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Endocrine Therapy-Resistant Breast Cancers With Kinase Fusions May Benefit From Targeted Drugs

NEW YORK – Based on the results of a study published in the Annals of Oncology in April, researchers suggested that testing metastatic breast cancer patients for kinase fusions, particularly those who become resistant to endocrine therapy, may identify targetable biomarkers and open up additional treatment opportunities.

About 70 percent of breast cancers are estrogen receptor-positive, which is a biomarker that makes patients more likely to respond well to antiestrogen treatment, such as endocrine therapy. However, if patients' cancers metastasize, they can develop resistance to endocrine therapy, often driven by ESR1 activating mutations.

ER-positive breast cancers can also express fusion proteins, though these tend to be rare events and poorly characterized. Recognizing that kinase fusions are targetable and may offer another avenue for treatment, researchers led by Dara Ross, Bo Liu, Sarat Chandarlapaty, and Jaclyn Hechtman from Memorial Sloan Kettering Cancer Center set out to investigate these features and their role in endocrine therapy resistance in breast cancer.  

They used the MSK-IMPACT next-generation sequencing panel and MSK-Fusion, an RNA-based targeted NGS test utilizing a custom panel from ArcherDx, to analyze the cancer profiles of 4,854 patients with metastatic breast cancer. The ArcherDx-based MSK-Fusion panel enables detection of fusions in ALK, BRAF, EGFR, ERBB2, ERBB4, FGFR1, FGFR2, FGFR3, KIT, MET, NTRK1, NTRK2, NTRK3, RET, ROS1, and ESR1.

Out of the 4,854 patients analyzed, 27, or 0.6 percent of patients, harbored fusions in these genes, with the majority of kinase fusions involving FGFR. Five patients had FGFR2 fusions, three patients had FGFR3 fusions, and three had FGFR1 fusions. Further, five patients had BRAF fusions, four patients had NTRK1 fusions, two patients had RET fusions, two patients had ROS1 fusions, one patient had an ALK fusion, one patient had an ERBB2 fusion, and one patient had a MET fusion.

Kinase fusions were detected in 19 metastatic breast tumors and eight primary breast tumors. Fifteen out of 19 of the metastatic tumors had been treated with endocrine therapy previously. Four metastatic tumors had not been treated with endocrine therapy previously, though three of the four were estrogen receptor-negative, and one patient declined adjuvant endocrine therapy. None of the eight primary tumors had been treated with endocrine therapy.

In the 15 metastatic, endocrine therapy-treated patients, eight had a pre-treatment tumor sample available for analysis. When researchers tested these samples, they found that six out of eight were fusion negative, "suggesting that these fusions arose as a mechanism of acquired resistance to [endocrine therapy]."

Among the 19 metastatic breast cancer cases with kinase fusions, five patients' receptor status changed from ER-positive in the primary tumor to ER-negative in the metastatic site. In these five cases, fusions were detected in NTRK1 in one patient, FGFR1 in one patient, FGFR3 in one patient, and BRAF in two patients.

The researchers noted that none of the breast cancer patients with an acquired kinase fusion harbored an ESR1 hotspot mutation.

Two patients whose tumors had acquired LMNA-NTRK1 fusions and metastatic disease received the TRK inhibitor larotrectinib (Bayer's Vitraki), which is approved in the US for solid tumors with NTRK gene fusions.

One of the patients with an acquired LMNA-NTRK1 fusion was originally diagnosed with hormone receptor-positive, HER2-negative invasive ductal carcinoma with regional lymph node metastasis, which spread further following adjuvant chemotherapy and endocrine therapy. The presence of a new LMNA-NTRK1 fusion, and its absence in the pre-treatment sample, was confirmed by MSK-IMPACT and MSK-Fusion with pan-Trk IHC staining. The patient then received larotrectinib and had a complete response.

The second patient was also originally hormone receptor-positive and didn't have a fusion in the pre-treatment tumor sample. The acquired LMNA-NTRK1 fusion was detected in a post-endocrine therapy liver metastasis sample. This patient then received larotrectinib and saw an 80 percent drop in pre-larotrectinib carcinoembryonic antigen (CEA) levels 23 days after treatment. Reductions in CEA levels in cancer patients have been associated with tumor response to treatment.

In laboratory models, the LMNA-NTRK1 fusion protein promoted hormone-independent tumor growth. Larotrectinib appeared to inhibit downstream signaling pathways in NTRK1 and suppress hormone-independent proliferation of fusion-expressing tumors.

"Endocrine therapy is the most effective treatment for ER-positive primary and metastatic [breast cancer]; however, acquired resistance remains a major clinical challenge," the authors wrote. "Our findings show that fusion testing of metastatic breast cancer, particularly those progressing after [endocrine therapy], may benefit select patients who harbor targetable kinase fusions."