Analysis of SPARC and TUBB3 as predictors for prognosis in esophageal squamous cell carcinoma receiving nab-paclitaxel plus cisplatin neoadjuvant chemotherapy: a prospective study

  • Lei Gong
  • Weimin Mao
  • Qixun Chen
  • Youhua Jiang
  • Yun FanEmail author
Original Article



The purpose of the study is to evaluate the predictive efficacy of secreted protein, acidic and rich in cysteine (SPARC) and the class III β-tubulin (β-tubulin III, TUBB3) in predicting therapeutic effect in patients with locally advanced esophageal squamous cell carcinoma(ESCC) who received nab-paclitaxel plus cisplatin neoadjuvant chemotherapy(CT) followed by surgery.


Patients with stage II to III esophageal squamous cell carcinoma of different stages are recruited. The tumor biopsy tissues prior treatment from enrolled patients were examined by SPARC and TUBB3 immunohistochemistry (IHC). Correlations between SPARC/TUBB3 expression and response to chemotherapy and long-term survival in patients received surgical resection was analyzed.


A total of 35 patients with stage II to III esophageal squamous cell carcinoma were enrolled. Of the 35 enrolled patients, 30 successfully completed neoadjuvant chemotherapy and underwent R0 resection, 3 refused surgery after chemotherapy, and 2 failed to undergo radical surgery after chemotherapy. Out of patients undergoing surgery, pathological complete response (pCR) was achieved in 6 patients (6/30, 20%). The 1, 2 and 5-year disease free survival (DFS) rates were 70.0%, 36.6% and 33.3%, respectively. The 1, 2 and 5-year overall survival (OS) rates were 83.3%, 63.3% and 36.6%, respectively. SPARC and TUBB3 IHC was performed on the tumor biopsy tissues which were obtained from patients before treatment. Correlation between SPARC/TUBB3 expression and long-term survival in patients was studied. Both the median DFS and OS between SPARC negative samples and SPARC positive staining samples have no statistical difference. However, the median DFS and OS in TUBB3 negative patients was better than those in TUBB3 positive patients (p = 0.002 for DFS, p = 0.001 for OS). In addition, patients with pCR had longer OS and DFS time than those without pCR.COX regression analysis showed that TUBB3 prior treatment and pCR were independent prognostic factors in ESCC patients undergoing sequential surgery after preoperative chemotherapy.


TUBB3 negative expression prior treatment and pCR may indicate a better prognosis for stage II and III ESCC patients after nab-paclitaxel plus cisplatin neoadjuvant chemotherapy following radical esophagectomy.


Esophageal carcinoma Nab-paclitaxel Neoadjuvant chemotherapy Secreted protein acidic and rich in cysteine Class III β-tubulin 



We wish to thank all the patients who volunteered for this study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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.

