乳腺癌患者Ki-67表达水平对新辅助化疗后病理学完全缓解的预测价值
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摘要
目的:探讨乳腺癌患者Ki-67表达水平对新辅助化疗(NAC)疗效的影响。方法:收集261例行NAC且临床病理资料相对完整的乳腺癌患者,分析患者Ki-67表达以及其他临床病理因素包括分子分型、激素受体状态等与患者NAC后病理学完全缓解(pCR)的关系。结果:单因素分析结果显示,患者NAC后pCR与孕激素受体(PR)及表皮生长因子受体2(Her-2)状态、分子分型与Ki-67水平明显有关(均P<0.05);多因素分析显示,Ki-67表达水平是NAC后pCR独立预测因素(OR=5.476,95%CI=2.637~11.372,P<0.05)。此外,在雌激素受体(ER)阳性患者中,Ki-67高表达患者pCR率为低表达患者的4.282倍(OR=4.282,95%CI=1.694~10.825,P=0.002),而PR阳性患者pCR率为阴性患者的0.303倍(OR=0.303,95%CI=0.113~0.810,P=0.017),Her-2阳性者的pCR率是Her-2阴性者的2.607倍(OR=2.607,95%CI=1.023~6.642,P=0.045)。结论:乳腺癌患者Ki-67高表达是NAC后高pCR率的预测因子,同时结合其他激素受体状态,将有助于更好的指导个体化NAC。
Objective: To investigate the impact of Ki-67 expression level on efficacy of neoadjuvant chemotherapy(NAC) in breast cancer patients.Methods: A total of 261 patients with relatively complete clinicopathologic data undergoing NAC were collected. The relations of pathological complete response(pCR) after NAC with Ki-67 expression and other clinicopathologic factors such as molecular subtype and hormone receptor status of the patients were analyzed. Results: The results of univariate analysis showed that pCR after NAC of the patients was significantly related to the status of progestrone receptor(PR) and epidermal growth factor receptor 2(Her-2) as well as molecular subtype and Ki-67 expression; the results of multivariate analysis revealed that only the Ki-67 expression level was the independent predictive factor for pCR after NAC(OR=5.476, 95% CI=2.637–11.372, P<0.05). In addition, among the patients with positive estrogen receptor(ER) expression, the pCR rate in cases with high Ki-67 expression was 4.282-fold of that in those with low Ki-67 expression(OR=4.282, 95% CI=1.694–10.825, P=0.002), in PR positive cases was 0.303-fold of that in PR negative ones(OR=0.303, 95% CI=0.113–0.810, P=0.017), and in Her-2 positive cases was 2.607-fold of that in their negative counterparts(OR=2.607, 95% CI=1.023–6.642, P=0.045).Conclusion: In breast cancer patients, high Ki-67 expression level is a predictive indicator for high pCR rate after NAC. Meanwhile, it may be helpful for better individualized NAC planning with combined considerations of the status of other hormone receptors.
Objective: To investigate the impact of Ki-67 expression level on efficacy of neoadjuvant chemotherapy(NAC) in breast cancer patients.Methods: A total of 261 patients with relatively complete clinicopathologic data undergoing NAC were collected. The relations of pathological complete response(pCR) after NAC with Ki-67 expression and other clinicopathologic factors such as molecular subtype and hormone receptor status of the patients were analyzed. Results: The results of univariate analysis showed that pCR after NAC of the patients was significantly related to the status of progestrone receptor(PR) and epidermal growth factor receptor 2(Her-2) as well as molecular subtype and Ki-67 expression; the results of multivariate analysis revealed that only the Ki-67 expression level was the independent predictive factor for pCR after NAC(OR=5.476, 95% CI=2.637–11.372, P<0.05). In addition, among the patients with positive estrogen receptor(ER) expression, the pCR rate in cases with high Ki-67 expression was 4.282-fold of that in those with low Ki-67 expression(OR=4.282, 95% CI=1.694–10.825, P=0.002), in PR positive cases was 0.303-fold of that in PR negative ones(OR=0.303, 95% CI=0.113–0.810, P=0.017), and in Her-2 positive cases was 2.607-fold of that in their negative counterparts(OR=2.607, 95% CI=1.023–6.642, P=0.045).Conclusion: In breast cancer patients, high Ki-67 expression level is a predictive indicator for high pCR rate after NAC. Meanwhile, it may be helpful for better individualized NAC planning with combined considerations of the status of other hormone receptors.
