Case ReportRapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion
Introduction
Human tropomyosin-related kinase (TRK) is a receptor tyrosine kinase family of neurotrophin receptors. Three isoforms of TRK have been described, TRKA, TRKB, and TRKC, which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These genes are prone to rearrangements, which place them adjacent to active genes such as ETV6, EML4, NPM, and TPM. The resulting fusion proteins exhibit transformative oncogenic potential. Targeting the TRK family of receptors has shown promising evidence of providing clinical benefit to patients with TRK fusion cancers.1, 2
Larotrectinib is a highly selective and potent inhibitor of the TRKs that in 2016 was awarded breakthrough designation by the US Food and Drug Administration on the basis of its promising early preclinical and clinical data in adults and children with tumors harboring TRK fusions. As reported by Hyman et al2 at the American Society of Clinical Oncology 2017 meeting, larotrectinib demonstrated a confirmed Response Evaluation Criteria in Solid Tumors (RECIST) overall response rate of 76% across 50 adult and pediatric patients with TRK fusions, encompassing 17 unique tumor types. At that time, the median duration of response and median progression-free survival had not been reached, and 93% of all responding patients either continued to receive the drug or underwent surgery with curative intent. Some ongoing responses lasted more than 18 months.2, 3 The most common treatment-emergent adverse events included fatigue (15% grade 1, 18% grade 2, 5% grade 3), dizziness (22% grade 1, 4% grade 2, 2% grade 3), nausea (20% grade 1, 5% grade 2, 2% grade 3), and anemia (8% grade 1, 9% grade 2, 9% grade 3). Seven patients (13%) required a dose reduction due to an adverse event, but all patients requiring dose reduction experienced tumor regression (1 complete response, 5 partial response, 1 stable disease), which continued on the reduced dose.
Triple-negative breast cancer (TNBC) accounts for 10% to 20% of all breast cancers (BCs). Systemic treatment strategies for advanced disease rely mostly on chemotherapy. Molecular characterization of TNBC demonstrates tumor heterogeneity, which limits efforts to identify molecular targets in this disease.4 Secretory breast carcinoma (SBC) is a rare (0.15% of breast carcinomas) histologic subtype of invasive ductal carcinoma, which usually belong to the TNBC spectrum.5, 6 It was first described in children and adolescents, and it was thought to have a good prognosis and indolent progression. However, it has since been recognized in adult populations, with favorable outcome being inversely related to age.6 In 2002, Tognon et al7 reported on the association of SBC with the ETV6-NTRK3 gene fusion, which is now confirmed to occur with a frequency of over 90% of SBC in several studies.6, 7, 8 Its chimeric product has been shown to be the driving oncogenic protein.
Here we report on a patient with advanced triple-negative SBC with a TRK fusion who experienced a rapid clinical and radiographic response to kinase inhibition with larotrectinib monotherapy provided as first-line treatment.
Section snippets
Case Report
A 37-year-old white woman was diagnosed in December 2012 with a left T2N0M0 stage 2a SBC, which immunohistochemistry found weakly positive for estrogen receptor (+1 in 30% of cells, +2 in 20% of cells, 0.7 out of 3 intensity index), progesterone receptor negative, and human epidermal growth factor receptor 2 (HER2) negative. She underwent a left skin-sparing mastectomy with tumor-free margins but declined adjuvant chemotherapy or radiotherapy. No BRAC1/2 testing was performed. In August 2015,
Discussion
We describe here a young patient with advanced triple-negative SBC who experienced significant clinical benefit from first-line TRK inhibition with larotrectinib provided for advanced disease. The natural history of her cancer, which was demonstrated as a result of her refusal of chemotherapy, is consistent with this reportedly indolent subtype of BC. After first recurrence, she had relatively slow-progressing disease, which even allowed her to carry a pregnancy to near-complete term. However,
Conclusion
Larotrectinib offers an effective option for therapy in cancers that harbor TRK fusions such as SBC, a rare and molecularly unique subtype of BC that usually presents as TNBC. Characterization of these BC subtypes can be identified by common pathologic tests, and confirmation of new molecular targets can be made with available molecular tests. Practitioners should be aware of these potential therapeutic implications and seek TRK fusion testing.
Disclosure
N.P. is a consultant for Pfizer, BI, Roche, Astra Zeneca, MSD, BMS, Lilly, Novartis, and NovellusDx. M.I. received honoraria from Pfizer, MSD, Roche, and Takeda. A.B.S. and S.M.A. are employees of Foundation Medicine Inc and own stock in Foundation Medicine Inc. N.K. is an employee of Loxo Oncology Inc. The other authors have stated that they have no conflict of interest.
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