Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel

George Fountzilas, Urania Dafni, Mattheos Bobos, Anna Batistatou, Vassiliki Kotoula, Helen Trihia, Vassiliki Malamou-Mitsi, Spyros Miliaras, Sofia Chrisafi, Savvas Papadopoulos, Maria Sotiropoulou, Theodoros Filippidis, Helen Gogas, Triantafyllia Koletsa, Dimitrios Bafaloukos, Despina Televantou, Konstantine T Kalogeras, Dimitrios Pectasides, Dimosthenis V Skarlos, Angelos Koutras, Meletios A Dimopoulos, George Fountzilas, Urania Dafni, Mattheos Bobos, Anna Batistatou, Vassiliki Kotoula, Helen Trihia, Vassiliki Malamou-Mitsi, Spyros Miliaras, Sofia Chrisafi, Savvas Papadopoulos, Maria Sotiropoulou, Theodoros Filippidis, Helen Gogas, Triantafyllia Koletsa, Dimitrios Bafaloukos, Despina Televantou, Konstantine T Kalogeras, Dimitrios Pectasides, Dimosthenis V Skarlos, Angelos Koutras, Meletios A Dimopoulos

Abstract

Background: The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC).

Materials and methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67(low)); luminal B (ER/PgR-positive, HER2-negative, Ki67(high)); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive).

Results: After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62-3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors.

Conclusions: Triple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment.

Conflict of interest statement

Competing Interests: TF is an employee in “Micromedica” Histopathology Laboratory, Athens, Greece. This does not alter the authors‘ adherence to all PLoS ONE policies on sharing data and materials. The remaining authors have declared that no competing interests exist.

Figures

Figure 1. REMARK diagram.
Figure 1. REMARK diagram.
Figure 2. DFS and OS according to…
Figure 2. DFS and OS according to breast cancer subtypes.
Patients were classified as: luminal A (ER-positive and/or PgR-positive, HER2-negative, Ki67low); luminal B (ER-positive and/or PgR-positive, HER2-negative, Ki67high); luminal-HER2 (ER-positive and/or PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); and triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative).
Figure 3. Forest plots from multivariate Cox…
Figure 3. Forest plots from multivariate Cox regression models: DFS (a) and OS (b) (for subtype description see Figure 2 legend).
Figure 4. DFS and OS in paclitaxel…
Figure 4. DFS and OS in paclitaxel and non-paclitaxel treated patients according to breast cancer subtypes (for subtype description see Figure 2 legend).

