Details

Autor(en) / Beteiligte

• Hartmaier, R.J.
• Trabucco, S.E.
• Priedigkeit, N.
• Chung, J.H.
• Parachoniak, C.A.
• Vanden Borre, P.
• Morley, S.
• Rosenzweig, M.
• Gay, L.M.
• Goldberg, M.E.
• Suh, J.
• Ali, S.M.
• Ross, J.
• Leyland-Jones, B.
• Young, B.
• Williams, C.
• Park, B.
• Tsai, M.
• Haley, B.
• Peguero, J.
• Callahan, R.D.
• Sachelarie, I.
• Cho, J.
• Atkinson, J.M.
• Bahreini, A.
• Nagle, A.M.
• Puhalla, S.L.
• Watters, R.J.
• Erdogan-Yildirim, Z.
• Cao, L.
• Oesterreich, S.
• Mathew, A.
• Lucas, P.C.
• Davidson, N.E.
• Brufsky, A.M.
• Frampton, G.M.
• Stephens, P.J.
• Chmielecki, J.
• Lee, A.V.

Titel

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

Ist Teil von

• Annals of oncology, 2018-04, Vol.29 (4), p.872-880

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.