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Molecular profiling of hormone receptor-positive, HER2-negative breast cancers from patients treated with neoadjuvant endocrine therapy in the CARMINA 02 trial (UCBG-0609)

Authors
  • Liang, Xu1, 2
  • Briaux, Adrien2
  • Becette, Véronique3
  • Benoist, Camille2
  • Boulai, Anais2
  • Chemlali, Walid2
  • Schnitzler, Anne2
  • Baulande, Sylvain4
  • Rivera, Sofia5
  • Mouret-Reynier, Marie-Ange6
  • Bouvet, Laurence Venat7
  • De La Motte Rouge, Thibaut8
  • Lemonnier, Jérôme9
  • Lerebours, Florence10
  • Callens, Céline2
  • 1 Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Beijing, China , Beijing (China)
  • 2 PSL Research University, Pharmacogenomic Unit, Department of Genetics, Curie Institute, Paris, France , Paris (France)
  • 3 René Huguenin Hospital, Department of Biopathology, Curie Institute, Saint-Cloud, France , Saint-Cloud (France)
  • 4 PSL Research University, Institut Curie Genomics of Excellence (ICGex) Platform, Curie Institute, Paris, France , Paris (France)
  • 5 Department of Radiotherapy, Gustave Roussy, Villejuif, France , Villejuif (France)
  • 6 Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France , Clermont-Ferrand (France)
  • 7 Department of Medical Oncology, CHU, Limoges, France , Limoges (France)
  • 8 Department of Medical Oncology, Centre Eugene Marquis, Rennes, France , Rennes (France)
  • 9 R&D Unicancer, UCBG, Paris, France , Paris (France)
  • 10 René Huguenin Hospital, Department of Medical Oncology, Curie Institute, Saint-Cloud, France , Saint-Cloud (France)
Type
Published Article
Journal
Journal of Hematology & Oncology
Publisher
BioMed Central
Publication Date
Oct 11, 2018
Volume
11
Issue
1
Identifiers
DOI: 10.1186/s13045-018-0670-9
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundPostmenopausal women with large, hormone receptor (HR)-positive/HER2-negative and low-proliferative breast cancer derived a benefit from neoadjuvant endocrine therapy (NET) in the CARMINA02 trial. This study was designed to correlate gene expression and mutation profiles with both response to NET and prognosis.MethodsGene expression profiling using RNA sequencing was performed in 86 pre-NET and post-NET tumor samples. Targeted next-generation sequencing of 91 candidate breast cancer-associated genes was performed on DNA samples from 89 patients. Molecular data were correlated with radiological response and relapse-free survival.ResultsThe transcriptional profile of tumors to NET in responders involved immune-associated genes enriched in activated Th1 pathway, which remained unchanged in non-responders. Immune response was confirmed by analysis of tumor-infiltrating lymphocytes (TILs). The percentage of TILs was significantly increased post-NET compared to pre-NET samples in responders (p = 0.0071), but not in non-responders (p = 0.0938). Gene expression revealed that lipid metabolism was the main molecular function related to prognosis, while PPARγ is the most important upstream regulator gene. The most frequently mutated genes were PIK3CA (48.3%), CDH1 (20.2%), PTEN (15.7%), TP53 (10.1%), LAMA2 (10.1%), BRCA2 (9.0%), MAP3K1 (7.9%), ALK (6.7%), INPP4B (6.7%), NCOR1 (6.7%), and NF1 (5.6%). Cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway were altered significantly more frequently in non-responders than in responders (p = 0.0017 and p = 0.0094, respectively). The average number of mutations per sample was significantly higher in endocrine-resistant tumors (2.88 vs. 1.64, p = 0.03), but no difference was observed in terms of prognosis. ESR1 hotspot mutations were detected in 3.4% of treatment-naive tumors.ConclusionsThe Th1-related immune system and lipid metabolism appear to play key roles in the response to endocrine therapy and prognosis in HR-positive/HER2-negative breast cancer. Deleterious somatic mutations in the cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway may be relevant for clinical management.Trial registrationThis trial is registered with ClinicalTrials.gov (NCT00629616) on March 6, 2008, retrospectively registered.

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