RESUMO
Background: Due to variations in perforator vasculature, deep inferior epigastric artery perforator (DIEP) flap preoperative imaging can minimize operative time required to locate the most suitable perforators. Dedicated computed tomography angiography (CTA) has been the gold standard; however, many patients have already undergone a staging computed tomography (CT) per oncologic workup. The benefits from CTA may also be realized with a staging CT or CT with IV contrast. Methods: Ten patients who underwent DIEP flap reconstruction with staging CT and CTA within 3 years of one another were included in this study. Reviewers evaluated axial views of both imaging modalities separately to identify each visible perforator in reference to the pubic symphysis from the xiphoid to the pubic symphysis. An intraclass correlation coefficient (ICC) was used to determine agreement in location of perforators between the two imaging studies. Statistical analysis was performed using an ICC and Wilcoxon signed rank-tests. Results: The identified perforators within the patient cohort had an excellent correlation between their location on CT and CTA based upon ICC. The mean number of perforators identified in the CT group was 15.3 (SD 4.9) and in the CTA group was 18.8 (SD 6.4), which was not statistically different (P = 0.247). Conclusions: CT has similar efficacy in identifying number of perforators and perforator location to dedicated CTA for preoperative planning in DIEP flaps. This has the potential for decreased patient contrast and ionizing radiation exposure as well as improved patient and healthcare resource utilization.
RESUMO
Background: Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Patients and Methods: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Results: Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis revealed a significant enrichment in TP53 SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease. Conclusion: Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of TP53 mutations and a potential enrichment in NOTCH pathway activation-but overall; a lack of major genomic differences. These results both reinforce the importance of TP53 alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.
RESUMO
The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.