Rassegna della letteratura – febbraio 2019

Biologia – Genetica – Laboratorio – Anatomia patologica

Szarszewska M, Markowska A, Jach R et Al. –  Significance of BRCA1 expression in breast and ovarian cancer patients with brain metastasis – A multicentre study. – Adv Med Sci. 2019 Feb 26;64(2):235-240.

Purpose Cerebral metastases develop in 10-30% of patients with breast cancer (BC) and in around 3.3 to 4% of patients with ovarian cancer (OC). The aim of the multicenter study is to investigate the correlation between the expression of estrogen alpha receptors (ERα), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), breast cancer metastasis suppressor 1 (BRMS1), astrocyte elevated gene 1 (AEG1), depending on the status of BRCA1 protein, in patients suffering from OC and BC with brain metastases. Methods The analysis included 51 patients: 29 with BC and 22 with OC, in whom brain metastases were disclosed.

Results In most patients (65.5% of BC patients and 68.2% of patients with OC tumors) BRCA1 protein loss was found. No correlation was disclosed between the levels of ERα, PR receptors, HER2, SDF1, CXCR4, AEG1, BRMS1 and BRCA1 status, patient age, stage of disease advancement, grade of histological maturity of the cells, presence of metastases to lymph nodes. A statistically significant correlation was disclosed between the negative expression of PR receptors and a high expression of CXCR4 in patients with BC. High values of the AEG1 protein (linked to metastases) were detected alongside a high expression of BRMS1 (a suppressor of metastases).

Conclusions Patients with BC and OC and brain metastases have a frequent loss of BRCA1 expression. The role of ERα, PR, HER2, SDF1, CXCR4, AEG1, BRMS1 in metastatic process needs further studies.

Lundberg A, Lindström LS, Li J et Al – The long-term prognostic and predictive capacity of cyclin D1 gene amplification in 2305 breast tumors – Breast Cancer Res. 2019 Feb 28;21(1):34.

Purpose Use of cyclin D1 (CCND1) gene amplification as a breast cancer biomarker has been hampered by conflicting assessments of the relationship between cyclin D1 protein levels and patient survival. Here, we aimed to clarify its prognostic and treatment predictive potential through comprehensive long-term survival analyses.

Methods CCND1 amplification was assessed using SNP arrays from two cohorts of 1965 and 340 patients with matching gene expression array and clinical follow-up data of over 15 years. Kaplan-Meier and multivariable Cox regression analyses were used to determine survival differences between CCND1 amplified vs. non-amplified tumours in clinically relevant patient sets, within PAM50 subtypes and within treatment-specific subgroups. Boxplots and differential gene expression analyses were performed to assess differences between amplified vs. non-amplified tumours within PAM50 subtypes.

Results When combining both cohorts, worse survival was found for patients with CCND1-amplified tumours in luminal A (HR = 1.68; 95% CI, 1.15-2.46), luminal B (1.37; 1.01-1.86) and ER+/LN-/HER2- (1.66; 1.14-2.41) subgroups. In gene expression analysis, CCND1-amplified luminal A tumours showed increased proliferation (P < 0.001) and decreased progesterone (P = 0.002) levels along with a large overlap in differentially expressed genes when comparing luminal A and B-amplified vs. non-amplified tumours.

Conclusions Our results indicate that CCND1 amplification is associated with worse 15-year survival in ER+/LN-/HER2-, luminal A and luminal B patients. Moreover, luminal A CCND1-amplified tumours display gene expression changes consistent with a more aggressive phenotype. These novel findings highlight the potential of CCND1 to identify patients that could benefit from long-term treatment strategies.

Park C, Yoon KA, Kim J et Al. Integrative molecular profiling identifies a novel cluster of ER-positive breast cancer in very young women – Cancer Sci. 2019 Feb 27.

Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor (ER) positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age < 35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were also compared with young ER+ patients of TCGA breast cancer. TP53, PIK3CA, and GATA3 were highly recurrent somatic mutation genes. APOBEC-associated mutation signature was more frequent in KYBR compared with TCGA young patients. Integrative profiling classified our patients into three subgroups based on molecular characteristics. Group A showed luminal A-like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of ubiquitin-mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification, lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial-mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics. This article is protected by copyright. All rights reserved.

Mejdahl MK, Wohlfahrt J – Breast cancer mortality in synchronous bilateral breast cancer patients – –Br J Cancer. 2019 Feb 26.

Purpose Evidence suggests that patients with synchronous bilateral breast cancer (SBBC), diagnosed within 4 months, have an inferior prognosis compared to unilateral breast cancer (UBC) patients. Using data from nationwide Danish clinical databases, this cohort study investigated whether the inferior prognosis could be explained by SBBC patients having a more aggressive disease, or whether the prognosis could be explained by the fact that they have two simultaneous cancers.

Methods Patients were diagnosed from 1999-2015. The main outcome was excess mortality, subtracting background population mortality from observed mortality. Differences between SBBC and UBC patients were evaluated by rate ratios (RR) and estimated by Poisson regression.

Results In total, 1214 SBBC and 59 177 UBC patients were included. SBBC patients had a significantly higher excess mortality than UBC patients after adjustment for age and period (RR = 1.73; 95% CI:1.44-2.08; p < 0.01) and after adjusting for characteristics of the worst tumour as traditionally done (RR = 1.31; 95% CI:1.08-1.57; p = 0.01). However, adjusting for characteristics of both tumours, using a more advanced competing risks model, no difference was observed (RR = 1.01; 95% CI:0.83-1.22; p = 0.93).

Conclusions Our study does not support that the inferior prognosis in SBBC patients is due to having more aggressive tumours per se, but rather the combined effect of having two simultaneous cancers.

Wani HA – Diagnostic utility of epigenetics in breast cancer – A review – Cancer Treat Res Commun. 2019 Feb 19;19:100125.

Epigenetic alterations are clearly involved in cancer initiation and progression as recent epigenetic studies of genomic DNA, histone modifications and micro-RNA alterations suggest that these are playing an important role in the incidence of breast cancer. Epigenetic information has recently gained the attention of researchers because epigenetic modification of the genome in breast cancer is still an evolving area for researchers. Several active compounds present in foods, poisons, drugs, and industrial chemicals may as a result of epigenetic mechanisms increase or decrease the risk of breast cancer. Epigenetic regulation is critical in normal growth and development and closely conditions the transcriptional potential of genes. Epigenetic mechanisms convey genomic adaption to an environment thereby ultimately contributing towards given phenotype. In addition to the use of epigenetic alterations as a means of screening, epigenetic alterations in a tumor or adjacent tissues or peripheral blood may also help clinicians in determining prognosis and treatment of breast cancer. As we understand specific epigenetic alterations contributing to breast tumorigenesis and prognosis, these discoveries will lead to significant advances for breast cancer treatment, like in therapeutics that target methylation and histone modifications in breast cancer and the newer versions of the drugs are likely to play an important role in future clinical treatment.

 

Pineda B, Diaz-Lagares A – A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients – Clin Epigenetics. 2019 Feb 20;11

Purpose Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature.

Methods Epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an independent cohort of TN patients and in TN cell lines.

Results Twenty-four and 30 patients were included in the discovery and validation cohorts, respectively. In the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under the ROC curve (AUC) = 0.905 (95% CI = 0.805-1.000). Patients with a positive epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if signature were negative.

Conclusions These results suggest that pCR in TNBC could be accurately predicted with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective validation of these findings is warranted