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Prospective study of cyclophosphamide, thiotepa, carboplatin combined with adoptive DC-CIK followed by metronomic cyclophosphamide therapy as salvage treatment for triple negative metastatic breast cancers patients (aged <45)

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Abstract

Background

The recent immunotherapy treatment on triple-negative breast cancer (TNBC) leads to the breakthrough assignation. In this study, we have tried the new combinations of specific chemo with DC-CIKs immunotherapy to treat those patients.

Patients and methods

Twenty-three metastatic anthracyclines and taxanes pretreated TNBC younger (mean 41.5 years) patients were initially mobilized with cyclophosphamide (3 g/m2) for the preparation of CD34+ peripheral blood mononuclear cells as the resources for generating DC/CIKs and marrow function supports. All cases were subsequently experienced 2 cycles of chemotherapy with cyclophosphamide 3 g/m2, thiotepa 150 mg/m2, and carboplatin AUC = 6, Q4w. The patients then received 3 infusions of DC-CIKs at the chemo intervals and followed by maintenance therapy with oral cyclophosphamide 50 mg daily. The endpoints were progression-free survival and overall survival.

Results

The partial response rate was 13.0 %, stable and progressive disease rates were 56.5 and 30.4 %, respectively. The median PFS was 13.5 months (95 % confidence interval (CI) 10.1–16.9 months) and OS was 15.2 months (95 % CI 12.5–18.1 months). The most common serious adverse events were neutropenia (100.0 %) and anemia (69.7 %) but without treatment-related mortality.

Conclusion

These data suggested that such combination therapy model be effective and safe for younger metastatic TNBC exposure to previous anthracyclines and taxanes based adjuvant chemotherapy.

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References

  1. Shastry M, Yardley DA. Updates in the treatment of basal/triple-negative breast cancer. Curr Opin Obstet Gynecol. 2013;25(1):40–8.

    Article  PubMed  Google Scholar 

  2. Colleoni M, Cole BF, Viale G, Regan MM, Price KN, Maiorano E, et al. Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple negative, node negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node negative breast cancer. J Clin Oncol. 2010;28:2966–73.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Cancello G, Bagnardi V, Sangalli C, Montagna E, Dellapasqua S, Sporchia A, et al. Phase II study with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel with metronomic cyclophosphamide as a preoperative treatment of triple-negative breast cancer. Clin Breast Cancer. 2015;. doi:10.1016/j.clbc.2015.03.002.

    Google Scholar 

  4. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig. 2011;121(7):2750–67.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:4429–34.

    Article  PubMed  Google Scholar 

  6. Anders CK, Zagar TM, Carey LA. The management of early-stage and metastatic triple-negative breast cancer: a review. Hematol Oncol Clin North Am. 2013;27(4):737–49.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Joensuu H, Gligorov J. Adjuvant treatments for triple-negative breast cancers. Ann Oncol. 2012;23(Suppl 6:vi):40–5.

    Google Scholar 

  8. Rodler E, Korde L, Gralow J. Current treatment options in triple negative breast cancer. Breast Dis. 2010;32(1–2):99–122.

    PubMed  Google Scholar 

  9. Gibson J. Anti-PD-L1 for metastatic triple-negative breast cancer. Lancet Oncol. 2015;16(6):e264. doi:10.1016/S1470-2045(15)70208-1.

    Article  PubMed  CAS  Google Scholar 

  10. Stagg J, Allard B. Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects. Ther Adv Med Oncol. 2013;5(3):169–81.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF. Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009;27(8):1323–33.

    Article  PubMed  CAS  Google Scholar 

  12. Wolff A, Hammond M, Schwartz J, Hagerty KL, Allred DC, Cote RJ, 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  PubMed  CAS  Google Scholar 

  13. Yu J, Ren J, Di LJ, Song GH, Zhu YL, Zhang J, et al. Mobilization of peripheral blood stem cells using regimen combining docetaxel with granulocyte colony-stimulating factor. Chin J Cancer Res. 2011;23:49–53.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Jiang HF, Song GH, Che L, Di LJ, Ren J. Metronomic low-dose oral cyclophosphamide plus endocrine therapy as systemic treatment for 23 metastatic breast cancer patients. Chin J Clin Oncol. 2011;38(2):104–7.

    CAS  Google Scholar 

  15. Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, et al. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol. 2006;24(22):3623–8.

    Article  PubMed  CAS  Google Scholar 

  16. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13(1):73–80.

    Article  PubMed  CAS  Google Scholar 

  17. Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD. Revised RECIST guideline version 1.1: what oncologists want to know and what radiologists need to know. Am J Roentgenol. 2010;195(2):281–9.

    Article  Google Scholar 

  18. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003;13(3):176–81.

    Article  PubMed  Google Scholar 

  19. Harris LN, Broadwater G, Lin NU, Miron A, Schnitt SJ, Cowan D, et al. Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342. Breast Cancer Res. 2006;8(6):R66.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Arnedos M, Bihan C, Delaloge S, Andre F. Triple-negative breast cancer: are we making headway at least? Ther Adv Med Oncol. 2012;4(4):195–210.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Brouckaert O, Wildiers H, Floris G, Neven P. Update on triple-negative breast cancer: prognosis and management strategies. Int J Womens Health. 2012;4:511–20.

