genomic and epigenomic aberrations, evaluation of transcriptomic profiles and performance of survival analyses and of bivariate correlations between layers of omics data. Notably, the genome-wide screening function of CTGS prioritizes candidate genes of clinical and biological significance among genes with copy number alteration, DNA methylation and dysregulated expression by the integrative analysis of different types of omics data in customized subgroups of breast cancer patients. These features may help in the identification of druggable cancer driver genes in a specific subtype or the clinical condition of human breast cancer. CTGS is available at http://ctgs.biohackers.net.