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. 2021 Jul 13;26(10):818–824. doi: 10.1002/onco.13880

Locally Recurrent Secretory Carcinoma of the Breast with NTRK3 Gene Fusion

Lindsey Mortensen 1,†, Zehra Ordulu 1,2,†, Ibiayi Dagogo‐Jack 1,2, Veerle Bossuyt 1,2, Loren Winters 1,2, Alphonse Taghian 1,2, Barbara L Smith 1,2, Leif W Ellisen 1,2, Lesli A Kiedrowski 3, Jochen K Lennerz 1,2, Aditya Bardia 1,2,✉, Laura M Spring 1,2
PMCID: PMC8488779  PMID: 34176200

Abstract

Enhanced understanding of the molecular events underlying oncogenesis has led to the development of “tumor‐agnostic” treatment strategies, which aim to target a tumor's genomic profile regardless of its anatomic site of origin. A classic example is the translocation resulting in an ETV6‐NTRK3 gene fusion, a characteristic driver of a histologically diverse array of cancers. The chimeric ETV6‐NTRK3 fusion protein elicits constitutive activation of the tropomyosin receptor kinase (TRK) C protein, leading to increased cell survival, growth, and proliferation. Two TRK inhibitors, larotrectinib and entrectinib, are currently approved for use in the metastatic setting for the treatment of advanced solid tumors harboring NTRK fusions. Here we report a rare case of recurrent secretory carcinoma of the breast (SCB) with NTRK3 gene fusion. Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case detailed here is the first to the authors' knowledge of recurrence within 1 year of surgery. We review the molecular findings and potential clinical significance.

Key Points

  • The translocation resulting in the ETV6‐NTRK3 gene fusion is a known oncogenic driver characteristic of secretory carcinoma of the breast (SCB).

  • Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case here with ETV6‐NTRK3 gene fusion had local recurrence within 1 year of surgery.

  • Two tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, are approved to treat NTRK fusion–positive tumors, demonstrating sustained high overall response rates in the metastatic setting.

  • Approval of TRK inhibitors necessitates optimization of NTRK fusion detection assays, including detection with liquid biopsies.

Keywords: NTRK3 gene fusion, Secretory carcinoma, Breast carcinoma, Latotrectinib and entrectinib

Short abstract

This article reports a rare case of recurrent secretory carcinoma of the breast with NTRK3 gene fusion, detailing the molecular findings and potential clinical significance.

Patient Story

A 46‐year‐old premenopausal woman presented with an area of architectural distortion in the left breast on screening mammogram. Core biopsy of the lesion showed grade 2 invasive ductal carcinoma (IDC). Based on imaging and examination she was determined to have clinical anatomic stage IIA (T2 N0) disease. Immunohistochemistry (IHC) revealed the carcinoma to be estrogen receptor (ER) weakly positive (1%–10%, faint staining), progesterone receptor negative (PR−), and human epidermal growth factor receptor 2 (also known as ERBB2) negative (HER2−). The patient has a personal history of Hodgkin's lymphoma at age 22 for which she received six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. She did not receive mantle radiation. A multigene germline panel test, including BRCA1/2 and TP53, was performed following her breast cancer diagnosis and did not identify any mutations. Her history is also notable for well‐controlled relapsing‐remitting multiple sclerosis on rituximab every 6 months.

The case was reviewed at multidisciplinary breast tumor board. Given essentially triple‐negative tumor biology, neoadjuvant chemotherapy was recommended. The docetaxel/carboplatin regimen was chosen to avoid anthracyclines given her prior exposure. After minimal response to four cycles of neoadjuvant docetaxel/carboplatin, it was decided to proceed to surgery. The patient underwent a left lumpectomy with sentinel lymph node evaluation revealing a 4.3 cm grade 1–2 ER‐positive (10%–50% faint staining), PR−, HER2− invasive secretory carcinoma of the breast (SCB) and grade 2 secretory and nonsecretory ductal carcinoma in situ (DCIS) within the regions of invasive carcinoma, without evidence of sentinel lymph node involvement (pathologic stage ypT2 N0) (Fig. 1). A margin was positive. She then underwent a re‐excision revealing SCB spanning 0.4 cm and secretory and focally nonsecretory DCIS spanning 1.5 cm, again with a positive margin. A completion left mastectomy with single stage implant reconstruction was then performed and revealed residual invasive secretory carcinoma and secretory DCIS. The patient's case was reviewed at tumor board. Given past chemotherapy exposure, the tumor's histology and associated minimal response to chemotherapy, and ER positivity, the consensus was to use adjuvant tamoxifen and defer additional chemotherapy. The patient opted to discontinue tamoxifen after 1 month.

