Abstract P1-02-11: Somatic alterations and PD-L1 positivity in advanced breast cancer
Authors: Finkelman Brian S , Cristofanilli Massimo , Blanco Luis Z , Behdad Amir , Platanias Leonidas C , Gradishar William J , Siziopikou Kalliopi P 
Published: March 2022

Background: With the recent FDA approvals of atezolizumab and pembrolizumab for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer, immuno-oncology (IO) therapy has become feasible for the first time in breast cancer, and PD-L1 immunohistochemistry (IHC) has become an essential assay in breast cancer diagnostics. However, relatively little is known about the molecular profile of PD-L1+ breast cancers compared to other tumors, such as lung cancer. Furthermore, although the initial data have shown the most benefit in triple-negative patients, it is unclear whether additional subgroups of patients with advanced breast cancer enriched for PD-L1 expression can be identified, and, therefore, might benefit from IO therapy. Methods: We identified 60 women with locally advanced or metastatic breast cancer who underwent next generation sequencing (NGS) of tumor samples obtained at our institution as part of their clinical care and performed PD-L1 testing using the Ventana SP142 platform. Samples were considered positive for PD-L1 if ≥1%. The NGS assay was designed to detect single nucleotide variants, insertions and deletions, copy number variants, and specific translocations in approximately 600 genes. Associations between PD-L1 status, molecular alterations, and tumor histopathologic features were assessed, with P &lt; 0.05 considered statistically significant. Results: Our cohort consisted of 60 women at a median age of 56 years (range 31-81). 50% of samples were from primary tumors within the breast, 15% were from regional lymph node metastases, and 35% were from distant metastatic sites. Most tumors showed ductal histology (80%) and were either grade 2 (38%) or grade 3 (57%), while half showed focal (27%) or extensive (23%) necrosis. Based on IHC, most tumors were Luminal B (54%), followed by triple-negative (25%), Luminal A (13%), and HER2-enriched (8%) tumors. About one third of tumors had either moderate (25%) or marked (8%) TILs, and about half showed positivity for PD-L1 (48%). Most tumors had a low tumor mutational burden (TMB), with 83% having &lt;5, 14% having 5-9, and 3% having ≥10 mutations per Mb. The median number of genes with reportable somatic alterations was 2 (IQR 1-3). The most common genes with somatic alterations were TP53 (51%), PIK3CA (23%), ERBB2 (16%), ESR1 (14%), FGFR1 (9%), AKT1 (7%), CDH1 (7%), GATA3 (7%), MYC (7%), and CCND1 (5%). 50% of luminal A, 38% of luminal B, 50% of HER2-enriched, and 75% of triple-negative tumors were PD-L1+, although this difference was not statistically significant (P = 0.22). PD-L1 positivity was more likely in grade 3 tumors (62% vs 31% grade 1-2, P = 0.02), and in tumors with extensive necrosis (85% vs 37% absent/focal, P = 0.004). Of all the genes tested, only TP53 was significantly associated with being PD-L1+ (69% TP53-mutant vs 32% TP53-wild-type; P = 0.008). Neither number of somatic alterations (P = 0.60) or TMB (P = 0.08) were significantly associated with PD-L1+ tumors. Of note, 53% of non-triple-negative PD-L1+ tumors had mutations in TP53, and 60% of non-triple-negative tumors with TP53 mutations were PD-L1+. Conclusions: Our data suggest that PD-L1 positivity is relatively common in patients with locally advanced or metastatic breast cancer, not only in triple-negative breast cancer but in all breast cancer subtypes. In addition, TP53 mutation is significantly associated with an increased likelihood of positivity for PD-L1, including in non-triple-negative tumors. This correlation could potentially be a useful marker for selecting non-triple-negative breast cancer patients for PD-L1 testing and, if positive, potentially offer them IO options for optimizing their response to therapy.

Citation Format: Brian S Finkelman, Massimo Cristofanilli, Luis Z Blanco, Jr, Amir Behdad, Leonidas C Platanias, William J Gradishar, Kalliopi P Siziopikou. Somatic alterations and PD-L1 positivity in advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-11.