Abstract PD9-09: High tumor mutational burden (&gt;=10 mut/Mb) is enriched in specific breast cancer pathological subtypes
Authors: Israel Mason A , Tierno Marni , Huang Richard SP , McGregor Kimberly , Sokol Ethan S , Reddy Prasanth , Ross Jeffrey S 
Published: February 2021

Background: Pembrolizumab recently received pan-tumor FDA approval for the treatment of patients with unresectable or metastatic solid tumors with tumor mutational burden (TMB) &gt;10 mutations per megabase (mut/Mb) and who have no satisfactory alternative treatment options. The KEYNOTE-119 and TAPUR trials have validated TMB as a predictive biomarker using TMB cutoffs of ≥ 10 mut/Mb and 9 mut/Mb, respectively, for benefit from single-agent pembrolizumab in subsets of patients with clinically advanced breast cancer (aBC). Limited data exist on which pathological subtypes of aBC are most likely to be TMB &gt;10 mut/Mb (TMB-High). This study analyzed the frequency of TMB-High tumors in aBC subtypes to evaluate variations between subtypes and correlation with additional immunotherapy biomarkers. Methods: Utilizing the Foundation Medicine breast cancer database, 5,475 samples with aBC and pathological subtype information were identified. Pathological subtypes included in this study were ER+/HER2-negative invasive ductal carcinoma (IDC), ER-negative/HER2+ IDC (HER2+), triple negative IDC (TNBC), invasive lobular, inflammatory, metaplastic, mucinous and papillary. TMB was determined on 0.8-1.1 Mb of sequenced DNA, and microsatellite instability (MSI) was assessed across 114 loci in 564 cases. PD-L1 was determined in a subset of cases by immunohistochemistry (Ventana SP142). Results: TMB-High (&gt;10 mut/Mb) was common in all breast cancer pathological subtypes except papillary carcinoma (Table 1). TMB-High was most often found in lobular, inflammatory and HER2+ carcinomas (16%, 14% and 12% of cases, respectively). Metaplastic, mucinous and papillary subtypes were least likely to be TMB-High (7%, 7% and 0% of cases, respectively). TMB-High was more common than MSI-High in all subtypes, excluding papillary. Emerging biomarkers that may play a role in mitigating immunotherapy response, such as MDM2 amplifications and STK11 alterations, were observed in most subtypes. The frequencies of these alterations, as well as alterations associated with FDA-approved therapies in breast cancer, are provided in Table 1 and will be further discussed. Conclusions: TMB-High (&gt;10 mut/Mb) is common in most pathological subtypes of clinically advanced breast cancer and can identify patients not identified by MSI or PD-L1 testing who may benefit from immunotherapy. Based on the high percentage of advanced breast cancer patients who are TMB-High or have genomic alterations in other biomarkers associated with FDA-approved targeted therapies, comprehensive genomic profiling including TMB and MSI should be considered for all pathological subtypes.

Table 1Pathological subtypeInvasive ductal carcinoma (IDC)ER+, HER2-negativeER-negative, HER2+Triple-negative (TNBC)Invasive Lobular CarcinomaInflammatory MetaplasticMucinousPapillaryCases (n)1,2371,9536411,180353892911Age55 (23-89)55 (20-89)53 (20-85)62 (24-89)54 (28-87)59 (28-89)55 (30-80)61 (38-78)Tumor mutational burden (TMB)TMB &gt; 10 mut/Mb8%12%9%16%14%7%7%0%TMB &gt; 20 mut/Mb2%2%3%7%6%2%3%0%Additional immunotherapy biomarkersMSI-High0.2%0.1%0.4%0%0%0%0%0%PD-L1+ (&gt;1% Ventana SP142)N/AN/A47%N/AN/A26%0%N/AMDM2 amplification6%5%3%2%0%2%3%18%STK11 alteration1%1%2%1%3%3%3%0%Additional biomarkers associated with FDA-approved therapiesBRCA1/2 alteration3%/6%2%/3%7%/3%1%/4%6%/6%4%/3%3%/0%0%/9%ERBB2 amplification0%100%0%3%26%3%34%9%NTRK 1/2/3 rearrangement0%/0%/0%0%/0%/0%0%/0%/0%1%/0%/0%0%/0%/0%0%/0%/1%0%/0%/0%0%/0%/0%PIK3CA alteration38%38%19%56%34%38%21%36%

Citation Format: Mason A Israel, Marni Tierno, Richard SP Huang, Kimberly McGregor, Ethan S Sokol, Prasanth Reddy, Jeffrey S Ross. High tumor mutational burden (&gt;=10 mut/Mb) is enriched in specific breast cancer pathological subtypes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD9-09.