Figure 1.

Figure 1

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Secretory breast carcinoma. Low power view (left panel) highlights the lobulated appearance of large nests of tumor cells separated by fibrous bands. High power view (right panel) shows that the tumor cells have bubbly cytoplasm and relatively uniform nuclei with small nucleoli. Eosinophilic secretory material is present in lumina.

Nearly 12 months following her mastectomy, the patient noted a firm area in the upper outer quadrant of her reconstructed left breast. Breast magnetic resonance imaging noted a suspicious superficial 1.7 cm mass in the left upper outer quadrant and a suspicious left axillary node. Core biopsies of the left breast mass and axillary node demonstrated grade 2 triple‐negative IDC. No evidence of distant metastatic disease was found on staging scans. She underwent excision of the mass and axillary lymph node dissection revealing a 1.6 cm grade 2 triple‐negative SCB, as well as a single small focus of DCIS, with involvement of one of seven axillary lymph nodes (1.3 cm macrometastasis). Margins were negative. The case was reviewed at the Massachusetts General Hospital molecular and precision medicine tumor board.

Molecular Tumor Board

Molecular testing of the initial surgical specimen and the recurrence specimen revealed an ETS variant transcription factor 6 (ETV6)–neurotrophic tyrosine receptor kinase 3 (NTRK3) gene fusion, which is characteristic of SCB (Fig. 2). The fusion was detected with an internal assay using anchored multiplex polymerase chain reaction (AMP) for targeted fusion transcript detection using next‐generation sequencing (NGS) [1]. The assay is validated for samples showing 5% or higher tumor cellularity.

Figure 2.

Figure 2

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Exon composition of the ETV6‐NTRK3 translocation. The fusion product is derived from 11 exons composed of five exons from the 5' partner ETV6 (NM_001987.5) contributing the sterile alpha motif/pointed domain and six exons from the 3' partner NTRK3 (NM_001012338.2) with conservation of the tyrosine kinase domain. Abbreviations: ETV6, ETS variant transcription factor 6; Ex, exon; NTRK3, neurotrophic tyrosine receptor kinase 3.

Clinical and Functional Significance of ETV6‐NTRK3 Fusions

The mutant ETV6‐NTRK3 gene fusion is found in a histologically diverse array of adult and pediatric cancers including SCB, which constitutes less than 0.15% of all breast carcinomas [2, 3]. The ETV6‐NTRK3 gene fusion is typically associated with slow‐growing, indolent tumors with a good clinical prognosis and rare instances of distant metastasis [4]. An analysis of 83 patients with SCB revealed a 5‐ and 10‐year overall survival of 87.2% and 76.5%, respectively, and a 5‐ and 10‐year cause‐specific survival of 94.4% and 91.4%, respectively [4]. Although rare, recurrences of SCB have been reported, usually occurring after a long disease‐free interval (typically 10–20 years after initial diagnosis) [5, 6]. The case detailed here is therefore an outlier to a majority of cases of SCB, as it is the first to the authors' knowledge of recurrence within 1 year of surgery.

Immunoprofiling of SCB tumor specimens indicates that most cases of SCB fall under the basal‐like molecular subgroup of breast cancer [2], which is characterized by triple‐negative receptor status (or weak ER expression) and increased expression of cytokeratins 5/6 and epidermal growth factor receptor [7]. Although basal‐like cancers are the most aggressive subtype of breast carcinoma [7], SCB's relatively favorable prognosis [4, 5] supports the notion that tumor genomics play a significant role in determining outcomes within molecular subtypes [2].

