Abstract P5-02-13: TRK inhibitor in a patient with metastatic triple negative breast cancer and NTRK fusions identified via cell-free DNA analysis
Authors: Keenan Jennifer C. , Medford Arielle J. , Oshry Lauren J. , Boyraz Baris , Dai Charles S. , Kiedrowski Lesli A. , Menshikova Sofia , Butusova Anna , Gogakos Tasos , Occhiogrosso Rachel , Ryan Phoebe , Lennerz Jochen , Spring Laura M. , Moy Beverly , Ellisen Leif , Bardia Aditya 
Published: March 2023

Abstract
Introduction: Tissue-agnostic indications for targeted therapies are expanding options for patients with advanced solid tumors. The FDA approvals of the PD-1 inhibitor pembrolizumab and the TRK inhibitors larotrectinib and entrectinib provide rationale for next generation sequencing (NGS) in effectively all advanced solid tumor patients, as findings may indicate targeted therapy even in disease that may seem otherwise refractory. Here, we present the case of a post-menopausal woman with metastatic triple negative breast cancer (TNBC) who had disease progression on multiple lines of therapy prior to the identification of two actionable NTRK mutations, identified via cell-free DNA (cfDNA) and tissue-based NGS. She was subsequently started on the TRK inhibitor larotrectinib and had a marked clinical response. Case Presentation: A 64-year-old woman presented with metastatic TNBC five years after being treated for a localized breast cancer. The cancer rapidly progressed through 4 lines of therapy in the metastatic setting, including immunotherapy [atezolizumab/nab-paclitaxel (progression after 5 months)], antibody-drug conjugate-based therapy [sacituzumab govitecan (progression after 2 months)], and chemotherapy [gemcitabine/carboplatin (progression after 3 months), eribulin (progression after 2 months)]. Her CA 15-3 had also been consistently increasing to a peak of 206 IU/mL. Germline genetic testing was negative. Ultimately, NGS evaluation of cfDNA via an 83-gene assay (Guardant Health, Inc.) identified two NTRK3 fusions: an ETV6-NTRK3 fusion [mutant allele fraction (MAF) = 10.9%] associated with the rare secretory breast carcinoma, and CRTC3-NTRK3 (MAF = 3.2%), a fusion partner previously undescribed in breast cancer. Liver biopsy was sent for whole exome sequencing and RNA-seq analysis (BostonGene, Inc), which provided orthogonal confirmation of both the ETV6-NTRK3 and CRTC3-NTRK3 fusions. Review of the tumor pathology showed invasive ductal carcinoma with secretory features; this pathology and the ETV6-NTRK3 fusion were consistent with a diagnosis of secretory breast carcinoma. She was started on the TRK inhibitor larotrectinib, and she had a significant clinical and radiographic response after only two months of therapy. Recheck of her CA 15-3 showed a decrease to 48 IU/mL, the lowest level in our records. Repeat cfDNA testing showed a decrease of the ETV6-NTRK3 fusion to MAF 0.40% and the CRTC3-NTRK3 fusion to MAF 0.07%. The patient took larotrectinib for 7 months with good disease control. Unfortunately, unrelated to her therapy, she had experienced multiple fractures secondary to her existing osseous metastases, and these led to significant morbidity. She and her family elected to transition to comfort measures, after which she passed away. Discussion: In the presented case, the identification of NTRK fusions by plasma-based genotyping resulted in matched selection of genotype-directed therapy, and this otherwise refractory TNBC exhibited marked response to targeted therapy. While TNBC had historically been considered a subtype of breast cancer without targetable options, the expanding roles of NGS testing and targeted therapies are changing the paradigm. The actionability of rare genomic events such as NTRK fusions makes identifying them critical for individual patients, particularly in heterogeneous diseases such as TNBC. Tissue-agnostic targeted therapies now give reason for NGS testing in most solid tumors, as reflected in updated consensus guidelines. This case demonstrates the significant potential benefits of NGS testing in advanced and refractory cancers.
Citation Format: Jennifer C. Keenan, Arielle J. Medford, Lauren J. Oshry, Baris Boyraz, Charles S. Dai, Lesli A. Kiedrowski, Sofia Menshikova, Anna Butusova, Tasos Gogakos, Rachel Occhiogrosso, Phoebe Ryan, Jochen Lennerz, Laura M. Spring, Beverly Moy, Leif Ellisen, Aditya Bardia. TRK inhibitor in a patient with metastatic triple negative breast cancer and NTRK fusions identified via cell-free DNA analysis. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-13.