57P - Somatic BRCA1 mutations determine different responses to platinum-based chemotherapy

Date 07 May 2015
Event IMPAKT 2015
Session Welcome reception and Poster Walk
Topics Anti-Cancer Agents & Biologic Therapy
Breast Cancer
Translational Research
Presenter Ekaterina Ignatova
Citation Annals of Oncology (2015) 26 (suppl_3): 15-24. 10.1093/annonc/mdv117
Authors E. Ignatova1, M. Frolova2, E. Glazkova2, M. Stenina1, A. Petrovsky3, A. Burdennyy4, V. Loginov4, M. Filippova5, L. Lyubchenko5, S. Tjulandin1
  • 1Clinical Pharmacology And Chemotherapy, N. N. Blokhin Russian Cancer Research Center, 115478 - Moscow/RU
  • 2Clinical Pharmacology And Chemotherapy, N. N. Blokhin Russian Cancer Research Center, Kashirskoye d.23 - Moscow/RU
  • 3Radiosurgery, N. N. Blokhin Russian Cancer Research Center, 115478 - Moscow/RU
  • 4Laboratory Of Patogenomics And Transcriptomics, FSBSI "Institute of General Pathology and Pathophysiology", 125315 - Moscow/RU
  • 5Laboratory Of Clinical Oncogenetics, N. N. Blokhin Russian Cancer Research Center, 115478 - Moscow/RU

Abstract

Body

Introduction: There is increasing evidence that BRCA1-related DNA-repair defects determine sensitivity to certain agents, such as platinum-based chemotherapy. Many clinical characteristics and molecular features are shared by sporadic triple-negative breast cancer and BRCA1-associated breast cancer. Identification of specific markers of BRCA1-dysfunction will be essential to translate an understanding of defective DNA repair into targeted treatments for this poor prognosis subtype.

Material and method: Twenty-two patients (pts) with triple-negative breast cancer (TNBC) were included in the study from 2011 to 2014. Seventeen рts with early TNBC (cT1-2N0-1M0) received cisplatin 30 mg/m2 iv weekly, doxorubicin 25 mg/m2 iv weekly, рaclitaxel 100 mg/m2 iv weekly for planned 8 weeks followed by surgery. Five рts with locally advanced TNBC (cT2-4N1-3M0) received carboplatin AUC2 iv weekly, рaclitaxel 60 mg/m2 iv weekly for planned 1-9 weeks, doxorubicin 25 mg/m2 iv weekly, cyclophosphamide 50 mg po daily and capecitabine 1500 mg po daily for planned 10-18 weeks followed by surgery. Pathologic treatment response was assessed in correlation with biomarkers of BRCA1-dysfunction.

Results and discussion: Twelve pts (54,5%) achieved a pathological complete response (pCR). We identified following biomarkers of BRCA1-dysfunction. BRCA1 mRNA expression was absent in 16/22 (72,7%) pts, low in 5/22 (22,7%). BRCA1 promoter methylation was detected in 9/22 (40,9%). RAD51 mRNA levels were low in 14/22 (63,6%), high in 1/22 (4,5%). High ID4 mRNA levels were determined in 5/22 (22,7%). p53 mutations were identified in 12/22 (54,5%). No patient had PTEN mutation. Eleven pts had BRCA1 somatic mutations: 6/22 (27,3%) - BRCA1 5382insC, 4/22 (18,2%) - BRCA1 185delAG, 3/22 (13,6%) – BRCA1 С61G, 1/22 (4,5%) – BRCA1 LOH. All pts with BRCA1 5382insC mutation achieved a pCR. All pts with BRCA1 185delAG mutation and BRCA1 С61G mutation had residual disease.

Conclusion: BRCA1 5382insC somatic mutation is associated with good response to platinum-based chemotherapy (р = 0,01). BRCA1 185delAG and C61G mutations in the BRCA1 RING domain predict resistance to platinum -based chemotherapy (0,04 and 0,1, accordingly).

Disclosure: All authors have declared no conflicts of interest.