Successful Targeted Therapy of Refractory Pediatric <i>ETV6-NTRK3</i> Fusion-Positive Secretory Breast Carcinoma

Shukla, Neerav; Roberts, Stephen S.; Baki, M.; Mushtaq, Qazi Danish; Goss, Paul E.; Park, Ben Ho; Gundem, Gunes; Tian, Ken; Geiger, Heather; Redfield, Kristie; Behr, Gerald; Benayed, Ryma; Zehir, Ahmet; Hechtman, Jaclyn F.; Darnell, Robert B.; Papaemmanuil, Elli; Ladanyi, Marc; Ku, Nora; Kung, Andrew L.; Baselga, José; Drilon, Alexander; Hyman, David M.

doi:10.1200/po.17.00034

Cited by 42 publications

(35 citation statements)

References 25 publications

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“…In addition, there was amplification of the 16p13.3 locus, which includes NTHL1, TSC2, TRAF7 and 3-phosphoinositide-dependent protein kinase-1 (PDPK1) genes. The patient ultimately received targeted therapy with a pan-Trk inhibitor and showed excellent initial response, the details of which have been reported by Shukla et al 34 Subsequent molecular testing revealed a TERT C228T promotor mutation. 34 Case 2 A 26-year-old previously healthy man presented with a palpable left breast mass.…”

Section: Casesupporting

confidence: 54%

“…The patient ultimately received targeted therapy with a pan-Trk inhibitor and showed excellent initial response, the details of which have been reported by Shukla et al 34 Subsequent molecular testing revealed a TERT C228T promotor mutation. 34 Case 2 A 26-year-old previously healthy man presented with a palpable left breast mass. The initial needle core biopsy and the subsequent simple mastectomy revealed a 2.0-cm SCB (Figure 3).…”

Section: Casesupporting

confidence: 54%

“…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%

“…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%

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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: Casesupporting

confidence: 54%

Section: Casesupporting

confidence: 54%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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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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“…An additional recent article describes a patient with secretory breast carcinoma and an ETV6-NTRK3 fusion who also responded to targeted TRK inhibition. 35 In order to treat patients with targeted therapies, however, the presence of the target must be confirmed, yet the current standard assays (ETV6 breakapart FISH or ETV6-NTRK3 RT-PCR) will miss cases with alternative fusion partners. In order to establish whether the EML4-NTRK3 fusion is recurrent, and to evaluate testing strategies that would capture alternative fusions, we collected archival cases whose differential diagnosis included infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma or secretory breast carcinoma, and screened these cases for rearrangements using either novel FISH probes, targeted multiplex sequencing, or both.…”

mentioning

confidence: 99%

Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

et al. 2018

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Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.

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Lessons learned from the developmental origins of childhood renal cancer

Chong

Cain

2019

The Anatomical Record

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Despite the rarity of renal tumors in children, many different types of malignant and nonmalignant renal neoplasms have been described. Therefore, the correct diagnosis and clinical management of these patients can represent a challenge. Here we provide a comprehensive review of the commonly diagnosed pediatric renal malignancies, including nephroblastoma (commonly known as Wilms tumor), clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, several subtypes of renal cell tumors (often collectively termed renal cell carcinoma), and congenital mesoblastic nephroma. The epidemiology, pathology, treatments, underlying genetic and molecular mechanisms, and proposed developmental origins are discussed in detail, highlighting differential features and potential improved therapeutic strategies for affected individuals.

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Successful Targeted Therapy of Refractory Pediatric ETV6-NTRK3 Fusion-Positive Secretory Breast Carcinoma

Cited by 42 publications

References 25 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

Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

Lessons learned from the developmental origins of childhood renal cancer

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