|Year : 2018 | Volume
| Issue : 2 | Page : 409-415
Candidate biomarkers predictive of anthracycline and taxane efficacy against breast cancer
Shoko Norimura1, Keiichi Kontani2, Takako Kubo3, Shin-ichiro Hashimoto2, Chisa Murazawa2, Koichiro Kenzaki3, Dage Liu2, Masafumi Tamaki3, Fuminori Aki4, Kazumasa Miura3, Kiyoshi Yoshizawa5, Akira Tangoku6, Hiroyasu Yokomise2
1 Department of Thoracic, Breast and Endocrine Surgery, Kagawa University, Faculty of Medicine, Kita-gun; Department of Surgery, Takamatsu Red Cross Hospital, Takamatsu, Japan
2 Department of Thoracic, Breast and Endocrine Surgery, Kagawa University, Faculty of Medicine, Kita-gun, Japan
3 Department of Surgery, Takamatsu Red Cross Hospital, Takamatsu, Japan
4 Department of Surgery, Ito Breast Surgical Clinic, Kouchi, Japan
5 Department of Surgery, Kumegawa Hospital, Higashimurayama, Japan
6 Department of Thoracic and Endocrine Surgery and Oncology, Faculty of Medicine, University of Tokushima, Tokushima, Japan
|Date of Web Publication||8-Mar-2018|
Department of Thoracic, Breast and Endocrine Surgery, Kagawa University Faculty of Medicine, Kita-gun
Source of Support: None, Conflict of Interest: None
Background: Since breast cancer shows diversity in clinical behaviors, a standard therapy does not always lead to favorable outcomes.
Materials and Methods: The expression statuses of candidate markers, including topoisomerase-II alpha (TOP2A), beta-tubulin (B-tub), and tissue inhibitor of metalloprotease-1 (TIMP-1), were immunohistochemically evaluated in 70 breast cancer tissues from 68 patients with advanced breast cancers receiving chemotherapy.
Results: The response rates to anthracycline and taxane were 70.5% and 67.2%, respectively. Overall, 25.1% ± 29.7%, 8.32% ± 10.1%, and 16.37% ±17.5% of cancer cells in the tumors studied were positive for B-tub, TOP2A, and TIMP-1 expressions, respectively. However, positive molecule expression did not differ between patients who did and did not exhibit clinical responses to treatment. The proportion of TOP2A-positive cancer cells was significantly higher among anthracycline responders than among nonresponders in HR-negative cancer (15.4% ±17.5% vs. 2.0% ± 2.4%, respectively, P = 0.048), whereas TOP2A and TIMP-1 expression statuses did not differ in HR-positive cancer. When patients were stratified according to B-tub, TOP2A, or TIMP-1 expression statuses (B-tub ≥10% vs. <10%, TOP2A ≥5% vs. <5%, TIMP-1 ≤20% vs. >20%, respectively), the proportion of patients with ≥10% B-tub-positive cancer cells was significantly higher in taxane responders than in nonresponders (72.4% vs. 37.5%, respectively, P = 0.016). Anthracycline responders showed a trend to have a higher proportion of patients with either ≥5% TOP2A-positive cancer cells or ≤20% TIMP-1-positive cancer cells compared to nonresponders (86.7% vs. 61.5%, respectively, P = 0.066).
Conclusion: Immunohistochemical TOP2A, TIMP-1, and B-tub expression analyses are expected to be useful for predicting tumor responses to chemotherapy.
