Shamir ER, et al. - Because pleomorphic (PLCIS) and florid (FLCIS) lobular carcinoma in situ are rare histologic variants of LCIS that are recognized as more aggressive than classic LCIS (CLCIS), but optimal treatment is controversial, experts sought to characterize the genetic drivers of these lesions and their clonal relationships to paired CLCIS and ILC. They utilized capture-based next-generation sequencing to profile 16 LCIS variants, involving paired synchronous ILC and CLCIS in 11 and nine cases, respectively. Recurrent pathogenic alterations involved CDH1, PIK3CA, ERBB2, ERBB3, FOXA1, TP53, and CCND1. Contrasted with ILC in the Cancer Genome Atlas (TCGA), PLCIS, FLCIS, and correlated ILC were enriched for ERBB2 mutations, and PLCIS was enriched for TP53 and FOXA1 mutations. Increased mean nonsynonymous mutations and additional pathogenic alterations and/or CNA in 80%, correlated with CLCIS to PLCIS progression. The outcomes highlight clonal relationships among PLCIS/FLCIS and CLCIS and implicate PLCIS as a genetically advanced ILC precursor. Frequent ERBB2/ERBB3 alterations in PLCIS and FLCIS were consistent with more aggressive behavior and might have predictive and therapeutic implications.