Clinical implications of proliferation activity in T1 or T2 male gastric cancer patients

다국어 초록 (Multilingual Abstract)

Proliferation activity has already been established as a prognostic marker or as a marker for anticancer drug sensitivity. In gastric cancer, however, the prognostic significance of proliferation activity is still being debated. Several studies evaluating proliferation activity using Ki-67 have shown controversial results in terms of the relationship between proliferation activity and overall survival (OS) or drug sensitivity in gastric cancer patients. Because cytoskeleton-associated protein 2 (CKAP2) staining has recently been introduced as a marker of proliferation activity, we analyzed 437 gastric cancer tissues through CKAP2 immunohistochemistry, and we evaluated the chromatin CKAP2-positive cell count (CPCC) for proliferation activity. Although the CPCC did not show any significant correlation with OS in the male, female or total number of cases, it did show a significant correlation in the T1 or T2 male patient subgroup, according to log-rank tests (P=0.001) and univariate analysis (P=0.045).
Additionally, multivariate analysis with the Cox proportional hazard regression model showed a significant correlation between the CPCC and OS (P=0.039) for the co-variables of age, gender, T stage, N stage, histology, tumor location, tumor size and adjuvant chemotherapy. In male gastric cancer cell lines, faster-growing cancer cells showed higher sensitivity to cisplatin than slow-growing cells. Thus our study indicates that CPCC-measured proliferation activity demonstrates a significantly worse prognosis in T1 or T2 male gastric cancer patients. The CPCC will help to more precisely classify gastric cancer patients and to select excellent candidates for adjuvant chemotherapy, which in turn will facilitate further clinical chemotherapeutic trials.

참고문헌 (Reference)

1 홍경욱, "Transient phosphorylation of tumor associated microtubule associated protein (TMAP)/cytoskeleton associated protein 2 (CKAP2) at Thr-596 during early phases of mitosis" 생화학분자생물학회 40 (40): 377-386, 2008

2 Carey LA, "The triple negative paradox : primary tumor chemosensitivity of breast cancer subtypes" 13 : 2329-2334, 2007

3 Klintman M, "The prognostic value of mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A, and Ki67, alone and in combinations, in node-negative premenopausal breast cancer" 8 : e81902-, 2013

4 Tsamandas AC, "The potential role of Bcl-2 expression, apoptosis and cell proliferation (Ki-67 expression) in cases of gastric carcinoma and correlation with classic prognostic factors and patient outcome" 29 : 703-709, 2009

5 Freedman ND, "The association of menstrual and reproductive factors with upper gastrointestinal tract cancers in the NIH-AARP cohort" 116 : 1572-1581, 2010

6 Liedtke C, "Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer" 26 : 1275-1281, 2008

7 Fujii R, "Relationships between the expression of thymidylate synthase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase and cell proliferative activity and 5-fluorouracil sensitivity in colorectal carcinoma" 8 : 72-78, 2003

8 van Diest PJ, "Proliferation markers in tumours : interpretation and clinical value" 51 : 716-724, 1998

9 van Diest PJ, "Prognostic value of proliferation in invasive breast cancer : a review" 57 : 675-681, 2004

10 Aleskandarany MA, "Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer" 14 : R3-, 2012

11 Munzone E, "Prognostic value of Ki-67 labeling index in patients with nodenegative, triple-negative breast cancer" 134 : 277-282, 2012

12 Pich A, "Prognostic relevance of cell proliferation in head and neck tumors" 15 : 1319-1329, 2004

13 Prayson RA, "Malignant meningioma : a clinicopathologic study of 23patients including MIB1 and p53 immunohistochemistry" 105 : 719-726, 1996

14 Lee HE, "Low Ki-67 proliferation index is an indicator of poor prognosis in gastric cancer" 102 : 201-206, 2010

15 Penault-Llorca F, "Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer" 27 : 2809-2815, 2009

16 Lazar D, "Ki-67expression in gastric cancer. Results from a prospective study with long-term follow-up" 51 : 655-661, 2010

17 Nishimura R, "Ki-67as a prognostic marker according to breast cancer subtype and a predictor of recurrence time in primary breast cancer" 1 : 747-754, 2010

18 Keam B, "Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis" 13 : R22-, 2011

19 Lee JR, "Gastrointestinal autonomic nerve tumor : immunohistochemical and molecular identity with gastrointestinal stromal tumor" 25 : 979-987, 2001

20 주영은, "Expression of Cyclooxygenase-2, p53 and Ki-67 in Gastric Cancer" 대한의학회 21 (21): 871-876, 2006

21 Amadori D, "Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study" 18 : 3125-3134, 2000

22 Kim HS, "Condensed chromatin staining of CKAP2 as surrogate marker for mitotic figures" 138 : 95-102, 2012

23 Xiao LJ, "Clinicopathological and prognostic significance of Ki-67, caspase-3 and p53 expression in gastric carcinomas" 6 : 1277-1284, 2013

24 Nishimura R, "Clinical significance of Ki-67 in neoadjuvant chemotherapy for primary breast cancer as a predictor for chemosensitivity and for prognosis" 17 : 269-275, 2010

25 Kim HS, "Chromatin CKAP2, a new proliferation marker, as independent prognostic indicator in breast cancer" 9 : e98160-, 2014

26 Hugh J, "Breast cancer subtypes and response to docetaxel in node-positive breast cancer : use of an immunohistochemical definition in the BCIRG 001 trial" 27 : 1168-1176, 2009

27 Chabner BA., "Antineoplastic Agents: Goodman & Gilman's The Pharmacological Basis of Therapeutics" McGraw-Hill 2011

28 Bang YJ, "Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial" 379 : 315-321, 2012

29 Deng N, "A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets" 61 : 673-684, 2012