Keywords: Anthracycline, beta-tubulin, breast cancer, predictive biomarker, taxane, tissue inhibitor of metalloprotease-1, topoisomerase-II alpha
|How to cite this article:|
Norimura S, Kontani K, Kubo T, Hashimoto Si, Murazawa C, Kenzaki K, Liu D, Tamaki M, Aki F, Miura K, Yoshizawa K, Tangoku A, Yokomise H. Candidate biomarkers predictive of anthracycline and taxane efficacy against breast cancer. J Can Res Ther 2018;14:409-15
|How to cite this URL:|
Norimura S, Kontani K, Kubo T, Hashimoto Si, Murazawa C, Kenzaki K, Liu D, Tamaki M, Aki F, Miura K, Yoshizawa K, Tangoku A, Yokomise H. Candidate biomarkers predictive of anthracycline and taxane efficacy against breast cancer. J Can Res Ther [serial online] 2018 [cited 2020 May 26];14:409-15. Available from: http://www.cancerjournal.net/text.asp?2018/14/2/409/214512
| > Introduction|| |
Breast cancers are known to be heterogeneous with respect to pathological features, hormone receptor and human epidermal growth factor receptor 2 (HER2) statuses, and clinical behaviors. Breast cancers can be classified into subtypes according to hormone receptor and HER2 expression statuses, and each subtype is associated with different proliferative capacities, responses to anticancer agents, and patient prognoses., For example, breast cancers can be classified into four subtypes, luminal A or B, luminal-HER2, HER2, and triple-negative cancer. However, the extent to which biomarkers, such as HER2 expression, are involved in clinical outcomes remains unclear. In addition to hormone receptor and HER2 expression, tumor size, nodal status, tumor grade, and proliferative ability have been reported as prognostic factors in patients with breast cancer. However, little is known about the clinical behaviors associated with each factor. Therefore, a novel strategy is needed to identify biomarkers in each subtype that would allow predictions of treatment efficacy and thus improve the survival of patients with breast cancer.
Anthracycline and taxane are used clinically as standard chemotherapeutic agents in both adjuvant and metastatic settings. Topoisomerase-II alpha (TOP2A) and beta-tubulin (B-tub) are known as target molecules of anthracycline and taxane, respectively. To our knowledge, few reports have described a close relationship between the levels of target molecule expression in tumors and clinical responses to the respective chemotherapeutic agents.,,,, Moreover, suitable methodologies to examine the expression of these molecules in tumors have not been established. The glycoprotein tissue inhibitor of metalloprotease-1 (TIMP-1) is known to inhibit matrix metalloproteinase activity and is reportedly associated with prognosis and anticancer agent efficacy in patients with breast cancer. For example, patients with high tumor TIMP-1 expression levels are more likely to experience early cancer relapse and have a poor prognosis.,,, Regarding chemotherapy responsiveness, patients with TIMP-1-negative tumors have been reported to respond favorably to epirubicin., whereas those with high TIPM-1 expression levels exhibited resistance to paclitaxel-based regimens. In addition, TIMP-1 expression has been associated with the clinical efficacy of classical chemotherapeutic regimens, including cyclophosphamide/methotrexate/5-fluorouracil (CMF) or epirubicin + CMF. Notably, some reports have described the use of combined TIPM-1 and HER2 or TIMP-1 and TOP2A profiling to predict responses to anthracycline-based chemotherapy.,,,,, However, these reports did not demonstrate the same results because of the differences in demographic features of patients studied, regimens implemented, and administration settings.
In this study, we examined the intratumoral expression of TOP2A, B-tub, and TIMP-1 immunohistochemically in breast cancers to determine whether the expression statuses of these molecules could predict the clinical efficacy of anthracycline- or taxane-based chemotherapeutic regimens.
| > Materials and Methods|| |
We examined 70 breast cancer tissues from 68 patients who had locally advanced, metastatic, or recurrent breast cancer and had received chemotherapy at our hospital from June 2006 to April 2014. All patients had been diagnosed with breast cancer through histological examination of specimens from the primary or metastatic lesions. Patients were administered either anthracycline- or taxane-based regimens. For patients with HER2-overexpressing cancers, trastuzumab was administered in combination with chemotherapeutic agents.
Evaluation of therapeutic efficacy
Tumor responses were assessed through physical examination, computed tomography, or magnetic resonance imaging, according to the Response Evaluation Criteria in Solid Tumors every 2–3 months during treatment. Complete response (CR) was defined as the lack of evidence of disease, partial response (PR) was defined as a reduction in the sum of target lesion diameters by 30%, and progressive disease (PD) was defined as an increase in the sum of target lesion diameters by 20% or the presence of a new lesion. A clinical response that did not meet any of the above definitions was classified as stable disease (SD). Objective response was defined as CR and PR; disease control was defined as CR, PR, and SD; and clinical benefit was defined as CR, PR, and SD during an observation period of 6 months.
