Urgensi Kompetensi Guru Dalam Implementasi Pendidikan Integratif

Abstract

Triple-negative breast cancer (TNBC) is a histological classification of a breast cancer subtype that is negative for the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBCs represent an important subtype of breast cancer as they have a lower recurrence-free and overall survival compared to receptor-positive disease, regardless of disease staging at time of diagnosis. It has been suggested that TNBCs may harbour mutations in genes involved in the BRCA-associated DNA repair pathway (i.e. BRCAness). Recent studies have shown that up to 20% of tumours classified as TNBC present with BRCA mutations. Additionally, TNBCs are over-represented in patients who harbour BRCA1 or BRCA2 mutations and are predominantly associated with early onset breast cancer. This suggests a link between the BRCA-associated DNA repair pathway and TNBC. Genomic DNA was obtained from a series of 347 consecutively-collected patients with histopathologically-diagnosed TNBC, irrespective of family history. BRCA1 and BRCA2 coding sequence (including the intron/exon boundaries) was amplified using Fluidigm 48.48 Access Arrays (184 primer sets designed to cover the coding regions of both BRCA1 and BRCA2 genes) were used to prepare the libraries. The libraries were paired-end sequenced on Illumina MiSeq and the data analyzed with NextGENe 2nd Generation Sequencing Software. Overall the number of pathogenic BRCA mutations detected was 30 (8.6%): 18 (5.2%) in BRCA1 and 12 (3.4%) in BRCA2. The proportion of pathogenic mutations observed in our cohort is not too dissimilar to the number of mutations detected in a familial breast cancer setting, which in our experience is approximately 12%. Investigation of the family histories of the TNBC patients revealed that 13/30 (43.3%) had a confirmed family history of disease. Examination of the families revealed that the disease spectrum was as expected for hereditary breast and ovarian cancer. The age of diagnosis of breast cancer in the TNBC BRCA mutation carriers (Mean = 51, SD = 16) was significantly different (p = .03) to those with wild-type BRCA (Mean = 58, SD15) suggesting a different disease trajectory. This study confirms that there a substantial proportion of BRCA1 and BRCA2 mutation carriers reside in populations of patients diagnosed with TNBC. This adds to the growing body of evidence suggesting that breast cancer with a triple-negative phenotype should be considered as an additional criterion for genetic testing of both BRCA genes