We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-tomesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a ''tumorigenic'' signature defined using CD44 + /CD24 À breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets. [Cancer Res 2009;69(10):4116-24]

Marking nodes with biopsy-confirmed metastatic disease allows for selective removal and improves pathologic evaluation for residual nodal disease after chemotherapy.

The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

No abstract

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a 5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often misdiagnosed as mastitis or generalized dermatitis. This review examines IBC's unique clinical presentation, pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease, which comprises systemic therapy, surgery, and radiation therapy. CA Cancer J Clin 2010;60:351-375.© 2010 American Cancer Society, Inc.To earn free CME credit or nursing contact hours for successfully completing the online quiz based on this article, go to http://CME.AmCancerSoc.org.Inflammatory breast cancer (IBC) is a clinicopathological entity characterized by rapid progression and aggressive behavior from onset of disease. Historically, its prognosis has been very grim. Especially before the introduction of systemic chemotherapy, attempts to control IBC with either surgery alone or surgery combined with radiation therapy resulted in median survival times of less than 15 months and local recurrence rates as high as 50%. 1 Although survival times have increased with multimodal therapy, they are still around 35% to 40% and much lower than those for other breast cancers. Because IBC is rare, clinicians are less familiar with it than with the more common types of noninflammatory breast cancers (non-IBC). The purpose of this review is to describe the clinical diagnosis, epidemiology, imaging, biology, and multidisciplinary treatment of IBC. We summarize both current practice and novel concepts under investigation.

BACKGROUNDUltrasound (US) is more sensitive than physical examination alone in determining axillary lymph node involvement during preliminary staging of breast carcinoma. Due to occasional overlap of sonographic features of benign and indeterminate lymph nodes, fine‐needle aspiration (FNA) of sonographically indeterminate/suspicious lymph nodes can provide a more definitive diagnosis than US alone. This study was undertaken to determine the diagnostic accuracy of US‐guided FNA of indeterminate/suspicious/metastatic‐appearing axillary lymph nodes during the initial staging of breast carcinoma.METHODSThe cytology of 103 cases of US‐guided FNA of nonpalpable indeterminate/suspicious/metastatic‐appearing lymph nodes was compared with the final histopathologic status of the entire axilla after axillary dissection. The final axillary lymph node status was categorized as either negative when all lymph nodes were negative for metastasis or positive when there was evidence of metastasis in one or more lymph nodes. The sensitivity, specificity, diagnostic accuracy, and false‐negative rate of US‐guided FNA of nonpalpable axillary lymph nodes in the preliminary staging process were calculated.RESULTSIn 51 of 103 cases (49.5%), the US‐guided FNA and histopathology were both positive for metastasis. In 24 of 103 cases (23.3%), both were negative. The apparent false‐positive FNA in 16 (15.5%) cases was explained by the complete response of the metastatic lymph nodes to neoadjuvant chemotherapy in the interval between FNA and axillary dissection. In 12 cases (11.6%), US‐guided FNA was negative, but metastasis was seen in histologic sections. All cases with three or more lymph nodes with metastatic disease and 93% of those with metastatic deposit measuring more than 0.5 mm were detected by US‐guided FNA. The probability of detecting lymph nodes with smaller metastatic deposit measuring less than 0.5 cm was 44%. The overall sensitivity of US‐guided FNA was 86.4%, the specificity was 100%, the diagnostic accuracy was 79.0%, the positive predictive value was 100%, and the negative predictive value was 67%.CONCLUSIONSUS‐guided FNA of nonpalpable indeterminate and suspicious axillary lymph nodes is a simple, minimally invasive, and reliable technique for the initial determination of axillary lymph node status in breast carcinoma. The common causes of discrepancy between the initial and final axillary lymph node status include failure to visualize all lymph nodes during US examination, small‐sized metastases, and preoperative neoadjuvant chemotherapy. Cancer 2002;95:982–8. © 2002 American Cancer Society.DOI 10.1002/cncr.10786