Tumor tissues obtained by core needle biopsy were fixed in 10% formalin, embedded in paraffin, and sliced in 10-μm-thick section. The sections were mounted on slides and dehydrated in ethanol followed by incubation in 2% normal goat serum to block nonspecific binding for 20 min and a phosphate-buffered saline (PBS) wash. The sections were subsequently incubated overnight at 4°C with monoclonal antibodies against TOP2 (1.00E+02, Abcam, Tokyo, Japan) at a concentration of 10 μg/ml, or B-tub (ab52623, Abnova, Taipei, Taiwan) at a 1:50 dilution, or with an anti-TIMP-1 polyclonal antibody (Abcam) at a 1:250 dilution. The sections were then washed in PBS and incubated with biotinylated anti-mouse or rabbit immunoglobulins (1:500 dilution) (Vector Laboratories, Inc., Burlingame, CA, USA) for 2 h, followed by incubation with an horse radish peroxidase-conjugated avidin solution (Vector Laboratories, Inc.) for 1.5 h at room temperature. Finally, the sections were treated with 0.1 mg/ml 3.3'-diaminobenzidine (Wako Pure Chemical Industries, Ltd., Osaka, Japan) for 10 min at room temperature to induce the colorimetric reaction, washed in tap water, and counterstained with 0.1% hematoxylin solution. Many cancer cells in breast cancer tissues were stained with anti-TOP2A antibody in the nucleus and were stained with anti-B-tub or TIMP antibodies in the cytoplasm [Figure 1]. To define the labeling index of antibodies used in this study, the breast tissues obtained from 25 patients with noncancerous diseases including mastopathy, mastitis, or fibroadenoma were examined. Mean percentages of mammary epithelial cells from the tissue samples positive for TOP2A, B-tub, or TIMP-1 expressions were 2.74% ± 1.02%, 4.66% ± 2.11%, or 13.7% ± 4.89%, respectively (data not shown). We defined the labeling index of the antibodies in reference to the mean percentages +2 standard deviations of mammary epithelial cells reactive with each antibody (5% for TOP2A, 10% for B-tub, and 20% for TIMP-1).
|Figure 1: Immunohistochemical study of breast cancer tissues using antibodies reactive with topoisomerase-II alpha, beta-tubulin, or tissue inhibitor of metalloprotease-1. Tumor samples from patients with breast cancer were immunohistochemically stained with anti-topoisomerase-II alpha (a), beta-tubulin (b), or TMP-1 antibody (c)|
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Mann–Whitney U-test or standard Chi-square test was used as appropriate to compare the two groups. For each variable, a 95% confidence interval (CI) was calculated for the median value using the method of Brookmeyer and Crowley. Statistical significance was defined at P < 0.05, and all P values were two sided. The SPSS statistical software package (SPSS Inc. Tokyo, Japan) was used for all calculations.
Ethical approval and consent to participate
This research was in compliance with the guidelines of our Institutional Ethics Committee and approved by the committee and conformed to the provision of the Declaration of Helsinki in 1995. We received written informed consent from all the study patients.
| > Results|| |
Clinicopathologic characteristics of the patients
The median age of the patients was 60 (32–76) years. The 70 evaluated tumors represented 37 locally advanced, 17 metastatic, and 16 recurrent breast cancers [Table 1]; of these, 42 (60%) were hormone sensitive and 17 (24.3%) were overexpressing HER2. Invasive ductal carcinoma accounted for 89.5% of the tumors, and 50%, 8.6%, 25.7%, and 15.7% of the tumors were classified as luminal A/B, luminal-HER2, triple-negative, and HER2 tumors, respectively. In addition, 62% and 81.7% of the patients received anthracycline- and taxane-based chemotherapy, respectively. Anthracycline was administered as the first, second, and third or later line of chemotherapy in 34 (47.9%) patients, 15 (21.1%) patients, and 1 patient (1.4%), respectively (data not shown), whereas taxane was administered as the first, second, and third or later line in 32 (45.1%), 27 (38%), and 7 patients (9.9%), respectively.
