Comprehensive review of molecular mechanisms and clinical features of invasive lobular cancer.

Invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancers in the United States, 80% of which is estrogen receptor (ER) positive, with an unusual metastatic pattern of spread to sites such as serosa, meninges, and ovaries, among others. Lobular cancer presents significant challenges in detection and clinical management given its multifocality and multicentricity at presentation. Despite the unique features of ILC, it is often lumped with hormone receptor positive invasive ductal cancers (IDC); consequently, ILC screening, treatment and follow up strategies are largely based on data from IDC. Despite both being treated as ER-positive breast cancer, querying the TCGA database show distinctive molecular aberrations in ILC compared to IDC, such as E-cadherin loss (66% vs. 3%), FOXA1 mutations (7% vs. 2%), GATA3 mutations (5% vs. 20%). Moreover, patients with ILC are less likely to undergo breast-conserving surgery, with lower rates of complete response following therapy as these tumors are less chemosensitive, compared to IDC patients. Taken together, this suggests that ILC are biologically distinct which may influence tumorigenesis and therapeutic strategies. Long term survival and clinical outcomes in ILC patients are worse than stage- and grade-matched IDC patients; therefore, nuanced criteria are needed to better define treatment goals and protocols tailored to ILC's unique biology. In this comprehensive review, we highlight the histologic and clinicopathologic features that distinguish ILC from IDC, with an in-depth discussion of ILC's molecular alterations and biomarkers, clinical trials and treatment strategies, and future targets for therapy. IMPLICATIONS FOR PRACTICE: Majority of invasive lobular breast cancers (ILC) are hormone receptor (HR) positive and low grade. Clinically, ILC is treated similar to HR positive invasive ductal cancer (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. Patients with ILC have worse clinical outcomes with late recurrences. Despite these differences, clinical trials treat HR positive breast cancers as a single disease and there is an unmet need for studies addressing the unique challenges faced by patients diagnosed with ILC.