December 2021 Case

The patient is a female in her 50’s presents with a large pelvic mass that measures 14.2 x 6.6 x10.4 cm with bony destruction in the left ilium. The pathologist noted that the histomorphologic and immunohistochemical staining characteristics of this malignant tumor are not entirely specific to one primary; however, the strong positive staining for GATA3 and strong positive staining in 100% of the malignant cells for estrogen receptor raises the possibility of breast primary. History includes a previous right lumpectomy for ER+, HER2 negative invasive ductal of the right breast in 2014, treated with Letrozole (Aromatase Inhibitor) therapy until 2019. Other possibilities include but are not limited to, gynecologic, pancreaticobiliary, and some genitourinary primaries.

Molecular profiling of the patient's pelvic mass biopsy was performed using the Cedars-Sinai comprehensive cancer panel, which is a targeted amplicon based NGS assay that utilizes DNA and RNA to detect single nucleotide variations, indels, copy number variations, and select rearrangements (inter and intragenic) in 161 genes as well as tumor mutational burden. Genomic profiling identified a ESR1::CCDC170 t(6:6) fusion and amplifications of both 11q13 (CCND1, FGF3, and FGF19) and FGFR1.

ER+ breast cancers can be classified into “luminal A” and “luminal B.” The luminal B are typically more aggressive and endocrine-resistant with high proliferative activity Ki-67 index (>10%). Luminal B breast cancer accounts for 15–20% of all breast cancers and is the most common subtype in young women. Recurrent gene rearrangements between ESR1 and its neighboring gene, coiled-coil domain containing 170 (CCDC170), in 6–8% of luminal B breast cancer, the majority of which are likely the result of tandem duplications (PMID 29360925).

The molecular profile strongly correlates with an invasive breast cancer, with over 30 cases found with co-amplification of 11q13 and FGFR1 (cBioPortal.org). Additionally, ESR1::CCDC170 fusions are found up to 6-8% of "Luminal B" subtype breast cancer (typically ER+ and HER2 negative), and correlate to more aggressive, endocrine resistant, and high Ki67 cancers (PMID 32771039).

Studies profiling ER+ endocrine resistant breast cancers revealed a correlation between 8p11-12 and 11q13 gene co-amplifications, including FGFR1 and CCND1, respectively, and high Ki67 (PMID 28794284). Notably, the same study also found the ESR1::CCDC170 fusion in 4 tumors that did not respond to Letrozole. Amplification of both FGFR1 and CCND1 may be synergistic, as FGFR1 is relevant in the crosslinking of cyclin D (CCND1) and CDK4/6. Of the five FGFRs, FGFR1 is associated with CDK4/6 inhibitor resistance. Clinically, FGFR1 overexpression mediated resistance to Palbociclib or Ribociclib when combined with endocrine therapy (Fulvestrant), however, this resistance could be reversed by the FGFR tyrosine kinase inhibitor (TKI) Lucitanib (PMID 30914635).

Estrogen receptor (ESR1) activating mutations are frequently detected in HR-positive HER2 negative patients with prior exposure to aromatase inhibitors (AIs) (NCCN, Breast cancer v1.2022). Tumors with activating ESR1 mutations are generally resistant to both AIs (exemestane, anastrozole, letrozole) and tamoxifen (NCCN, Breast cancer v1.2022). However, this fusion only includes the 5'UTR of the estrogen receptor and not the ligand binding domain or hinge region that are typically altered in treatment resistance (see figure above), and the resistance mechanism in question is yet to be elucidated. The functional portion of the fusion encodes for the protein of CCDC170. The group that initially reported and performed the original functional studies (PMID 25099679) recently published additional studies showing the functional portion of the expressed CCDC170 protein binds to HER2 in the cell, and that treatment these fusions are sensitive to HER2/EGFR inhibitor Lapatanib and/or SRC inhibitor Dasatinib, with best results seen when additionally combined with Fulvestrant (PMID 32771039).