Case Report: Genomic Testing Identifies NTRK Fusions in Patient With Refractory Metastatic Breast Cancer
Key findings
- A 69-year-old patient presented to Massachusetts General Hospital with triple-negative metastatic breast cancer five years after treatment for localized disease
- The patient experienced no objective response to any of four lines of therapy in the metastatic setting, including immunotherapy, and next-generation sequencing of cell-free DNA identified two NTRK3 gene fusions
- Two months after the patient started TRK inhibitor larotrectinib she experienced dramatic improvement on repeat scans; continuing the drug for seven months with good disease control. She later transitioned to comfort care due to complications from bone mets
- Plasma-based genotyping may identify targetable variants, in both the tissue-specific and the tissue-agnostic setting. NTRK fusions are indications for use of a TRK inhibitor, either larotrectinib or entrectinib, regardless of tissue of origin
- This case is proof of concept that tissue-agnostic FDA approvals provide a rationale for next-generation sequencing in effectively all patients with advanced solid tumors
Neurotrophic tyrosine kinase (NTRK) gene fusions are rare but have recently gained significant attention. They qualify cancer patients for FDA-approved targeted TRK inhibition with larotrectinib or entrectinib regardless of a solid tumor's tissue of origin.
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Physicians at Massachusetts General Hospital have described the case of a patient with triple-negative breast cancer whose disease rapidly progressed on multiple lines of therapy until genomic testing identified two NTRK fusions. Once she was started on larotrectinib, she experienced marked clinical response within two months.
Arielle Medford, MD, oncology fellow, and Aditya Bardia, MD, MPH, oncologist at the Mass General Cancer Center, and colleagues report the case and its lessons in Therapeutic Advances in Medical Oncology.
Case Report
The patient presented to Mass General at age 69 with metastatic recurrence of triple negative breast cancer five years after treatment for localized breast cancer.
Germline genetic testing at Mass General was normal. The patient demonstrated no objective response to any subsequent therapy, including two chemotherapy regimens, antibody–drug conjugate-based therapy and immunotherapy.
Next-generation sequencing of cell-free DNA (cfDNA) via an 83-gene assay (Guardant Health, Inc.) identified two NTRK3 fusions, including ETV6–NTRK3, which is associated with secretory breast carcinoma (represents <1% of breast cancers), and CRTC3–NTRK3, a fusion not previously described in breast cancer. Liver biopsy tissue was sent for whole-exome and RNA sequencing (BostonGene, Inc.), which confirmed both gene fusions.
Two months after the patient started larotrectinib, repeat imaging demonstrated dramatic improvement in the metastases. Repeat cfDNA testing showed substantial reductions in the mutant allele fraction for both fusions. The patient tolerated the drug well and continued it for seven months with good disease control.
Unfortunately, she had already experienced multiple fractures because of bone metastases. These ultimately led to substantial morbidity and she decided to transition to comfort care, after which she passed away.
Takeaway Messages
The American Society of Clinical Oncology recently issued a provisional opinion that patients with advanced solid tumors should undergo somatic testing if more than one biomarker might lead to targeted therapy.
Given an increasing number of tissue-agnostic drug approvals, including pembrolizumab for patients with microsatellite instability and/or high tumor mutational burden, and larotrectinib and entrectinib for patients with NTRK fusions, the document effectively recommends somatic testing for all patients with advanced solid tumors.
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