Deciphering the Clinical Behaviour of Invasive Lobular Carcinoma of the Breast Defines an Aggressive Subtype

Background: Invasive lobular carcinoma (ILC), the most common special type of breast cancer (BC), has unique clinical behaviour and is different from invasive ductal carcinoma of no special type (IDC-NST). However, ILC further comprises a diverse group of tumours with distinct features. This study aims to examine the clinicopathological and prognostic features of different variants of ILC, with a particular focus on characterising aggressive subtypes. Methods: A large (n = 7140) well-characterised and histologically reviewed BC cohort with treatment and long-term follow-up data was investigated. The cohort was classified based on the WHO classification of tumours into main histological subtypes, including ILC and IDC-NST. ILCs were further classified into variants. Clinicopathological parameters and patient outcomes in terms of BC-specific survival (BCSS) and disease-free survival (DFS) were evaluated. Results: ILC constituted 11% of the cohort. The most common non-classic ILC variants were pleomorphic (pILC) and solid (sILC), constituting 19% of ILC. Compared to classic and related variants (alveolar, trabecular, papillary, and tubulolobular; cILC), pILC and sILC variants were associated with aggressive tumour characteristics. The histologic grade of ILC was an important prognostic variable. The survival patterns identified an aggressive ILC subtype encompassing pILC and high-grade sILC. These tumours, which comprised 14% of the cases, were associated with clinicopathological characteristics of poor prognosis and had high BC-specific death and recurrence rates compared not only to cILC (p < 0.001) but also to IDC-NST (p = 0.02) patients. Contrasting this, cILC patients had significantly longer BCSS and DFS than IDC-NST patients in the first 10 to 15 years of follow-up. Adjuvant chemotherapy did not improve the outcome of patients with aggressive ILC subtypes. Conclusions: pILC and high-grade sILC variants comprise an aggressive ILC subtype associated with poor prognostic characteristics and a poor response to chemotherapy. These results warrant confirmation in randomised clinical trials.