引文
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[24]Mamounas EP,Anderson SJ,Dignam JJ,et al.Predictors of locoregional recurrence after neoadjuvant chemotherapy:results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27[J].J Clin Oncol,2012,30(32):3960-3966.doi:10.1200/JCO.2011.40.8369.
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[27]von Minckwitz G KM,Kümmel S,Fasching P,et al.Integrated meta-analysis on 6402 patients with early breast cancer receiving neoadjuvant anthracycline-taxane±trastuzumab containing chemotherapy[Abstract 792008].SABCS Abstract 792008,2008.
[28]Gianni L,Eiermann W,Semiglazov V,et al.Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone,in patients with HER2-positive locally advanced breast cancer(the NOAH trial):a randomised controlled superiority trial with a parallel HER2-negative cohort[J].Lancet,2010,375(9712):377-384.doi:10.1016/S0140-6736(09)61964-4.
[29]Untch M,Rezai M,Loibl S,et al.Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer:results from the Gepar Quattro study[J].J Clin Oncol,2010,28(12):2024-2031.doi:10.1200/JCO.2009.23.8451.
[30]Untch M,Stoeckl D,Konecny G,et al.A multicenter phase ii study of preoperative epirubicin,cyclophosphamide(ec)followed by paclitaxel(p)plus trastuzumab(t)in her2 positive primary breast cancer[abstract 1064].Breast Cancer Res Treat,2005,94:60-61.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.doi:10.3322/caac.21338.
[3]Bonnefoi H,Piccart M,Bogaerts J,et al.TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer(EORTC 10994/BIG 1-00):a randomised phase 3 trial[J].Lancet Oncol,2011,12(6):527-539.doi:10.1016/S1470-2045(11)70094-8.
[4]Prat A,Cheang MC,Martín M,et al.Prognostic significance of progesterone receptor-positive tumor cells with in immunohistochemically defined luminal A breast cancer[J].J Clin Oncol,2013,31(2):203-209.doi:10.1200/JCO.2012.43.4134.
[5]Caudle AS,Gonzalez-Angulo AM,Hunt KK,et al.Predictors of tumor progression during neoadjuvant chemotherapy in breast cancer[J].J Clin Oncol,2010,28(11):1821-1828.doi:10.1200/JCO.2009.25.3286.
[6]Kuerer HM,Newman LA,Smith TL,et al.Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy[J].J Clin Oncol,1999,17(2):460-469.doi:10.1200/JCO.1999.17.2.460.
[7]Liedtke C,Mazouni C,Hess KR,et al.Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer[J].J Clin Oncol,2008,26(8):1275-1281.doi:10.1200/JCO.2007.14.4147.
[8]Guarneri V,Broglio K,Kau SW,et al.Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors[J].J Clin Oncol,2006,24(7):1037-1044.doi:10.1200/JCO.2005.02.6914.
[9]Cortazar P,Zhang L,Untch M,et al.Pathological complete response and long-term clinical benefit in breast cancer:the CTNeo BC pooled analysis[J].Lancet,2014,384(9938):164-172.doi:10.1016/S0140-6736(13)62422-8.
[10]Viale G,Regan MM,Mastropasqua MG,et al.Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer[J].J Natl Cancer Inst,2008,100(3):207-212.doi:10.1093/jnci/djm289.
[11]Hugh J,Hanson J,Cheang MC,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].J Clin Oncol,2009,27(8):1168-1176.doi:10.1200/JCO.2008.18.1024.
[12]Penault-Llorca F,AndréF,Sagan C,et al.Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer[J].J Clin Oncol,2009,27(17):2809-2815.doi:10.1200/JCO.2008.18.2808.
[13]Bartlett JM,Munro A,Cameron DA,et al.Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial[J].J Clin Oncol,2008,26(31):5027-5035.doi:10.1200/JCO.2007.14.6597.
[14]中国抗癌协会乳腺癌专业委员会.中国抗癌协会乳腺癌诊治指南与规范(2017年版)[J].中国癌症杂志,2017,27(9):695-759.Committee of Breast Cancer Society of Chinese Anti-Cancer Association.Guidelines and standardization for diagnosis and treatment of breast cancer of Chinese Anti-Cancer Association(2017edition)[J].China Oncology,2017,27(9):695-759.
[15]Edge SB,Compton CC.The American Joint Committee on cancer:the 7th edition of the AJCC cancer staging manual and the future of TNM[J].Ann Surg Oncol,2010,17(6):1471-1474.doi:10.1245/s10434-010-0985-4.
[16]Levy MH,Back A,Benedetti C,et al.NCCN clinical practice guidelines in oncology:palliative care[J].J Natl Compr Canc Netw,2009,7(4):436-473.
[17]Stuart-Harris R,Caldas C,Pinder SE,et al.Proliferation markers and survival in early breast cancer:a systematic review and meta-analysis of 85 studies in 32,825 patients[J].Breast,2008,17(4):323-334.doi:10.1016/j.breast.2008.02.002.
[18]Penault-Llorca F,Abrial C,Raoelfils I,et al.Changes and predictive and prognostic value of the mitotic index,Ki-67,cyclin D1,and cyclo-oxygenase-2 in 710 operable breast cancer patients treated with neoadjuvant chemotherapy[J].Oncologist,2008,13(12):1235-1245.doi:10.1634/theoncologist.2008-0073.
[19]Petit T,Wilt M,Velten M,et al.Comparative value of tumour grade,hormonal receptors,Ki-67,HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy[J].Eur J Cancer,2004,40(2):205-211.
[20]Pohl G,Rudas M,Taucher S,et al.Expression of cell cycle regulatory proteins in breast carcinomas before and after preoperative chemotherapy[J].Breast Cancer Res Treat,2003,78(1):97-103.
[21]von Minckwitz G,Sinn HP,Raab G,et al.Clinical response after two cycles compared to HER2,Ki-67,p53,and bcl-2 in independently predicting a pathological complete response after preoperative chemotherapy in patients with operable carcinoma of the breast[J].Breast Cancer Res,2008,10(2):R30.doi:10.1186/bcr1989.
[22]Yerushalmi R,Woods R,Ravdin PM,et al.Ki67 in breast cancer:prognostic and predictive potential[J].Lancet Oncol,2010,11(2):174-183.doi:10.1016/S1470-2045(09)70262-1.
[23]Fasching PA,Heusinger K,Haeberle L,et al.Ki67,chemotherapy response,and prognosis in breast cancer patients receiving neoadjuvant treatment[J].BMC Cancer,2011,11:486.doi:10.1186/1471-2407-11-486.
[24]Mamounas EP,Anderson SJ,Dignam JJ,et al.Predictors of locoregional recurrence after neoadjuvant chemotherapy:results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27[J].J Clin Oncol,2012,30(32):3960-3966.doi:10.1200/JCO.2011.40.8369.
[25]von Minckwitz G,Blohmer JU,Costa SD,et al.Response-guided neoadjuvant chemotherapy for breast cancer[J].J Clin Oncol,2013,31(29):3623-3630.doi:10.1200/JCO.2012.45.0940.
[26]Bonnefoi H,Litière S,Piccart M,et al.Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes:a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial[J].Ann Oncol,2014,25(6):1128-1136.doi:10.1093/annonc/mdu118.
[27]von Minckwitz G KM,Kümmel S,Fasching P,et al.Integrated meta-analysis on 6402 patients with early breast cancer receiving neoadjuvant anthracycline-taxane±trastuzumab containing chemotherapy[Abstract 792008].SABCS Abstract 792008,2008.
[28]Gianni L,Eiermann W,Semiglazov V,et al.Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone,in patients with HER2-positive locally advanced breast cancer(the NOAH trial):a randomised controlled superiority trial with a parallel HER2-negative cohort[J].Lancet,2010,375(9712):377-384.doi:10.1016/S0140-6736(09)61964-4.
[29]Untch M,Rezai M,Loibl S,et al.Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer:results from the Gepar Quattro study[J].J Clin Oncol,2010,28(12):2024-2031.doi:10.1200/JCO.2009.23.8451.
[30]Untch M,Stoeckl D,Konecny G,et al.A multicenter phase ii study of preoperative epirubicin,cyclophosphamide(ec)followed by paclitaxel(p)plus trastuzumab(t)in her2 positive primary breast cancer[abstract 1064].Breast Cancer Res Treat,2005,94:60-61.