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BRCA1 promoter methylation in breast cancer patients is associated with response to olaparib/eribulin combination therapy

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Abstract

Background

A PARP inhibitor is effective in breast cancer patients with BRCA1/2 germline mutations, and in cell lines with BRCA1 promoter methylation. However, its efficacy in breast cancer patients with BRCA1 promoter methylation is still unknown.

Methods

Biopsy samples were obtained from 32 triple-negative breast cancer (TNBC) patients treated with eribulin/olaparib combination therapy in a clinical trial (UMINID: 000009498) and analyzed for their mutations by FoundationOne CDx. DNA methylation was evaluated by quantitative methylation-specific PCR and bisulfite sequencing, and its level was adjusted for tumor cell fraction.

Results

Among 20 TNBC patients evaluable for both methylation and mutations, one (5%) and five (25%) patients had a high (> 80%) and low (30–80%) BRCA1 promoter methylation levels, respectively. One patient with a high methylation level, also having a BRCA2 mutation of unknown significance, displayed complete response. Among the 5 patients with low methylation levels, only one patient with a BRCA2 mutation of unknown significance displayed long-lasting disease control (24 weeks). Patients with a BRCA1 or BRCA2 mutation, or high BRCA1 promoter methylation showed better 6-month progression-free survival (PFS) compared with the other patients (P = 0.009).

Conclusion

Quantitative methylation analysis suggested that addition of homozygous BRCA1 promoter methylation to mutations may more accurately identify TNBC patients who would benefit from olaparib/eribulin combination therapy. (209 words)

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References

  1. Lord CJ, Ashworth A (2017) PARP inhibitors: synthetic lethality in the clinic. Science 355:1152–1158. https://doi.org/10.1126/science.aam7344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244. https://doi.org/10.1016/S0140-6736(10)60892-6

    Article  CAS  PubMed  Google Scholar 

  3. Litton JK, Scoggins ME, Hess KR, Adrada BE, Murthy RK, Damodaran S, DeSnyder SM, Brewster AM, Barcenas CH, Valero V, Whitman GJ, Schwartz-Gomez J, Mittendorf EA, Thompson AM, Helgason T, Ibrahim N, Piwnica-Worms H, Moulder SL, Arun BK (2019) Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol J. https://doi.org/10.1200/JCO.19.01304

    Article  Google Scholar 

  4. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523–533. https://doi.org/10.1056/NEJMoa1706450

    Article  CAS  PubMed  Google Scholar 

  5. He C, Kawaguchi K, Toi M (2020) DNA damage repair functions and targeted treatment in breast cancer. Breast Cancer. https://doi.org/10.1007/s12282-019-01038-2

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lord CJ, Ashworth A (2016) BRCAness revisited. Nat Rev Cancer 16:110–120. https://doi.org/10.1038/nrc.2015.21

    Article  CAS  PubMed  Google Scholar 

  7. Jonsson P, Bandlamudi C, Cheng ML, Srinivasan P, Chavan SS, Friedman ND, Rosen EY, Richards AL, Bouvier N, Selcuklu SD, Bielski CM, Abida W, Mandelker D, Birsoy O, Zhang L, Zehir A, Donoghue MTA, Baselga J, Offit K, Scher HI, O'Reilly EM, Stadler ZK, Schultz N, Socci ND, Viale A, Ladanyi M, Robson ME, Hyman DM, Berger MF, Solit DB, Taylor BS (2019) Tumour lineage shapes BRCA-mediated phenotypes. Nature 571:576–579. https://doi.org/10.1038/s41586-019-1382-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hattori N, Ushijima T (2014) Compendium of aberrant DNA methylation and histone modifications in cancer. Biochem Biophys Res Commun 455:3–9. https://doi.org/10.1016/j.bbrc.2014.08.140

    Article  CAS  PubMed  Google Scholar 

  9. Veeck J, Ropero S, Setien F, Gonzalez-Suarez E, Osorio A, Benitez J, Herman JG, Esteller M (2010) BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors. J Clin Oncol 28:e563–e564. https://doi.org/10.1200/JCO.2010.30.1010

    Article  PubMed  Google Scholar 

  10. Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, Coleman RL, Tinker AV, O'Malley DM, Kristeleit RS, Ma L, Bell-McGuinn KM, Brenton JD, Cragun JM, Oaknin A, Ray-Coquard I, Harrell MI, Mann E, Kaufmann SH, Floquet A, Leary A, Harding TC, Goble S, Maloney L, Isaacson J, Allen AR, Rolfe L, Yelensky R, Raponi M, McNeish IA (2017) Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 18:75–87. https://doi.org/10.1016/S1470-2045(16)30559-9

