MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB–NFIB fusion gene

Breast adenoid cystic carcinoma (AdCC), a rare type of triple-negative breast cancer, has been shown to be driven by MYB pathway activation, most often underpinned by the MYB–NFIB fusion gene. Alternative genetic mechanisms, such as MYBL1 rearrangements, have been reported in MYB–NFIB-negative salivary gland AdCCs. Here we report on the molecular characterization by massively parallel sequencing of four breast AdCCs lacking the MYB–NFIB fusion gene. In two cases, we identified MYBL1 rearrangements (MYBL1–ACTN1 and MYBL1–NFIB), which were associated with MYBL1 overexpression. A third AdCC harboured a high-level MYB amplification, which resulted in MYB overexpression at the mRNA and protein levels. RNA-sequencing and whole-genome sequencing revealed no definite alternative driver in the fourth AdCC studied, despite high levels of MYB expression and the activation of pathways similar to those activated in MYB–NFIB-positive AdCCs. In this case, a deletion encompassing the last intron and part of exon 15 of MYB, including the binding site of ERG-1, a transcription factor that may downregulate MYB, and the exon 15 splice site, was detected. In conclusion, we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression. These observations emphasize that breast AdCCs probably constitute a convergent phenotype, whereby activation of MYB and MYBL1 and their downstream targets can be driven by the MYB–NFIB fusion gene, MYBL1 rearrangements, MYB amplification, or other yet to be identified mechanisms. Copyright © 2017 Pathological Society of Great Britain and Ireland

Adjuvant enzalutamide for the treatment of early-stage androgen-receptor positive, triple-negative breast cancer: a feasibility study.

PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population

Phyllodes tumors with and without fibroadenoma-like areas display distinct genomic features and may evolve through distinct pathways

Breast fibroepithelial lesions (fibroadenomas and phyllodes tumors) are underpinned by recurrent; MED12; exon 2 mutations, which are more common in fibroadenomas and benign phyllodes tumors.; TERT; promoter hotspot mutations have been documented in phyllodes tumors, and found to be more frequent in borderline and malignant lesions. Several lines of evidence suggest that a subset of phyllodes tumors might arise from fibroadenomas. Here we sought to investigate the genetic differences between phyllodes tumors with fibroadenoma-like areas vs. those without. We retrieved data for 16 borderline/ malignant phyllodes tumors, including seven phyllodes tumors with fibroadenoma-like areas and nine phyllodes tumors without fibroadenoma-like areas, which had been previously subjected to targeted capture massively parallel sequencing. Whilst; MED12; exon 2 mutations were significantly more frequent in tumors with fibroadenoma-like areas (71 vs. 11%), an enrichment in genetic alterations targeting; bona fide; cancer genes was found in those without fibroadenoma-like areas, in particular in; EGFR; mutations and amplifications (78 vs. 14%). No significant difference in the frequency of; TERT; genetic alterations was observed (71% in cases with fibroadenoma-like areas vs 56% in those without fibroadenoma-like areas). Our data suggest that the development of phyllodes tumors might follow two different evolutionary pathways: a; MED12; -mutant pathway that involves the progression from a fibroadenoma to a malignant phyllodes tumor; and a; MED12; -wild-type pathway, where malignant phyllodes tumors arise de novo through the acquisition of genetic alterations targeting cancer genes. Additional studies are warranted to confirm our observations and define whether the outcome differs between both pathways

Positive predictive value of biopsy of palpable masses following mastectomy.

Determine the positive predictive value (PPV) of biopsy of palpable masses following mastectomy (MX). Determine if there are patient characteristics, tumor, or imaging features more predictive of cancer. IRB-approved retrospective review of 16 396 breast ultrasounds June 2008-December 2015 identified patients with MX presenting with palpable masses. Medical records and imaging studies were reviewed. Statistical analysis was performed using Fishers exact test. 95% confidence intervals (CI) were calculated. In all, 117 patients presented with palpable masses on the MX side. 101/117 patients who had a palpable mass on physical examination had a true sonographic mass to correlate with the clinical findings. 91/101 (90%) underwent biopsy: 19/91 (21%, 95% CI; 13-31) biopsies were malignant. 72/91 (79%) were benign. All 19 cancers were on the original cancer side. Recurrences ranged from 0.4 to 4.5 cm maximum diameter, mean 1.3 cm. Prophylactic vs therapeutic mastectomy was very statistically significant (P = .01). The use of tamoxifen or an AI was also statistically significant (P = .04). Patient age (P = 1.0), radiation therapy (P = 1.05), chemotherapy (P = .2), immediate breast reconstruction (P = .2), or implant vs flap (P = .2) had no statistically significant association with finding cancer on biopsy. Lesion shape (irregular vs oval/round) was highly statistically significant (P = .0003) as was non-parallel orientation on ultrasound (P = .008). Circumscribed vs non-circumscribed margins was also statistically significant (P = .008). The PPV of biopsy of palpable masses on the side of MX was 21% (95% CI; 13-31). All recurrences were on the original cancer side and this was very statistically significant

Infiltrating epitheliosis of the breast: characterization of histological features, immunophenotype and genomic profile

AimsInfiltrating epitheliosis is a rare complex sclerosing lesion (CSL) of the breast, characterized by infiltrating ducts immersed in a scleroelastotic stroma and filled with cells having architectural and cytological patterns reminiscent of those of usual ductal hyperplasia. In this study we sought to define the molecular characteristics of infiltrating epitheliosis.Methods and resultsEight infiltrating epitheliosis, adjacent breast lesions (one usual ductal hyperplasia, one papilloma, one micropapillary ductal carcinoma in situ and one low‐grade adenosquamous carcinoma), and corresponding normal breast tissue from each case were microdissected and subjected to massively parallel sequencing analysis targeting all coding regions of 254 genes mutated recurrently in breast cancer and/or related to DNA repair. Mutations in components of the PI3K pathway were found in all infiltrating epitheliosis samples, seven of which harboured PIK3CA hotspot mutations, while the remaining case displayed a PIK3R1 somatic mutation.ConclusionsSomatic mutations affecting PI3K pathway genes were found to be highly prevalent in infiltrating epitheliosis, suggesting that these lesions may be neoplastic rather than hyperplastic. The landscape of somatic genetic alterations found in infiltrating epitheliosis is similar to that of radial scars/CSLs, suggesting that infiltrating epitheliosis may represent one end of this spectrum of lesions