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Poster Discussion - Breast cancer, early stage

3933 - Neoadjuvant olaparib monotherapy in primary triple negative breast cancer

Date

28 Sep 2019

Session

Poster Discussion - Breast cancer, early stage

Presenters

Hans Eikesdal

Citation

Annals of Oncology (2019) 30 (suppl_5): v55-v98. 10.1093/annonc/mdz240

Authors

H.P. Eikesdal1, S. Yndestad2, E.S. Blix3, S. Lundgren4, G. Vagstad5, H. Espelid6, B. Gilje7, E.A. Janssen8, J. Geisler9, T. Aas10, H. Aase11, S. Knappskog12, P.E. Lønning1

Author affiliations

  • 1 Dept. Of Oncology, Haukeland University Hospital, 5021 - Bergen/NO
  • 2 Section Of Oncology, Dept. Of Clinical Science, University of Bergen, 5020 - Bergen/NO
  • 3 Dept. Of Oncology, University Hospital of North Norway, Tromsø/NO
  • 4 Dept. Of Oncology, St.Olavs University Hospital, Trondheim/NO
  • 5 Dept. Of Oncology, Førde Hospital, Førde/NO
  • 6 Dept. Of Surgery, Haugesund Hospital, Haugesund/NO
  • 7 Dept. Of Oncology, Stavanger University Hospital, Stavanger/NO
  • 8 Dept. Of Pathology, Stavanger University Hospital, Stavanger/NO
  • 9 Institute Of Clinical Medicine, University of Oslo, Akershus/NO
  • 10 Dept. Of Surgery, Haukeland University Hospital, 5021 - Bergen/NO
  • 11 Dept. Of Radiology, Haukeland University Hospital, 5021 - Bergen/NO
  • 12 Section Of Oncology, Dept. Of Clinical Science, University of Bergen, 5021 - Bergen/NO

Resources

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Abstract 3933

Background

Neoadjuvant treatment of triple negative breast cancer (TNBC) in general implies different chemotherapy regimens administered in sequence. PARP inhibitors like olaparib have revealed clinical benefit in TNBC harboring BRCA germline mutations, but were ineffective when tested as monotherapy for BRCA WT metastatic breast cancer. While combining a PARP inhibitor with chemotherapy may be beneficial, such therapy is limited by bone marrow toxicity.

Methods

In the phase 2 PETREMAC trial (NCT02624973), we assessed the efficacy of primary olaparib monotherapy for 10 weeks, followed by chemotherapy, in TNBC (T > 2 cm). Tumor biopsies and blood leucocytes for targeted DNA sequencing of 360 cancer-related genes were collected prior to therapy and after 10 weeks on olaparib.

Results

31 patients with TNBC were included (mean tumor size 59 mm; range 33-97). Olaparib monotherapy was well tolerated, yielding a clinical CR in 5 and a PR in 15 patients (all-over objective response rate; ORR 64%). Olaparib had no major impact on subsequent chemotherapy toxicity. The average pretreatment mutation rate was 3.3 indels/point mutations per tumor with no differences in mutation burden recorded between responders and non-responders or BRCA carriers vs. non-carriers. Among five patients harboring pathogenic BRCA1/2 mutations (4 germline, 1 somatic) all responded to olaparib, and n = 3/5 obtained pathological complete response. Interestingly, mutations in genes associated with DNA damage repair (ATRX, BRCA1/2, EMSY, MSH6, PARP10, PPM1D) occurred in n = 9/20 olaparib responders, but in none of the 11 non-responders (p = 0.011). Non-responders were characterized by mutations in oncogenic pathways (PIK3CA, AKT1, KRAS, IGF2R, NF2 and TGFBR2) in 7 out of 11 tumors (P = 0.00013). No significant association was observed between TP53 mutations (recorded in 23/31 tumors) and response to olaparib. Targeted DNA sequencing is ongoing for biopsies taken after 10 weeks of olaparib monotherapy; the results will be presented.

Conclusions

Olaparib yielded a high response rate when administered to treatment-naïve, large TNBC, indicating a potential role in sequential neoadjuvant therapy, for patients both with and without BRCA1/2 germline mutations.

Clinical trial identification

NCT02624973; 2015-002816-34.

Editorial acknowledgement

Legal entity responsible for the study

Haukeland University Hospital, Bergen, Norway.

Funding

Det Regionale Samarbeidsorganet/Helse Vest, AstraZeneca.

Disclosure

H.P. Eikesdal: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self): HAI Interaktiv AS; Honoraria (self): Dagens Medisin; Honoraria (self): Brysol-Mayers-Squibb; Advisory / Consultancy: Lilly; Research grant / Funding (institution): Abbvie. E.S. Blix: Honoraria (self): Pfizer. B. Gilje: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Astellas Oncology; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Pierre Fabre. E.A. Janssen: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer. J. Geisler: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Speaker Bureau / Expert testimony: Brystol-Myers-Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer. T. Aas: Honoraria (self): AstraZeneca; Honoraria (self): Roche. S. Knappskog: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Licensing / Royalties: Patent EP2389450 A1,Patent WO 2012/010661.. P.E. Lønning: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Honoraria (self), Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self): Roche; Advisory / Consultancy: Laboratorios Farmaceuticos Rovi; Licensing / Royalties: Cytovation. All other authors have declared no conflicts of interest.

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