    Article  CAS  PubMed  Google Scholar 

  11. Yonemori K, Shimomura A, Yasojima H, Masuda N, Aogi K, Takahashi M, Naito Y, Shimizu S, Nakamura R, Hashimoto J, Yamamoto H, Hirakawa A, Michimae H, Hamada A, Yoshida T, Sukigara T, Tamura K, Fujiwara Y (2019) A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes. Eur J Cancer 109:84–91. https://doi.org/10.1016/j.ejca.2018.11.014

    Article  CAS  PubMed  Google Scholar 

  12. Shimomura A, Yonemori K, Yoshida M, Yoshida T, Yasojima H, Masuda N, Aogi K, Takahashi M, Naito Y, Shimizu S, Nakamura R, Hamada A, Michimae H, Hashimoto J, Yamamoto H, Kawachi A, Shimizu C, Fujiwara Y, Tamura K (2019) Gene alterations in triple-negative breast cancer patients in a phase I/II study of eribulin and olaparib combination therapy. Transl Oncol 12:1386–1394. https://doi.org/10.1016/j.tranon.2019.07.013

    Article  PubMed  PubMed Central  Google Scholar 

  13. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  14. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD (2015) Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 5:1137–1154. https://doi.org/10.1158/2159-8290.CD-15-0714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yoshida S, Yamashita S, Niwa T, Mori A, Ito S, Ichinose M, Ushijima T (2017) Epigenetic inactivation of FAT4 contributes to gastric field cancerization. Gastric Cancer 20:136–145. https://doi.org/10.1007/s10120-016-0593-5

    Article  CAS  PubMed  Google Scholar 

  16. Kondrashova O, Topp M, Nesic K, Lieschke E, Ho GY, Harrell MI, Zapparoli GV, Hadley A, Holian R, Boehm E, Heong V, Sanij E, Pearson RB, Krais JJ, Johnson N, McNally O, Ananda S, Alsop K, Hutt KJ, Kaufmann SH, Lin KK, Harding TC, Traficante N, Australian Ovarian Cancer S, deFazio A, McNeish IA, Bowtell DD, Swisher EM, Dobrovic A, Wakefield MJ, Scott CL (2018) Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. Nat Commun 9:3970. https://doi.org/10.1038/s41467-018-05564-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to acknowledge the study staff, Hiroyuki Yasojima, Norikazu Masuda, Kenjiro Aogi, Masato Takahashi, Yoichi Naito, Satoru Shimizu, Rikiya Nakamura, Jun Hashimoto, Harukaze Yamamoto, Hirofumi Michimae, Akinobu Hamada, Teruhiko Yoshida, Tamie Sukigara.

Funding

The research described in this report was funded by the Program for Promoting Platform of Genomics based Drug Discovery (Grant No. 18kk0305004h0003) from the Japan Agency for Medical Research and Development, AMED. This research was conducted with support from an Externally Sponsored Research Program of AstraZeneca.

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Authors and Affiliations

  1. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan

    Asuka Kawachi, Satoshi Yamashita, Eriko Okochi-Takada & Toshikazu Ushijima

  2. Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

    Asuka Kawachi, Akihiko Shimomura, Yuki Kojima, Kan Yonemori, Yasuhiro Fujiwara & Kenji Tamura

  3. Department of Biostatistics and Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Akihiro Hirakawa

  4. Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan

    Hitoshi Tsuda

  5. Department of Breast Surgery, National Cancer Center Hospital, Tokyo, Japan

    Takayuki Kinoshita

  6. Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Toshikazu Ushijima

Authors
  1. Asuka Kawachi
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  2. Satoshi Yamashita
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  3. Eriko Okochi-Takada
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  4. Akihiro Hirakawa
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  6. Akihiko Shimomura
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  9. Yasuhiro Fujiwara
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  10. Takayuki Kinoshita
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  11. Toshikazu Ushijima
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  12. Kenji Tamura
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Contributions

AK, TU and KT conceived the study and designed the experiments. AK, SY, and EO conducted the experiments, and AH performed statistical analysis. KY, TK and KT collected the samples. YK collected clinical information. AK and TU interpreted data and wrote the manuscript. TU and KT provided support for the studies. All the authors have read and approved the submission of the manuscript.

Corresponding author

Correspondence to Toshikazu Ushijima.

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Kawachi, A., Yamashita, S., Okochi-Takada, E. et al. BRCA1 promoter methylation in breast cancer patients is associated with response to olaparib/eribulin combination therapy. Breast Cancer Res Treat 181, 323–329 (2020). https://doi.org/10.1007/s10549-020-05647-w

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  • DOI: https://doi.org/10.1007/s10549-020-05647-w

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