Skip to main content

Advertisement

SpringerLink
Log in

Genomic Impact of Neoadjuvant Therapy on Breast Cancer: Incomplete Response is Associated with Altered Diagnostic Gene Signatures

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Neoadjuvant therapy (NAT) has been shown to clinically downstage locally advanced breast cancers. This study aimed to determine whether a meaningful change in gene signatures occurs between pre- and post-NAT breast cancers for patients who do not achieve a pathologic complete response.

Methods

The current analysis included women from the prospective Neoadjuvant Breast Registry Symphony Trial who had breast cancer and awaited NAT. MammaPrint and BluePrint (Agendia, Inc., Irvine, CA) assays were performed on pre- and post-NAT breast tumor samples.

Results

At the completion of NAT, 93 patients with residual disease had their remaining tumor analyzed for MammaPrint and BluePrint. Of 93 patients, 21 switched tumor classification: 16 from high risk (HR) to low risk (LR) and 1 from LR to HR (p < 0.001). Four additional patients switched molecular subtype but remained HR. Although only 17 patients switched in their MammaPrint risk classification, the underlying MPIndex was significantly altered after treatment across all patients (p < 0.001). Additionally, the three BluePrint indices for luminal, human epidermal growth factor receptor 2 (HER2), and basal type also were significantly altered after treatment, in a subtype-dependent manner.

Conclusion

This substudy showed that NAT significantly altered the genomic signature of the patient’s breast cancer compared with the patient’s pretreatment genomic profile. These alterations occurred in a subtype-dependent manner, suggesting that NAT may have either eliminated the most susceptible tumor subclone, leaving the treatment resistant clone with a different genetic signature, or altered molecular characteristics of the original cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–72.

    Article  PubMed  Google Scholar 

  2. Esserman LJ, Berry DA, DeMichele A, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL–CALGB 150007/150012, ACRIN 6657. J Clin Oncol. 2012;30:3242–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kawajiri H, Takashima T, Aomatsu N, et al. Prognostic significance of pathological complete response following neoadjuvant chemotherapy for operable breast cancer. Oncol Lett. 2014;7:663–8.

    PubMed  PubMed Central  Google Scholar 

  4. Perou CM, Borresen-Dale AL. Systems biology and genomics of breast cancer. Cold Spring Harb Perspect Biol. 2011;3:a003293.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Perou CM, Parker JS, Prat A, Ellis MJ, Bernard PS. Clinical implementation of the intrinsic subtypes of breast cancer. Lancet Oncol. 2010;11:718–9; author reply 711–20.

  6. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796–804.

    Article  Google Scholar 

  7. Gluck S, de Snoo F, Peeters J, Stork-Sloots L, Somlo G. Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy. Breast Cancer Res Treat. 2013;139:759–67.

    Article  PubMed  Google Scholar 

  8. Krijgsman O, Roepman P, Zwart W, et al. A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response. Breast Cancer Res Treat. 2012;133:37–47.

    Article  CAS  PubMed  Google Scholar 

  9. Whitworth P, Stork-Sloots L, de Snoo FA, et al. Chemosensitivity predicted by BluePrint 80-gene functional subtype and MammaPrint in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST). Ann Surg Oncol. 2014;21:3261–7.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Glas AM, Floore A, Delahaye LJ, et al. Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics. 2006;7:278.

    Article  Google Scholar 

  11. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010;134:e48–72.

    CAS  PubMed  Google Scholar 

  12. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.

    Article  PubMed  Google Scholar 

  13. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–45.

    Article  CAS  PubMed  Google Scholar 

  14. Sapino A, Roepman P, Linn SC, et al. MammaPrint molecular diagnostics on formalin-fixed, paraffin-embedded tissue. J Mol Diagn. 2014;16:190–7.

    Article  CAS  PubMed  Google Scholar 

  15. Gahlaut R, Bennett A, Fatayer H, et al. Effect of neoadjuvant chemotherapy on breast cancer phenotype, ER/PR and HER2 expression: implications for the practising oncologist. Eur J Cancer. 2016;60:40–8.

    Article  CAS  PubMed  Google Scholar 

  16. van de Ven S, Smit VT, Dekker TJ, Nortier JW, Kroep JR. Discordances in ER, PR, and HER2 receptors after neoadjuvant chemotherapy in breast cancer. Cancer Treat Rev. 2011;37:422–30.

    PubMed  Google Scholar 

  17. Somlo G, Lau SK, Frankel P, et al. Multiple biomarker expression on circulating tumor cells in comparison to tumor tissues from primary and metastatic sites in patients with locally advanced/inflammatory, and stage IV breast cancer, using a novel detection technology. Breast Cancer Res Treat. 2011;128:155–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Burstein HJ, Harris LN, Gelman R, et al. Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. J Clin Oncol. 2003;21:46–53.

    Article  CAS  PubMed  Google Scholar 

  19. Guarneri V, Dieci MV, Barbieri E, et al. Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients. Ann Oncol. 2013;24:2990–4.

    Article  CAS  PubMed  Google Scholar 

  20. Harris LN, You F, Schnitt SJ, et al. Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res. 2007;13:1198–207.

    Article  CAS  PubMed  Google Scholar 

  21. Mittendorf EA, Wu Y, Scaltriti M, et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Cancer Res. 2009;15:7381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009;86:97–100.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all the women who participated in this study and all the investigators, surgeons, pathologists, and research nurses. The authors also thank Sammy Mee, Divya Malhotra, and Laboratory Operations (Agendia Inc.) for sample processing support.

Conflict of interest

Tina Treece, PhD and Erin Yoder, MS are employed by Agendia, Inc.

Author information

Authors and Affiliations

  1. Dallas Surgical Group, Dallas, TX, USA

    Peter Beitsch MD

  2. Nashville Breast Center, Nashville, TN, USA

    Pat Whitworth MD

  3. Breast & Melanoma Specialist of Charleston, Charleston, SC, USA

    Paul Baron MD

  4. Bon Secours Virginia Breast Center, Midlothian, VA, USA

    James Pellicane MD

  5. Agendia, Inc., Irvine, CA, USA

    Tina Treece PhD & Erin Yoder MS

  6. Breast Care Specialists, Allentown, PA, USA

    Mark Gittleman MD

Authors
  1. Peter Beitsch MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pat Whitworth MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Baron MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James Pellicane MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tina Treece PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Erin Yoder MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Gittleman MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

NBRST Investigators Group

Corresponding author

Correspondence to Peter Beitsch MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beitsch, P., Whitworth, P., Baron, P. et al. Genomic Impact of Neoadjuvant Therapy on Breast Cancer: Incomplete Response is Associated with Altered Diagnostic Gene Signatures. Ann Surg Oncol 23, 3317–3323 (2016). https://doi.org/10.1245/s10434-016-5329-6

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-016-5329-6

Keywords

Search

Navigation