Background: The majority of invasive lobular breast cancers (ILC) are hormone receptor (HR)-positive, HER2-negative and are clinically treated similarly to HR+ HER2-negative invasive ductal cancers (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. It is currently unknown if patients with ILC or mixed ductal/lobular (MDL) histologies derive similar benefits as IDC from endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), mTOR inhibitor everolimus or PI3K inhibitor alpelisib. Methods: We retrospectively searched for patients treated at MD Anderson Cancer Center with a diagnosis of HR+, HER2-negative metastatic breast cancer (MBC) with ET in combination with CDK4/6is, everolimus or alpelisib. Patients were divided into 3 groups based on their histology: ILC, IDC and mixed. We obtained data on demographics, estrogen (ER) and progesterone (PR) receptor status, menopausal status, treatment duration and survival status. The Kaplan-Meier product-limit method was used to compare progression-free survival (PFS) and overall survival (OS) between the three different groups stratified by the treatment received. Results: We identified 2,971 patients (2,432 IDC [82%], 427 ILC [14%], 112 Mixed [4%]) with HR+ HER2-negative MBC treated with ET in combination with CDK4/6is, everolimus and/or alpelisib between 2010 and 2021. Median age was around 50 years in all groups. Around 80% of patients were white, 10% Hispanic and 5% black. Around 55% of patients were post-menopausal, 99% had ER+ and 88% PR+ tumors; 1,895 patients (81% IDC, 15% ILC, 4% mixed) received CDK4/6is, 1,027 (82% IDC, 14% ILC, 4% mixed) received everolimus and 49 (81% IDC, 19% ILC) received alpelisib. PFS and OS were not statistically different between the 3 groups (Table). Conclusions: HR+ HER2-negative MBC patients with IDC, ILC and MDL benefited from ET in combination with CDK4/6is, everolimus or alpelisib similarly with no significant differences in PFS and OS.