The translocation resulting in the ETV6‐NTRK3 gene fusion is a known oncogenic driver of SCB. Neurotrophic tyrosine receptor kinases (NTRKs) 1, 2, and 3 (NTRK1, NTRK2, NTRK3) encode tropomyosin receptor kinases A, B, and C (TRKA, TRKB, TRKC), respectively. The NTRK family is expressed primarily in nervous system tissues [8] and regulates multiple signal transduction pathways mediated by binding events with neurotrophins that affect nervous system development and function [9]. The ETV6 gene encodes the ETV6 protein, which regulates maintenance and development of hematologic tissues and oncogenesis [10].

There are multiple known mechanisms for oncogenic activation of TRK [11], but the most notable found in nearly all cases of secretory carcinoma are ETV6‐NTRK3 gene fusions [12]. Cases of secretory carcinoma containing the ETV6‐NTRK3 fusion result from the translocation of DNA between ETV6 on the short arm of chromosome 12 (12p13.2) and NTRK3 on the long arm of chromosome 15 (15q25.3) to form a chromosome 15 derivative [12]. The gene fusion encodes a chimeric protein containing the catalytic tyrosine kinase domain of NTRK3 (TRKC) linked to the sterile α motif dimerization domain of ETV6 (ETV6) [12]. Although the precise oncogenic mechanism remains unclear, homo‐ or heterodimerization with another ETV6‐NTRK3 fusion protein or endogenous ETV6 elicits aberrant constitutive, ligand‐independent activation of NTRK1–3 signal transduction effectors, including RAS–mitogen‐activated protein kinase, phosphoinositide 3‐kinase–anaplastic lymphoma kinase, and phospholipase‐C γ, leading to increased cell survival, growth, and proliferation [13, 14] (Fig. 3).

Figure 3.

Figure 3

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Therapeutic inhibition of oncogenic signaling in ETV6‐NTRK3 fusion–positive tumors. The wild‐type transmembrane TRKC protein dimerizes and auto‐phosphorylates following NT‐3 binding, leading to regulated activation of the PI3K‐AKT pathway. NT‐3 also binds with lower affinity to wild‐type TRKA and TRKB, activating downstream signal trasnduction effectors including PI3K‐AKT, RAS‐MAPK, and PLCγ. In ETV6‐NTRK3 fusion–positive tumors, the intracellular ETV6‐NTRK3 chimeric protein undergoes ligand‐independent homo‐ or hetero‐dimerization, leading to constitutive, aberrant activation of oncogenic signaling, causing increased cell growth, survival, and differentiation. The U.S. Food and Drug Administration–approved TRK inhibitors larotrectinib and entrectinib bind and block the ATP binding site of the ETV6‐NTRK3 fusion protein to prevent its oncogenic signaling. Created with BioRender.com. Abbreviations: AKT, anaplastic lymphoma kinase; ETV6, ETS variant transcription factor 6; MAPK, mitogen‐activated protein kinase; NT‐3, neurotrophin 3; NTRK3, neurotrophic tyrosine receptor kinase 3; PI3K, phosphoinositide 3‐kinase; PLCγ, phospholipase‐C γ; TRKA–C, tropomyosin receptor kinase A–C; WT, wild type.

Strategies to Target NTRK Fusions

Oncogenic activation of NTRK1–3 through fusions with other partner genes occurs in a myriad of other cancer types in addition to SCB, including mammary analog sescretory carcinoma, cellular and mixed congenital mesoblastic nephroma, and infantile fibrosarcoma [3]. “Tumor‐agnostic” treatment strategies were developed in an effort to target the shared oncogenic machinery driving the subset of cancers harboring NTRK fusions in a manner independent of tumor histology and anatomic site of origin. The pan‐TRK inhibitor larotrectinib was the second tumor‐agnostic agent to be developed and approved by the U.S. Food and Drug Administration, following the programmed cell death protein 1 inhibitor pembrolizumab approved for tumors with high microsatellite instability or deficient DNA mismatch repair [15, 16]. Within the cell, larotrectinib selectively binds and blocks the ATP binding site of TRK, inhibiting downstream proliferation mechanisms and leading to arrest at the G1 transition, apoptosis, and subsequent tumor regression [17].