References

    1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. Cancer statistics, 2009. CA: a cancer journal for clinicians. 2009;59:225–249.
    1. Early Breast Cancer Trialists' Collaborative G. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100?000 women in 123 randomised trials. The Lancet. 2012;379(9814):432–444.
    1. Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, et al. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009;373:1681–1692.
    1. Bedard PL, Di Leo A, Piccart-Gebhart MJ. Taxanes: optimizing adjuvant chemotherapy for early-stage breast cancer. Nat Rev Clin Oncol. 2010;7:22–36.
    1. Qin YY, Li H, Guo XJ, Ye XF, Wei X, et al. Adjuvant chemotherapy, with or without taxanes, in early or operable breast cancer: a meta-analysis of 19 randomized trials with 30698 patients. PLoS One. 2011;6:e26946.
    1. Jacquin JP, Jones S, Magne N, Chapelle C, Ellis P, et al. Consistency of effect independent of nodal and biomarker status: a meta-analysis of 14 randomized clinical trials. Breast Cancer Res Treat; 2012. Docetaxel-containing adjuvant chemotherapy in patients with early stage breast cancer. doi: .
    1. Gianni L, Munzone E, Capri G, Villani F, Spreafico C, et al. Paclitaxel in metastatic breast cancer: a trial of two doses by a 3-hour infusion in patients with disease recurrence after prior therapy with anthracyclines. J Natl Cancer Inst. 1995;87:1169–1175.
    1. Fountzilas G, Athanassiadis A, Kalogera-Fountzila A, Aravantinos G, Bafaloukos D, et al. Paclitaxel by 3-h infusion and carboplatin in anthracycline-resistant advanced breast cancer. A phase II study conducted by the Hellenic Cooperative Oncology Group. Eur J Cancer. 1997;33:1893–1895.
    1. Fountzilas G, Nicolaides C, Bafaloukos D, Kalogera-Fountzila A, Kalofonos H, et al. Docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer: a Hellenic Cooperative Oncology Group Phase II study. Cancer investigation. 2000;18:503–509.
    1. O'Shaughnessy J, Twelves C, Aapro M. Treatment for anthracycline-pretreated metastatic breast cancer. Oncologist. 2002;7(Suppl 6):4–12.
    1. Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, et al. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011;29:3877–3884.
    1. Norton L. Theoretical concepts and the emerging role of taxanes in adjuvant therapy. Oncologist. 2001;6(Suppl 3):30–35.
    1. Citron ML. Dose density in adjuvant chemotherapy for breast cancer. Cancer investigation. 2004;22:555–568.
    1. Orzano JA, Swain SM. Concepts and clinical trials of dose-dense chemotherapy for breast cancer. Clin Breast Cancer. 2005;6:402–411.
    1. Seidman AD. Current status of dose-dense chemotherapy for breast cancer. Cancer Chemother Pharmacol. 2005;56(Suppl 1):78–83.
    1. Zauderer M, Patil S, Hurria A. Feasibility and toxicity of dose-dense adjuvant chemotherapy in older women with breast cancer. Breast Cancer Research and Treatment. 2009;117:205–210.
    1. Gianni L, Norton L, Wolmark N, Suter TM, Bonadonna G, et al. Role of Anthracyclines in the Treatment of Early Breast Cancer. Journal of Clinical Oncology. 2009;27:4798–4808.
    1. Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, et al. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2005;16:1762–1771.
    1. Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, et al. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011;29:3247–3254.
    1. Fountzilas G, Dafni U, Gogas H, Linardou H, Kalofonos HP, et al. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Ann Oncol. 2008;19:853–860.
    1. Gogas H, Dafni U, Karina M, Papadimitriou C, Batistatou A, et al. Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat. 2012;132:609–619.
    1. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–752.
    1. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–10874.
    1. Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, et al. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 2010;28:1684–1691.
    1. Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011;128:447–456.
    1. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, et al. REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat. 2006;100:229–235.
    1. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844–847.
    1. Skacel M, Skilton B, Pettay JD, Tubbs RR. Tissue microarrays: a powerful tool for high-throughput analysis of clinical specimens: a review of the method with validation data. Appl Immunohistochem Mol Morphol. 2002;10:1–6.
    1. Skarlos P, Christodoulou C, Kalogeras KT, Eleftheraki AG, Bobos M, et al. Triple-negative phenotype is of adverse prognostic value in patients treated with dose-dense sequential adjuvant chemotherapy: a translational research analysis in the context of a Hellenic Cooperative Oncology Group (HeCOG) randomized phase III trial. Cancer Chemother Pharmacol. 2012;69:533–546.
    1. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101:736–750.
    1. Diallo-Danebrock R, Ting E, Gluz O, Herr A, Mohrmann S, et al. Protein expression profiling in high-risk breast cancer patients treated with high-dose or conventional dose-dense chemotherapy. Clin Cancer Res. 2007;13:488–497.
    1. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–2795.
    1. Schippinger W, Dandachi N, Regitnig P, Hofmann G, Balic M, et al. The predictive value of EGFR and HER-2/neu in tumor tissue and serum for response to anthracycline-based neoadjuvant chemotherapy of breast cancer. Am J Clin Pathol. 2007;128:630–637.
    1. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18–43.
    1. Psyrri A, Kalogeras KT, Kronenwett R, Wirtz RM, Batistatou A, et al. A Hellenic Cooperative Oncology Group (HeCOG) Study. Ann Oncol; 2011. Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. doi: .
    1. Fountzilas G, Ciuleanu E, Bobos M, Kalogera-Fountzila A, Eleftheraki AG, et al. Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. Ann Oncol. 2011;23(2):427–435.
    1. Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, et al. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol. 2011;29:859–867.
    1. Vanden Bempt I, Van Loo P, Drijkoningen M, Neven P, Smeets A, et al. Polysomy 17 in breast cancer: clinicopathologic significance and impact on HER-2 testing. J Clin Oncol. 2008;26:4869–4874.
    1. Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25:2127–2132.
    1. Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, et al. 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. 2010;7:e1000279.
    1. Sihto H, Lundin J, Lundin M, Lehtimaki T, Ristimaki A, et al. Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study. Breast Cancer Res. 2011;13:R87.
    1. Vallejos CS, Gómez HL, Cruz WR, Pinto JA, Dyer RR, et al. Breast Cancer Classification According to Immunohistochemistry Markers: Subtypes and Association With Clinicopathologic Variables in a Peruvian Hospital Database. Clinical Breast Cancer. 2010;10:294–300.
    1. Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol. 2009;27:1168–1176.
    1. Martin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, et al. Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer. Breast Cancer Res Treat. 2010;123:149–157.
    1. Kostopoulos I, Arapantoni-Dadioti P, Gogas H, Papadopoulos S, Malamou-Mitsi V, et al. Evaluation of the prognostic value of HER-2 and VEGF in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy. Breast Cancer Res Treat. 2006;96:251–261.
    1. Hayes DF, Thor AD, Dressler LG, Weaver D, Edgerton S, et al. HER2 and Response to Paclitaxel in Node-Positive Breast Cancer. New England Journal of Medicine. 2007;357:1496–1506.
    1. Iwata H, Sato N, Masuda N, Nakamura S, Yamamoto N, et al. Docetaxel followed by fluorouracil/epirubicin/cyclophosphamide as neoadjuvant chemotherapy for patients with primary breast cancer. Jpn J Clin Oncol. 2011;41:867–875.
    1. Roche H, Fumoleau P, Spielmann M, Canon JL, Delozier T, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006;24:5664–5671.
    1. Jacquemier J, Boher JM, Roche H, Esterni B, Serin D, et al. Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC – PACS 01 randomized trial. Breast Cancer Res. 2011;13:R109.
    1. Millar EK, Graham PH, O'Toole SA, McNeil CM, Browne L, et al. Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel. J Clin Oncol. 2009;27:4701–4708.
    1. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28:3271–3277.
    1. Miller KD, Weathers T, Haney LG, Timmerman R, Dickler M, et al. Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol. 2003;14:1072–1077.
    1. Dawood S, Broglio K, Esteva FJ, Yang W, Kau SW, et al. Survival among women with triple receptor-negative breast cancer and brain metastases. Ann Oncol. 2009;20:621–627.
    1. Kallioniemi OP, Holli K, Visakorpi T, Koivula T, Helin HH, et al. Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer. 1991;49:650–655.
    1. Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin Cancer Res. 2007;13:1648–1655.
    1. Pestalozzi BC, Zahrieh D, Price KN, Holmberg SB, Lindtner J, et al. Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol. 2006;17:935–944.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi