Targetable alterations in invasive pleomorphic lobular carcinoma of the breast

Gregory M Riedlinger,Shridar Ganesan,Kim M Hirshfield,Sonali Joshi,Nicola Barnard

doi:10.1186/s13058-020-01385-5

Abstract

BackgroundInvasive pleomorphic lobular carcinoma (PLC) of the breast is a subtype of invasive lobular cancer which compromises approximately 1% of all epithelial breast malignancies and is characterized by higher nuclear pleomorphism and poorer prognosis than classic invasive lobular cancer (ILC). Since PLC is more aggressive than classical ILC, we examined the underlying molecular alterations in this subtype of breast cancer to understand the possible benefit from targeted therapies.MethodsIn this study, we investigate the clinical characteristics and molecular alterations in 16 PLC from our institution. Additionally, we examined the clinical and genomic features in 31 PLC from the Cancer Genome Atlas (TCGA).ResultsOverall, our analysis of PLC found that 28% had activating ERBB2 mutations, 21% had ERBB2 amplification, and 49% activating PIK3CA mutations. Among cases from our institution, we found 19% with activating ERBB2 mutations, 25% had ERBB2 amplification, and 38% with activating PIK3CA mutations. In data from TCGA, 32% had activating ERBB2 mutations, 19% had ERBB2 amplification, and 55% had activating PIK3CA mutations. While classic ILC in TCGA had similar percentages of PIK3CA alterations compared to PLC, activating ERBB2 alterations were exceedingly rare, with no activating ERBB2 mutations and only one case with ERBB2 amplification. Interestingly, in further examining TCGA data which included FGFR1 and PTEN, 94% of PLC had alterations in ERBB2, FGFR1, or the PI3K pathway.ConclusionsOur results show a high frequency of ERBB2 and PIK3CA alterations in PLC and suggest all PLC should be tested for potential therapeutic targeting.

Highlights

Invasive pleomorphic lobular carcinoma (PLC) of the breast is a subtype of invasive lobular cancer which compromises approximately 1% of all epithelial breast malignancies and is characterized by higher nuclear pleomorphism and poorer prognosis than classic invasive lobular cancer (ILC)
PLC has been reported to present at a more advanced stage compared to invasive ductal carcinoma (IDC) or classical ILC and be more likely to recur compared to classical ILC [5, 6]
To gain a better of the underlying molecular alterations in PLC and the potential for therapeutic intervention, we report here on the characterization of 47 invasive lobular breast cancers with pleomorphic features which we believe is the largest series of this subtype

Summary

Introduction

Invasive pleomorphic lobular carcinoma (PLC) of the breast is a subtype of invasive lobular cancer which compromises approximately 1% of all epithelial breast malignancies and is characterized by higher nuclear pleomorphism and poorer prognosis than classic invasive lobular cancer (ILC). The second most common histologic subtype of invasive breast cancer is invasive lobular carcinoma (ILC) compromising up to 15% of all cases. It is more frequently multifocal and bilateral than other primary breast cancers. While classical ILC generally has a good prognosis, several variants of ILC have been described Among these is pleomorphic lobular carcinoma (PLC) which (2021) 23:7 was first described by Page and Anderson in 1987 but was not officially recognized by the WHO until 2003 [3, 4]. PLC is reported to more frequently have ERBB2 amplification or TP53 alterations than classical ILC and more typical of high grade IDC [10, 11]

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