Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion

Landman, Yosef; Ilouze, Maya; Wein, Simon; Neiman, Victoria; Yerushalmi, Rinat; Yakimov, Maxim; Ku, Nora; Schrock, Alexa B.; Ali, Siraj M.; Peled, Nir

doi:10.1016/j.clbc.2017.11.017

Cited by 19 publications

(18 citation statements)

References 7 publications

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“…Targeted kinase inhibitor therapy in such TRK fusion-positive tumours, including secretory carcinoma of the breast, has shown some efficacy. 34,63,64 This study has several limitations. Although our study cohort is limited by small sample size, due to the rarity of secretory breast carcinoma, we sought to identify all reports of secretory carcinoma of the breast with distant metastases in the literature to characterise clinical outcomes of aggressive cases.…”

Section: Discussionmentioning

confidence: 96%

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Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasising distant metastatic potential

et al. 2019

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Aims Secretory carcinoma of the breast (SCB) is a rare histological type of breast carcinoma with a generally indolent clinical behaviour. We aim to elucidate the clinical, pathological and molecular findings of SCB cases and identify characteristics associated with aggressive clinical courses. Methods and results Fourteen patients with SCB were identified, including 12 women and two men, with a median age of 56 years (range = 8–81 years). Clinical data, histological diagnosis, molecular findings and follow‐up were reviewed. Eight patients presented with palpable masses and four patients with radiographic abnormalities. All cases were unilateral. Surgical procedures included excisional biopsies and ipsilateral mastectomies. In 10 cases, oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results were obtained, with six cases positive for ER and three positive for PR. All cases lacked HER2 overexpression. Sentinel lymph node biopsy was performed in 10 cases, and two patients had axillary lymph node metastasis. Follow‐up ranged from 21 to 212 months (median = 70 months). Two patients developed distant metastasis of SCB. Molecular analysis of these aggressive tumours revealed amplification of the 16p13.3 locus, a TERT promotor mutation and loss of 9p21.3 locus. Review of the literature for SCB cases with distant metastasis was performed. Conclusions Although SCBs are generally associated with a favourable prognosis, our study and review demonstrate that a subset of SCBs may develop distant metastases. Further studies are warranted to identify markers predictive of more aggressive clinical behaviour in this rare breast cancer subtype.

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Section: Discussionmentioning

confidence: 96%

“…Further molecular studies are necessary to fully understand the genetic landscape of breast secretory carcinoma and identify those mutations associated with aggressive clinical behaviour. Targeted kinase inhibitor therapy in such TRK fusion‐positive tumours, including secretory carcinoma of the breast, has shown some efficacy …”

Section: Discussionmentioning

confidence: 99%

Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasising distant metastatic potential

et al. 2019

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“…The clinical impact of TRK inhibition was initially suggested in case reports of patients with TRK fusion cancer treated with larotrectinib 95 , 96 , 97 , 98 and entrectinib. 35 , 43 , 63 , 93 This potential impact was subsequently confirmed in an integrated analysis of the first 55 adult and pediatric patients with tumors of 17 different types harboring NTRK gene fusions.…”

Section: Ntrk Genes In Cancermentioning

confidence: 99%

Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy

Hsiao

Zehir

Sireci

et al. 2019

The Journal of Molecular Diagnostics

184

173

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Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/ neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types. NTRK gene fusions have been shown to be actionable genomic events that are predictive of response to TRK kinase inhibitors, making their routine detection an evolving clinical priority. In certain exceedingly rare tumor types, NTRK gene fusions may be seen in the overwhelming majority of cases, whereas in a range of common cancers, reported incidences are in the range of 0.1% to 2%. Herein, we review the structure of the three NTRK genes and the nature and incidence of NTRK gene fusions in different solid tumor types, and we summarize the clinical data showing the importance of identifying tumors harboring such genomic events. We also outline the laboratory techniques that can be used to diagnose NTRK gene fusions in clinical samples. Finally, we propose a diagnostic algorithm for solid tumors to facilitate the identification of patients with TRK fusion cancer. This algorithm accounts for the widely varying frequencies by tumor histology and the underlying prevalence of TRK expression in the absence of NTRK gene fusions and is based on a combination of fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry assays.

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“…A novel NTRK inhibitor, larotrectinib has shown activity against advanced secretory breast carcinoma, a rare special subtype of TNBC, which harbor an ETV6-NTRK3 gene fusion [25].…”

Section: Molecular Profiling Of Advanced Breast Cancermentioning

confidence: 99%

Molecular profiling in breast cancer—ready for clinical routine?

Tendl

Bagó-Horváth

2020

memo

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The herald of genomic testing opened novel diagnostic and therapeutic possibilities for many tumor entities. For breast cancer, molecular profiling has become an integral part of disease management on multiple levels. Genetic testing allows for the identification of hereditary cancer syndromes in patients with a family history of malignancies and contributes to the successful prevention of breast cancer. In early breast cancer, several prospective randomized trials demonstrated the prognostic significance of commercially available mRNA-based gene expression analyses, which now have become part of standard of care in the adjuvant setting. In advanced breast cancer, testing for targetable mutations ensures personalized cancer treatment. Poly-ADPribose polymerase (PARP) inhibitors provide the first targeted alternative for patients with BRCA 1/2-associated breast cancer. In advanced breast cancer of luminal type, the detection of Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) mutations provides a novel treatment option with alpelisib, a PIK3CA inhibitor. Further targetable mutations include NTRK3 in rare cases of secretory breast carcinoma and human epidermal growth factor receptor 2 (HER2). Recent data support the importance of the analysis of circulating tumor cells and cell-free DNA. These "liquid biopsies" open novel possibilities of molecular profiling. However, clinical benefit of such analyses remains to be confirmed.

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Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion

Cited by 19 publications

References 7 publications

Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasising distant metastatic potential

Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasising distant metastatic potential

Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy

Molecular profiling in breast cancer—ready for clinical routine?

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