Informed consent

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


  1. 1.
    Di Pardo BJ, Bronson NW, Diggs BS, Thomas CR Jr, Hunter JG, Dolan JP (2016) The global burden of esophageal cancer: a disability-adjusted life-year approach. World J Surg 40(2):395–401. CrossRefGoogle Scholar
  2. 2.
    Tang WR, Fang JY, Wu KS, Shi XJ, Luo JY, Lin K (2014) Epidemiological characteristics and prediction of esophageal cancer mortality in China from 1991 to 2012. Asian Pac J Cancer Prev 15(16):6929–6934CrossRefGoogle Scholar
  3. 3.
    Domper Arnal MJ, Ferrandez Arenas A, Lanas Arbeloa A (2015) Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol 21(26):7933–7943. CrossRefGoogle Scholar
  4. 4.
    Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, Takiyama W, Watanabe H, Isono K, Aoyama N, Makuuchi H, Tanaka O, Yamana H, Ikeuchi S, Kabuto T, Nagai K, Shimada Y, Kinjo Y, Fukuda H, Japan Clinical Oncology G (2003) Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study-JCOG9204. J Clin Oncol 21(24):4592–4596. CrossRefGoogle Scholar
  5. 5.
    Kranzfelder M, Schuster T, Geinitz H, Friess H, Buchler P (2011) Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer. Br J Surg 98(6):768–783. CrossRefGoogle Scholar
  6. 6.
    Chen J, Pan J, Zheng X, Zhu K, Li J, Chen M, Wang J, Liao Z (2012) Number and location of positive nodes, postoperative radiotherapy, and survival after esophagectomy with three-field lymph node dissection for thoracic esophageal squamous cell carcinoma. Int J Radiat Oncol Biol Phys 82(1):475–482. CrossRefGoogle Scholar
  7. 7.
    Lyu X, Huang J, Mao Y, Liu Y, Feng Q, Shao K, Gao S, Jiang Y, Wang J, He J (2014) Adjuvant chemotherapy after esophagectomy: is there a role in the treatment of the lymph node positive thoracic esophageal squamous cell carcinoma? J Surg Oncol 110(7):864–868. CrossRefGoogle Scholar
  8. 8.
    Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy AB, Anker CJ, Thakrar H, Horiba N, Dubey A, Greenberger JS, Raben A, Giguere J, Roof K, Videtic G, Pollock J, Safran H, Crane CH (2017) Effect of the addition of cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with esophageal cancer: the NRG oncology RTOG 0436 phase 3 randomized clinical trial. JAMA Oncol 3(11):1520–1528. CrossRefGoogle Scholar
  9. 9.
    Chen H, Wu Z, Chen J, Lin X, Zheng C, Fan Y, Zhang Z, Yao X, Wu J, Xu L, Li E (2015) Postoperative adjuvant therapy for resectable thoracic esophageal squamous cell carcinoma: a retrospective analysis of 426 cases. Med Oncol 32(1):417. CrossRefGoogle Scholar
  10. 10.
    Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, Gebski V, Australasian Gastro-Intestinal Trials G (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 12(7):681–692. CrossRefGoogle Scholar
  11. 11.
    Stinchcombe TE (2007) Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL-free formulation of paclitaxel. Nanomedicine (Lond) 2(4):415–423. CrossRefGoogle Scholar
  12. 12.
    Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 12(4):1317–1324. CrossRefGoogle Scholar
  13. 13.
    Bradshaw AD, Sage EH (2001) SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. J Clin Invest 107(9):1049–1054. CrossRefGoogle Scholar
  14. 14.
    Feng J, Tang L (2014) SPARC in tumor pathophysiology and as a potential therapeutic target. Curr Pharm Des 20(39):6182–6190CrossRefGoogle Scholar
  15. 15.
    Ribeiro N, Sousa SR, Brekken RA, Monteiro FJ (2014) Role of SPARC in bone remodeling and cancer-related bone metastasis. J Cell Biochem 115(1):17–26. CrossRefGoogle Scholar
  16. 16.
    Al-Batran SE, Geissler M, Seufferlein T, Oettle H (2014) Nab-paclitaxel for metastatic pancreatic cancer: clinical outcomes and potential mechanisms of action. Oncol Res Treat 37(3):128–134. CrossRefGoogle Scholar
  17. 17.
    Jordan MA (2002) Mechanism of action of antitumor drugs that interact with microtubules and tubulin. Curr Med Chem Anticancer Agents 2(1):1–17CrossRefGoogle Scholar
  18. 18.
    Giannakakou P, Sackett DL, Kang YK, Zhan Z, Buters JT, Fojo T, Poruchynsky MS (1997) Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 272(27):17118–17125CrossRefGoogle Scholar
  19. 19.
    Monzo M, Rosell R, Sanchez JJ, Lee JS, O’Brate A, Gonzalez-Larriba JL, Alberola V, Lorenzo JC, Nunez L, Ro JY, Martin C (1999) Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. J Clin Oncol 17(6):1786–1793. CrossRefGoogle Scholar
  20. 20.
    Mozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, Gallo D, Martinelli E, Ranelletti FO, Ferrandina G, Scambia G (2005) Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res 11(1):298–305Google Scholar
  21. 21.
    Paradiso A, Mangia A, Chiriatti A, Tommasi S, Zito A, Latorre A, Schittulli F, Lorusso V (2005) Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. Ann Oncol 16(Suppl 4):iv14–i19. CrossRefGoogle Scholar
  22. 22.
    Seve P, Mackey J, Isaac S, Tredan O, Souquet PJ, Perol M, Lai R, Voloch A, Dumontet C (2005) Class III beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Ther 4(12):2001–2007. CrossRefGoogle Scholar
  23. 23.
    Azuma K, Sasada T, Kawahara A, Takamori S, Hattori S, Ikeda J, Itoh K, Yamada A, Kage M, Kuwano M, Aizawa H (2009) Expression of ERCC1 and class III beta-tubulin in non-small cell lung cancer patients treated with carboplatin and paclitaxel. Lung Cancer 64(3):326–333. CrossRefGoogle Scholar
  24. 24.
    Ferrandina G, Zannoni GF, Martinelli E, Paglia A, Gallotta V, Mozzetti S, Scambia G, Ferlini C (2006) Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients. Clin Cancer Res 12(9):2774–2779. CrossRefGoogle Scholar
  25. 25.
    Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG, Radiation Therapy Oncology G, Intergroup USA (2007) Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 25(24):3719–3725. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Thoracic Medical OncologyZhejiang Cancer HospitalHangzhouPeople’s Republic of China
  2. 2.Zhejiang Key laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus)Zhejiang Cancer HospitalHangzhouPeople’s Republic of China
  3. 3.Department of Thoracic SurgeryZhejiang Cancer HospitalHangzhouPeople’s Republic of China

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