    PubMed  PubMed Central  Google Scholar 

  22. Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28:375–9.

    Article  PubMed  CAS  Google Scholar 

  23. Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant cisplatin in triple negative breast cancer. J Clin Oncol. 2010;28:1145–53.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple negative breast cancer. N Engl J Med. 2011;364:205–14.

    Article  PubMed  Google Scholar 

  25. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235–44.

    Article  PubMed  CAS  Google Scholar 

  26. Nanda R, Chow QL, Dees EC, Berger R, Gupta S, Geva R, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. 2014; San Antonio Breast Cancer Symposium (SABCS) ABSTRACT #S1–09.

  27. Ren J, Di L, Song G, Jia J, Zhu Y, Yan Y, et al. Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences. Clin Trans Oncol. 2013;15(10):780–8.

    Article  CAS  Google Scholar 

  28. Rodenhuis S, Bontenbal M, van Hoesel QG, Smit WM, Nooij MA, Voest EE, et al. Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer. Ann Oncol. 2006;17:588–96.

    Article  PubMed  CAS  Google Scholar 

  29. Nitz UA, Gluz O, Herr A, Ting E, Mohrmann S, Frick M, et al. Retrospective analysis of WSG AM01 tandem high dose chemotherapy trial in high risk primary breast cancer: A hypothesis generating study. Proc Am Soc Clin Oncol 2006; 24:665. (Abstr).

  30. Sohn HJ, Kim SH, Lee GW, Kim S, Ahn JH, Kim SB, et al. High-dose chemotherapy of cyclophosphamide, thiotepa and carboplatin (CTCb) followed by autologous stem-cell transplantation as a consolidation for breast cancer patients with 10 or more positive lymph nodes: a 5-year follow-up results. Cancer Res Treat. 2005;37(3):137–42.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Vanderwalde A, Ye W, Frankel P, Asuncion D, Leong L, Luu T, et al. Long-term survival after high-dose chemotherapy followed by peripheral stem cell rescue for high-risk, locally advanced/inflammatory, and metastatic breast cancer. Biol Blood Marrow Transplant. 2012;18(8):1273–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Suzuki K, Kadota K, Sima CS, Nitadori J, Rusch VW, Travis WD, et al. Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor β2 (IL-12Rβ2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence. J Clin Oncol. 2013;31(4):490–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Lu Z, Jia J, Di L, Song G, Yuan Y, Ma B, et al. DNA methyltransferase inhibitor CDA-2 synergizes with high-dose thiotepa and paclitaxel in killing breast cancer stem cells. Front Biosci. 2011;1:240–9.

    Article  CAS  Google Scholar 

  34. Sun H, Jia J, Wang X, Ma B, Di L, Song G, et al. CD44+/CD24− breast cancer cells isolated from MCF-7 cultures exhibit enhanced angiogenic properties. Clin Trans Oncol. 2012;15:46–54.

    Article  Google Scholar 

  35. Radojvic V, Bezak K, Skarica M, Pletneva MA, Yoshimura K, Schulick RD, et al. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother. 2010;59:137–48.

    Article  Google Scholar 

Download references

Acknowledgments

We thank and remember the extraordinary courage and fortitude of the patients enrolled in this study who consent to participating this novel therapeutic model. We thank Sherry Gu PhD from Duke Clinical Research Institute of Duke University, Durham, NC, USA, for her assistance with the statistical analysis.

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Authors and Affiliations

  1. Beijing Key Laboratory of Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University Cancer Center, 10 Tieyi Road, Beijing, 100038, China

    X. Wang, J. Ren, N. Jiang, X. Zhou & H. Yang

  2. Department of Medical Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Beijing, 100142, China

    X. Wang, J. Ren, J. Zhang, Y. Yan, J. Yu, L. Di, G. Song, L. Che, J. Jia, X. Zhou & H. Yang

  3. Department of Surgery, Duke University Medical Center, 571 Research Drive, Suite 433, Box 2606, Durham, NC, 27710, USA

    J. Ren & H. K. Lyerly

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  1. X. Wang
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  3. J. Zhang
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  4. Y. Yan
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  13. H. K. Lyerly
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Corresponding authors

Correspondence to J. Ren or H. K. Lyerly.

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Conflict of interest

There is no any interest conflict of all authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

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.

Funding

Beijing Municipal Science and Technology Project (Z151100004015183), Beijing Oncological Leadership Grant (No. 2009-2-16) and Natural Science Foundation of China (No. 81172534).

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Wang, X., Ren, J., Zhang, J. et al. Prospective study of cyclophosphamide, thiotepa, carboplatin combined with adoptive DC-CIK followed by metronomic cyclophosphamide therapy as salvage treatment for triple negative metastatic breast cancers patients (aged <45). Clin Transl Oncol 18, 82–87 (2016). https://doi.org/10.1007/s12094-015-1339-2

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  • DOI: https://doi.org/10.1007/s12094-015-1339-2

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