In a pooled analysis of single‐arm studies with a primary endpoint of objective response according to investigator assessment, larotrectinib demonstrated an impressive 79% objective response across the three trials, with sustained response to therapy after 1 year in a majority of patients [16, 18]. The study reported few instances of serious adverse events, with fatigue, nausea, dizziness, vomiting, increased aspartate aminotransferase and alanine aminotransferase, cough, constipation, and diarrhea being the most common adverse events observed [16, 18]. Larotrectinib received accelerated approval in 2018 for the treatment of adult and pediatric metastatic disease (or disease where surgical resection would result in severe morbidity) harboring an NTRK fusion without other satisfactory treatment options [19]. Of the six patients with TRK fusion–positive breast cancer cases treated with larotrectinib on the study (including three cases of SCB and three cases of nonsecretory carcinoma), five patients (83%) exhibited a partial response [20], similar to the response reported across all tumor types [18]. The three cases of SCB harboring the ETV6‐NTRK3 fusion all exhibited a partial response to larotrectinib [20]. In 2019, entrectinib, another competitive inhibitor targeting the TRK ATP binding site, was approved for use in NTRK fusion–positive solid tumors based on pooled data from three single‐arm basket trials [21, 22]. There are multiple ongoing clinical trials seeking to assess the safety and efficacy of TRK inhibitors in a tumor‐agnostic manner (Table 1).

Table 1.

Select clinical trials investigating the safety and tumor‐agnostic efficacy of TRK inhibitors

Trial name Study ID Phase NTRK inhibitor
A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects with NTRK Fusion‐Positive Tumors NCT02576431 II Larotrectinib
A Phase I/II Study of the Oral TRK Inhibitor LOXO‐101 in Pediatric Patients with Advanced Solid or Primary Central Nervous System Tumors NCT02637687 I/II Larotrectinib
NCI‐COG Pediatric MATCH (Molecular Analysis for Therapy Choice) ‐ Phase 2 Subprotocol of LOXO‐101 (Larotrectinib) in Patients with Tumors Harboring Actionable NTRK Fusions NCT03213704 II Larotrectinib
A Phase I Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients with Solid Tumors NCT02122913 I Larotrectinib
NCI‐COG Pediatric MATCH (Molecular Analysis for Therapy Choice) Screening Protocol NCT03155620 II Larotrectinib
Larotrectinib (LOXO‐101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias NCT03834961 II Larotrectinib
Molecular Analysis for Therapy Choice (MATCH) NCT02465060 II Larotrectinib
An Open‐Label, Multicenter, Global Phase II Basket Study of Entrectinib for the Treatment of Patients with Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements NCT02568267 II Entrectinib
A Phase I/II, Open‐Label, Dose‐Escalation and Expansion Study Of Entrectinib (Rxdx‐101) In Pediatrics with Locally Advanced or Metastatic Solid or Primary CNS Tumors and/or Who Have No Satisfactory Treatment Options NCT02650401 I/II Entrectinib
The Rome Trial from Histology to Target: The Road to Personalize Target Therapy and Immunotherapy NCT04591431 II Entrectinib
Genomically‐Guided Treatment Trial in Brain Metastases NCT03994796 II Entrectinib
Tumor‐Agnostic Precision Immunooncology and Somatic Targeting Rational for You (TAPISTRY) Phase II Platform Trial NCT04589845 II Entrectinib
A Phase I/II, Open‐Label, Safety, Tolerability, Pharmacokinetics, and Anti‐Tumor Activity Study of Repotrectinib in Pediatric and Young Adult Subjects with Advanced or Metastatic Malignancies Harboring ALK, ROS1, NTRK1‐3 Alterations NCT04094610 I/II Repotrectinib
A Phase I/II, Open‐Label, Multi‐Center, First‐in‐Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti‐Tumor Activity of TPX‐0005 in Patients with Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1‐3 Rearrangements (TRIDENT‐1) NCT03093116 I/II Repotrectinib
A Phase I/II Study of the TRK Inhibitor Selitrectinib in Adult and Pediatric Subjects with Previously Treated NTRK Fusion Cancers NCT03215511 I/II Selitrectinib
A Phase II, Multicenter, Open, Basket Study of AB‐106 to Treat the Subjects with Local Progression or Systemic Metastasis Solid Tumors with NTRK Gene Fusion NCT04617054 II AB‐106
A Phase II Study of Merestinib in Non‐Small Cell Lung Cancers Harboring MET Exon 14 Mutations and Solid Tumors with NTRK Rearrangements NCT02920996 II Merestinib
Phase 1 Study of DS‐6051b in Japanese Subjects with Advanced Solid Malignant Tumors Harboring Either a ROS1 or NTRK Fusion Gene NCT02675491 I DS‐6051b
A Phase I/1b Study of MGCD516 in Patients with Advanced Solid Tumor Malignancies NCT02219711 I MGCD516
Single‐Arm, Open, Multi‐Center Phase I/Phase II Clinical Study to Assess the Safety, Tolerability, Pharmacokinetic and Effectiveness of VC004 NCT04614740 I/II VC004
MegaMOST ‐ A Multicenter, Open‐Label, Biology Driven, Phase II Study Evaluating the Activity of Anti‐Cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced/Metastatic Tumors NCT04116541 II Cabozantinib
An Open‐Label, Multiple‐Dose, Dose‐Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of VMD‐928 in Subjects with Solid Tumors or Lymphoma NCT03556228 I VMD‐928
Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR): A Phase II Basket Trial NCT03297606 II Temsirolimus
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Abbreviations: ALK, anaplastic lymphoma kinase; CNS, central nervous system; NCI‐COG, National Cancer Institute Children's Oncology Group; NTRK, neurotrophic tyrosine receptor kinase; ROS1, ROS proto‐oncogene 1; TRK, tropomyosin receptor kinase.

Detecting NTRK Fusions

The advent of tumor‐agnostic therapies necessitates optimization of biomarker detection. Specific to employing NTRK gene fusion–targeted therapies, challenges in detection exist because NTRK1–3 fusions can occur with a multitude of fusion partners. Each fusion pair can have different breakpoints, and the NTRK genes contain large intronic regions that may not be covered by DNA‐based NGS panels [23]. A retrospective analysis comparing IHC and a targeted DNA‐based NGS panel with RNA‐based NGS in 33,997 solid tumor cases found variable sensitivity and specificity of each assay in a manner dependent on both tumor type and NTRK fusion partner [24]. The specificity in detecting NTRK fusions by pan‐TRK IHC appeared lower in breast (82%) and salivary gland (52%) carcinomas when compared with other cancer types [24]. Pan‐TRK IHC had a sensitivity and specificity of detecting NTRK1–3 fusions of 87.9% and 81.1%, respectively, whereas the study's DNA‐based cancer gene panel NGS had a sensitivity and specificity of 81.1% and 99.86%, respectively [24]. The DNA‐based NGS demonstrated very high sensitivity in detecting NTRK1 and ETV6‐NTRK3 fusions, as the intronic regions of NTRK1 and ETV6 are covered by the panel. However, because NTRK2 and NTRK3's intronic regions were not included in the panel, their fusions (excluding those with ETV6) were not always detected with DNA‐based NGS [24]. Generally speaking, caution should be exercised if examining for the presence of novel NTRK fusion partners using DNA‐based NGS without adequate sequencing coverage of both partners.

In our clinical practice, we primarily use RNA‐based NGS to define NTRK fusion–positive tumors. Technologies like NGS‐based AMP using RNA input were developed to assess gene rearrangements without requiring precise knowledge of both fusion partners [1]. AMP uniquely assesses for possible fusions by targeting one commonly involved fusion partner (e.g., NTRK1–3) regardless of the identity of the other fusion partner and was used to identify the ETV6‐NTRK3 fusion in the case of SCB reported here. Despite RNA‐based NGS simplifying challenges resulting from NTRK1–3 introns and probing for variable fusion partners, it is not entirely optimal nor comprehensive, as it does not detect all genomic events, is relatively costly, and requires sufficient quantity of high‐quality RNA [24].

Another area of promise for NTRK fusion detection is plasma‐based genotyping. Guardant360 is a commercially available, NGS‐based assay that identifies potential tumor‐related (somatic) genomic alterations via sequencing of critical exons within up to 83 cancer‐related genes [25, 26]. The assay is also able to detect and report fusions in a subset of the genes on the panel and as such includes coverage of some intronic regions with known involvement in oncogenic rearrangements. However, given that this technology is based on DNA, it is subject to the same NGS limitations described above for tissue‐based NGS assays, in which some fusions may be captured while others may not based on specific regions of assay coverage. Sensitivity of plasma‐based testing is also highly time‐sensitive and dependent on tumor biology at the time of blood sample collection; the presence of circulating tumor DNA in the blood can be limited by a variety of factors including volume of disease and current treatment. As a whole, analyzing and detecting NTRK fusions requires foresight and acknowledgment of the relative strengths and weaknesses of the various assays available as well as technical advances to better optimize biomarker detection.

