Abstract
Purpose
In an era where neoadjuvant dual blockade is emerging as the standard of care for early and locally advanced HER2-positive breast cancer, we aimed to identify predictors of response to single-blockade chemotherapy.
Methods
This retrospective analysis reviewed all the incident stage I–III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in three institutions. pCR was defined as the absence of invasive tumor in breast and axillary nodes (ypT0/isypN0).
Results
From 2008 to 2015, 84 patients receiving neoadjuvant TCH were identified within our institutions. The mean age at diagnosis was 51.8 years. 59.5% of the patients were hormone receptor (HR) positive, lymph node involvement occurred in 67.9%, and clinical distribution was 2.4, 65.5, and 32.1% for stage I, II, and III, respectively. pCR rate was 47.6%; there was a significantly lower response in HR-positive patients compared to HR-negative ones (34 vs 67.6%, p = 0.005). pCR rate was associated with tumor size, whereas differences did not reach significance either for stage or for nodal status. Multivariate analysis found that only HR status was associated with response (p = 0.003). At a median follow-up of 31.7 months, disease-free survival, distant disease-free survival, and overall survival were 78.6, 85.7, and 94%, respectively. Breast-conserving surgery was performed in 44% of the patients. Overall, TCH was well tolerated, with low rates of grade 3–4 adverse events, and neither late toxicities nor cardiac dysfunctions were reported.
Conclusions
Neoadjuvant TCH, an anthracycline-free single-blockade regimen, achieved a pCR of 47.6%. Further molecular analyses are required in order to identify stronger predictive markers of pCR and thus for an accurate selection of patients who do not benefit from dual blockade.
Abbreviations
- TCH:
-
Docetaxel, carboplatin, trastuzumab
- pCR:
-
Pathologic complete response
- HR:
-
Hormone receptor
- NACT:
-
Neoadjuvant chemotherapy
- DFS:
-
Disease-free survival
- DDFS:
-
Distant disease-free survival
- OS:
-
Overall survival
- IHC:
-
Immunohistochemistry
- LVEF:
-
Left ventricular ejection fraction
References
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672
Mauri D, Pavlidis N, Ioannidis JPA (2005) Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. JNCI J Natl Cancer Inst. 97(3):188–194
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N et al (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172
Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25(28):4414–4422
Broglio KR, Quintana M, Foster M, Olinger M, McGlothlin A, Berry SM, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol [Internet]. 2016. http://oncology.jamanetwork.com/article.aspx?doi=10.1001/jamaoncol.2015.6113. Accessed 10 Mar 2016
Denduluri N, Somerfield MR, Eisen A, Holloway JN, Hurria A, King TA et al (2016) Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)-negative and adjuvant targeted therapy for HER2-positive breast cancers: an American Society of Clinical Oncology guideline adaptation of the cancer care Ontario clinical practice guideline. J Clin Oncol 34(20):2416–2427
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M et al (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283
Coudert BP, Largillier R, Arnould L, Chollet P, Campone M, Coeffic D et al (2007) Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2 overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. J Clin Oncol 25(19):2678–2684
J Crown, L Coate, M Keane, J Kennedy, S O’Reilly, C Kelly et al (2013) Randomized phase II study of pre-operative docetaxel, carboplatin with trastuzumab (TCH) and/or/lapatinib (L) in HER-2 positive (H+) breast cancer patients (BC pts). ICORG 10-05. In San Antonio. 73(24 Suppl): Abstract nr P4-12-25; 2013
Hurvitz S, Miller J, Dichmann R, Perez A, Patel R, Zehngebot L et al (2013) Abstract S1-02: final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/or lapatinib in patients with HER2+ breast cancer (TRIO-US B07). Cancer Res 73(24 Supplement):S1-2-S1-2
Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R et al (2013) Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24(9):2278–2284
Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C et al (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(1):25–32
Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH et al (2013) 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 31(31):3997–4013
Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al (2006) 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 25(1):118–145
Tiwari SR, Mishra P, Raska P, Calhoun B, Abraham J, Moore H et al (2016) Retrospective study of the efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab/pertuzumab (TCH-P) in nonmetastatic HER2-positive breast cancer. Breast Cancer Res Treat 158(1):189–193
Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang C-S, Thompson AM et al. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). Chicago: J Clin Oncol 34, 2016 (suppl; abstr 500); 2016. http://meetinglibrary.asco.org/content/166834-176
Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN et al (2015) Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol [Internet]. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.62.1268. Accessed 3 Dec 2016
Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E et al (2015) PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol 33(12):1334–1339
Fumagalli D, Venet D, Ignatiadis M, Azim HA, Maetens M, Rothé F et al (2016) RNA sequencing to predict response to neoadjuvant anti-HER2 therapy: a secondary analysis of the NeoALTTO randomized clinical trial. JAMA Oncol [Internet]. http://oncology.jamanetwork.com/article.aspx?doi=10.1001/jamaoncol.2016.3824. Accessed 4 Oct 2016
Eustace AJ, Toomey S, Fay J, Teiserkiene A, Milewska M, Kay E et al (2016) The clinical impact of early immunological responses in human HER2-positive breast cancers on responsiveness to trastuzumab-based therapy. Chicago: J Clin Oncol. p. No 15_suppl (May 20 Supplement), 2016: 587
Gianni L, Bianchini G, Valagussa P, Belousov A, Thomas M, Ross G et al (2012). Abstract S6-7: Adaptive immune system and immune checkpoints are associated with response to pertuzumab (P) and trastuzumab (H) in the NeoSphere study. Cancer Res. 72(24 Supplement):S6-7-S6-7
Schneeweiss A, Chia S, Hegg R, Tausch C, Deb R, Ratnayake J et al (2014) Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res 16(4):R73
Bayraktar S, Gonzalez-Angulo AM, Lei X, Buzdar AU, Valero V, Melhem-Bertrandt A et al (2012) Efficacy of neoadjuvant therapy with trastuzumab concurrent with anthracycline- and nonanthracycline-based regimens for HER2-positive breast cancer: neoadjuvant therapy for breast cancer. Cancer 118(9):2385–2393
Kolberg HC, Akpolat-Basci L (2015) Neoadjuvant chemotherapy with docetaxel, carboplatin, and weekly trastuzumab (TCH) activity in HER2-positive early breast cancer: results after a median follow-up of 4.5 years. San Antonio; 2015
Chen W, He J, Song S, Wang M, Wu H, Wang X (2015) Efficacy of TCH/TEC neoadjuvant chemotherapy for the treatment of HER-2-overexpressing breast cancer. Oncol Lett [Internet]. http://www.spandidos-publications.com/10.3892/ol.2015.2912. Accessed 8 Dec 2016
Acknowledgments
This work was partially supported by ERDF (FEDER) Funds from the European Commission, “A way of making Europe” (RECTICC-RD12/0036/0076).
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“All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”
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10549_2016_4098_MOESM1_ESM.jpg
Supplementary material 1. Survival curves and prognostic value of outcomes after neoadjuvant TCH according to hormone-receptor status. Estimated Kaplan–Meier for: A) Disease-free survival (DFS) for hormone receptor-positive (HR +) patients with pathological complete response (pCR) and residual disease (RD). B) Distant-disease free survival (DDFS) for HR + patients with pCR and RD. C) Overall survival (OS) for HR + patients with pCR and RD. D) DFS for hormone receptor-negative (HR-) patients with pCR and RD. E) DDFS for HR- patients with pCR and RD. F) OS for HR- patients with pCR and RD
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Echavarria, I., Granja, M., Bueno, C. et al. Multicenter analysis of neoadjuvant docetaxel, carboplatin, and trastuzumab in HER2-positive breast cancer. Breast Cancer Res Treat 162, 181–189 (2017). https://doi.org/10.1007/s10549-016-4098-z
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DOI: https://doi.org/10.1007/s10549-016-4098-z