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Breast Cancer Research and Treatment

, Volume 139, Issue 3, pp 759–767 | Cite as

Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy

  • Stefan Glück
  • Femke de Snoo
  • Justine Peeters
  • Lisette Stork-Sloots
  • George Somlo
Clinical trial

Abstract

The aim of this study was to analyze the correlation between the pathologic complete response (pCR) rate after neoadjuvant chemotherapy and long-term outcome (distant metastases-free survival [DMFS]) in patients with early-stage breast cancer using BluePrint and MammaPrint molecular subtyping versus clinical subtyping using immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) for the determination of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2). Data were analyzed from 437 patients in four neoadjuvant chemotherapy trials. BluePrint and MammaPrint outcomes were determined from 44K Agilent arrays, the I-SPY 1 data portal, or Affymetrix U133A arrays. The pCR rate differed substantially among BluePrint molecular subgroups: 6 % in Luminal A-type, 10 % in Luminal B-type, 47 % in HER2-type, and 37 % in Basal-type patients. In the Luminal A-type group (n = 90; including seven HER2-positive patients and eight triple-negative patients by IHC/FISH), the 5-year DMFS rate was 93 %. The pCR rate provided no prognostic information, suggesting these patients may not benefit from chemotherapy. Forty-three of 107 (40 %) HER2-positive patients were classified as Luminal-type by BluePrint and may have lower response rates to targeted therapy. Molecular subtyping identified 90 of 435 (21 %) patients as Luminal A-type (BluePrint Luminal-type/MammaPrint Low Risk) with excellent survival. The pCR rate provided no prognostic information. Molecular subtyping can improve the stratification of patients in the neoadjuvant setting: Luminal A-type (MammaPrint Low Risk) patients have a good prognosis with excellent survival and do not seem to benefit from chemotherapy. We observed marked benefit in response and DMFS to neoadjuvant treatment in patients subtyped as HER2-type and Basal-type. BluePrint with MammaPrint molecular subtyping helps to improve prognostic estimation and the choice of therapy versus IHC/FISH.

Keywords

BluePrint (80-gene profile) Early-stage breast cancer MammaPrint (70-gene profile) Molecular subtyping Prognosis Response 

Abbreviations

ACAC

Doxorubicin, cyclophosphamide, carboplatin, and nab-paclitaxel

DMFS

Distant metastases-free survival

ER

Estrogen receptor

ESBC

Early-stage breast cancer

FDA

Food and drug administration

FISH

Fluorescence in situ hybridization

HER2

Human epidermal growth factor receptor-2

HR

Hormone receptor

IHC

Immunohistochemistry

LABC

Locally advanced breast cancer

pCR

Pathologic complete response

PR

Progesterone receptor

TAC

Docetaxel, doxorubicin, and cyclophosphamide

Notes

Acknowledgments

This study was funded by an unrestricted grant from Agendia. The City of Hope trial was supported by American Bioscience (now Celgene). The authors would like to thank Kevin De-Voy (freelance medical writer funded by Agendia) for writing support.

Conflict of interest

SG has received research support from and been an advisory board member for Agendia and Genomic Health Inc. FdS, JP, and LS-S are employees of Agendia. GS had received grants from the National Institutes of Health and has been an advisory board member and speaker for Celgene and Genentech. George Somlo has received research support from Celgene.

References

  1. 1.
    Aigner J, Schneeweiss A, Sohn C, Marmé F (2011) The role of neoadjuvant chemotherapy in the management of primary breast cancer. Minerva Ginecol 63:261–274PubMedGoogle Scholar
  2. 2.
    Kaufmann M, von Minckwitz G, Mamounas EP, Cameron D, Carey LA, Cristofanilli M, Denkert C, Eiermann W, Gnant M, Harris JR, Karn T, Liedtke C, Mauri D, Rouzier R, Ruckhaeberle E, Semiglazov V, Symmans WF, Tutt A, Pusztai L (2012) Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol 19:1508–1516PubMedCrossRefGoogle Scholar
  3. 3.
    Mieog JS, van de Velde CJ (2009) Neoadjuvant chemotherapy for early breast cancer. Expert Opin Pharmacother 10:1423–1434PubMedCrossRefGoogle Scholar
  4. 4.
    Hortobagyi GN (2012) Neoadjuvant systemic therapy: promising experimental model, or improved standard of care? San Antonio breast cancer symposium, William L. McGuire Memorial LectureGoogle Scholar
  5. 5.
    Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRefGoogle Scholar
  6. 6.
    Glück S, Ross JS, Royce M, McKenna EF Jr, Perou CM, Avisar E, Wu L (2012) TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine ± trastuzumab. Breast Cancer Res Treat 132:781–791PubMedCrossRefGoogle Scholar
  7. 7.
    Parker JS, Prat A, Cheang MCU, Lenburg ME, Paik S, Perou CM (2009) Breast cancer molecular subtypes predict response to anthracycline/taxane-based chemotherapy. San Antonio breast cancer symposium, abstract 2019Google Scholar
  8. 8.
    Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685PubMedCrossRefGoogle Scholar
  9. 9.
    Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lønning PE, Børresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874PubMedCrossRefGoogle Scholar
  10. 10.
    Prowell TM, Pazdur R (2012) Pathological complete response and accelerated drug approval in early breast cancer. New Engl J Med 366:2438–2441PubMedCrossRefGoogle Scholar
  11. 11.
    von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30:1796–1804CrossRefGoogle Scholar
  12. 12.
    Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N (2008) Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 26:778–785PubMedCrossRefGoogle Scholar
  13. 13.
    Mauri D, Pavlidis N, Ioannidis JP (2005) Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97:188–194PubMedCrossRefGoogle Scholar
  14. 14.
    Mieog JS, van der Hage JA, van de Velde CJ (2007) Neoadjuvant chemotherapy for operable breast cancer. Br J Surg 94:1189–1200PubMedCrossRefGoogle Scholar
  15. 15.
    Food and Drug Administration Guidance for Industry (2012) Pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pdf. Accessed 2 Aug 2012
  16. 16.
    Perlmutter J, Axler S, Bass CC, Beckwith BJ, Bonoff A, Brain S, Delapine M, Devine M, Frank E, Fraser V, Gallece M, Geoghegan C, Hamade H, Heditsian D, Hirschhorn B, Kandell S, Laxague D, Lestage B, Lyzen M, Madden D, Mertz SA, Parker BJ, Roach N, Sauers N, Vincent L, Waddell D, Wetzel M, Wright K (2012) Advocates’ perspective: neoadjuvant chemotherapy for breast cancer. J Clin Oncol 30:4586–4588PubMedCrossRefGoogle Scholar
  17. 17.
    Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E (2012) Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer 48:3342–3354PubMedCrossRefGoogle Scholar
  18. 18.
    Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, Hudis C, Gray JW, Perou C, Yau C, Livasy C, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, van ‘t Veer L, Hylton N (2012) 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 30:3242–3249PubMedCrossRefGoogle Scholar
  19. 19.
    Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32PubMedCrossRefGoogle Scholar
  20. 20.
    Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M, NeoALTTO Study Team (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379:633–640PubMedCrossRefGoogle Scholar
  21. 21.
    Cortazar P, Zhang L, Untch M, Mehta K, Costantino J, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Zujewski JA, Justice R, Loibl S, Wickerham L, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas E, Bergh J, Semiglazov V, Prowell T, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching P, Swain SM, Slaets L, Tang S, Gerber B, Geyer C, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Mincwitz G (2012) Meta-analysis results from the collaborative trials in neoadjuvant breast cancer (CTNeoBC). Cancer Res 72(24 Suppl):S1–S11Google Scholar
  22. 22.
    Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. New Engl J Med 360:790–800PubMedCrossRefGoogle Scholar
  23. 23.
    Krijgsman O, Roepman P, Zwart W, roll JS, Tian S, de Snoo FA, Bender RA, Bernards R, Glas AM (2012) A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response. Breast Cancer Res Treat 133:37–47PubMedCrossRefGoogle Scholar
  24. 24.
    Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160–1167PubMedCrossRefGoogle Scholar
  25. 25.
    Prat A, Ellis MJ, Perou CM (2011) Practical implications of gene-expression-based assays for breast oncologists. Nat Rev Clin Oncol 9:48–57PubMedCrossRefGoogle Scholar
  26. 26.
    Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, Heikkilä P, Heikkinen T, Nevanlinna H, Akslen LA, Bégin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L, Giles GG, Severi G, McLean CA, Southey MC, Rakha E, Green AR, Ellis IO, Sherman ME, Lissowska J, Anderson WF, Cox A, Cross SS, Reed MW, Provenzano E, Dawson SJ, Dunning AM, Humphreys M, Easton DF, García-Closas M, Caldas C, Pharoah PD, Huntsman D (2010) Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med 7:e1000279PubMedCrossRefGoogle Scholar
  27. 27.
    Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T, Davies SR, Snider J, Stijleman IJ, Reed J, Cheang MC, Mardis ER, Perou CM, Bernard PS, Ellis MJ (2010) A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res 16:5222–5232PubMedCrossRefGoogle Scholar
  28. 28.
    Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ, Panel members (2011) Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol 22:1736–1747PubMedCrossRefGoogle Scholar
  29. 29.
    Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, Mariani G, Rodriguez J, Carcangiu M, Watson D, Valagussa P, Rouzier R, Symmans WF, Ross JS, Hortobagyi GN, Pusztai L, Shak S (2005) Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 23:7265–7277PubMedCrossRefGoogle Scholar
  30. 30.
    Straver ME, Glas AM, Hannemann J, Wesseling J, van de Vijver MJ, Rutgers EJ, Vrancken Peeters MJ, van Tinteren H, Van’t Veer LJ, Rodenhuis S (2010) The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 119:551–558PubMedCrossRefGoogle Scholar
  31. 31.
    Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, DeMichele A, Gray JW, Conway-Dorsey K, Lenburg ME, Buxton MB, Davis SE, van’t Veer LJ, Hudis C, Chin K, Wolf D, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Livasy C, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, Au A, Hylton N, I-SPY 1 TRIAL Investigators (2012) Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat 132:1049–1062PubMedCrossRefGoogle Scholar
  32. 32.
    Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, Booser D, Theriault RL, Buzdar AU, Dempsey PJ, Rouzier R, Sneige N, Ross JS, Vidaurre T, Gómez HL, Hortobagyi GN, Pusztai L (2006) Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol 24:4236–4244PubMedCrossRefGoogle Scholar
  33. 33.
    Iwamoto T, Lee JS, Bianchini G, Hubbard RE, Young E, Matsuoka J, Kim SB, Symmans WF, Hortobagyi GN, Pusztai L (2011) First generation prognostic gene signatures for breast cancer predict both survival and chemotherapy sensitivity and identify overlapping patient populations. Breast Cancer Res Treat 130:155–164PubMedCrossRefGoogle Scholar
  34. 34.
    Somlo G, Frankel PH, Vora L, Lau S, Luu TH, Kruper L, Yim J, Yen Y, de Snoo F, Bender RA (2010) Gene signatures as predictors of response to neoadjuvant chemotherapy (NCT) with docetaxel, doxorubicin, cyclophosphamide (TAC), or AC and nab-paclitaxel (nab-P) and carboplatin ± trastuzumab in patients (pts) with stage II–III and inflammatory breast cancer (IBC). J Clin Oncol 28(Suppl):540Google Scholar
  35. 35.
    National Cancer Institute. (2012) I-SPY home page. http://ispy.nci.nih.gov. Accessed 2 Aug 2012

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Stefan Glück
    • 1
  • Femke de Snoo
    • 2
  • Justine Peeters
    • 2
  • Lisette Stork-Sloots
    • 2
  • George Somlo
    • 3
  1. 1.Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiUSA
  2. 2.AgendiaAmsterdamThe Netherlands
  3. 3.Department of Medical Oncology, Therapeutics ResearchCity of Hope Cancer CenterDuarteUSA

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