Patient Update

The patient recovered well from surgery and underwent post‐mastectomy radiation with coverage of the regional lymph nodes. Additional chemotherapy was not recommended because of prior chemotherapy exposure and relative chemotherapeutic insensitivity of SCB. She requested circulating tumor DNA analysis to assess for potential minimal residual disease, and the Guardant360 expanded panel assay was sent. Results did not reveal an ETV6‐NTRK3 fusion. The introns surrounding the impacted exons in this case do not have complete sequencing coverage on the assay. Given that the fusion was detected only via RNA‐based testing and the specific intronic breakpoint is unknown, it is not clear whether it would be captured by the plasma‐based assay. Furthermore, this patient's blood sample was collected when she had no clinical evidence of disease, so the lack of oncogenic fusion molecules present in cell‐free DNA is consistent with the clinical history. If there is evidence of a systemic recurrence in the future, targeted therapy with an approved NTRK inhibitor would be favored given the confirmed ETV6‐NTRK3 fusion target. The patient currently has no evidence of disease and is being monitored clinically.

Glossary of Genomic Terms and Nomenclature

ALK: anaplastic lymphoma kinase

ETV6: ETS variant transcription factor 6

NGS: next‐generation sequencing

NTRK: neurotrophic tyrosine receptor kinase

ROS‐1: ROS proto‐oncogene 1

TRK: tropomyosin receptor kinase/tyrosine receptor kinase

Author Contributions

Conception/design: Lindsey Mortensen, Zehra Ordulu, Aditya Bardia, Laura M. Spring

Provision of study material or patients: Lindsey Mortensen, Zehra Ordulu, Veerle Bossuyt, Barbara L. Smith, Lesli A. Kiedrowski, Jochen K. Lennerz, Laura M. Spring

Collection and/or assembly of data: Lindsey Mortensen, Zehra Ordulu, Veerle Bossuyt, Loren Winters, Alphonse Taghian, Barbara L. Smith, Lesli A. Kiedrowski, Jochen K. Lennerz, Laura M. Spring

Data analysis and interpretation: Lindsey Mortensen, Zehra Ordulu, Ibiayi Dagogo‐Jack, Veerle Bossuyt, Loren Winters, Alphonse Taghian, Barbara L. Smith, Leif W. Ellisen, Lesli A. Kiedrowski, Jochen K. Lennerz, Aditya Bardia, Laura M. Spring

Manuscript writing: Lindsey Mortensen, Zehra Ordulu, Aditya Bardia, Laura M. Spring

Final approval of manuscript: Lindsey Mortensen, Zehra Ordulu, Ibiayi Dagogo‐Jack, Veerle Bossuyt, Loren Winters, Alphonse Taghian, Barbara L. Smith, Leif W. Ellisen, Lesli A. Kiedrowski, Jochen K. Lennerz, Aditya Bardia, Laura M. Spring

Disclosures

Ibiayi Dagogo‐Jack: Pfizer, Xcovery, Novocure, AstraZeneca, Catalyst, BostonGene, Syros (C/A), Genentech, Pfizer, Array, Novartis (RF), American Lung Association, Creative Education Concepts (H); Lesli A. Kiedrowski: Guardant Health (E, OI); Aditya Bardia: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Diiachi Pharma/Astra Zeneca, Puma (C/A), Biothernostics Inc., Phillips, Eli Lilly & Co., Foundation Medicine (C/A), Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Diiachi Pharma/AstraZeneca (RF—institution); Laura M. Spring: Novartis, Avrobio (C/A). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Acknowledgments

The patient gave consent for images and clinical information relating to her case to be reported in this medical publication.

Disclosures of potential conflicts of interest may be found at the end of this article.

No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact commercialreprints@wiley.com. For permission information contact permissions@wiley.com.

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