Overall, 85.5% of the patients exhibited responses to either anthracycline- or taxane-based chemotherapy [Table 2]; the agent-specific response rates were 70.5% for anthracycline, 67.2% for taxane, and 88.9% for trastuzumab. The response rates to either anthracycline or taxane according to the subtypes were 58.6% for luminal A/B, 83.3% for luminal-HER2, 45.5% for triple-negative, and 75.0% for HER2 tumors [Table 3]. To compare the efficacy of administered agents among subtypes, response rates to anthracycline and taxane were 74.1% and 60.9%, respectively, in luminal A/B; 100% and 66.7%, respectively, in luminal-HER2; 50.0% and 42.1%, respectively, in triple-negative; and 83.3% and 83.3%, respectively, in HER2 groups [Table 3]. Patients with HER2-overexpressing tumors had fairly high response rates to trastuzumab-containing regimens.
|Table 3: Response rates to anthracycline and taxane according to tumor subtype|
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Candidate molecule expression in the tumor
The expression of candidate molecules, including B-tub, TOP2A, and TIMP-1, was evaluated in primary or metastatic tumors from all the enrolled patients; 25.6% ± 29.8%, 8.5% ± 10.1%, and 16.6% ±17.7% of tumors were positive for these molecules, respectively [Table 4]. As both the hormone receptor and HER2 status are known as predictors of chemotherapeutic efficacy, for instance, patients with hormone receptor-negative or HER2-overexpressing cancers have been reported to exhibit good responses to anthracycline or taxane. We compared tumor responses to chemotherapy and candidate molecule expression statuses in tumors according to HR or HER2 status. The response rates to taxane did not differ significantly between patients with HR-positive and HR-negative tumors [75.8% vs. 58.3%, respectively, P = 0.166, [Table 5], and taxane responders and nonresponders did not differ with respect to proportion of B-tub-positive cancer cells (24.0% ± 29.0% vs. 25.4% ± 27.4%, respectively, P = 0.841). Similarly, the rates of responses to anthracycline did not differ between patients with HR-positive and HR-negative tumors (76.9% vs. 61.1%, respectively, P = 0.264). Furthermore, patients with HR-positive and HR-negative tumors did not differ with respect to TOP2A or TIMP-1 expression (TOP2A, 7.1% ±9.6% vs. 10.5% ± 14.0%, P = 0.307; TIMP-1, 14.6% ±22.5% vs. 19.5% ±28.1%, P = 0.44). Patients with and without HER2-overexpressing tumors did not differ in terms of responses to taxane or anthracycline [taxane, 87.5% and 65.3%, P = 0.215; anthracycline, 50.5% and 67.7%, P = 0.703, [Table 6] or the tumor expression of B-tub (32.2% ± 32.7% vs. 23.9% ± 26.6%, respectively, P = 0.606) or TOP2A (19.0% ± 21.5% vs. 6.9% ± 9.3%, respectively, P = 0.325). However, compared to patients with HER2-normal tumors, those with HER2-overexpressing tumors had a significantly lower proportion of TIMP-1-positive cancer cells (8.8% ±9.3% vs. 20.4% ±25.6%, respectively, P = 0.031).
|Table 4: Proportions of cancer cells with positive target molecule expressions among responders and nonresponders|
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|Table 5: Chemotherapeutic efficacy and tumor target molecule expressions according to hormone receptor status|
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|Table 6: Chemotherapeutic efficacy and tumor target molecule expressions according to human epidermal growth factor receptor 2 status|
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Expression of candidate molecules in responders and nonresponders to chemotherapy
A comparison of candidate molecule expression in patients who did and did not respond to chemotherapy revealed no significant differences [B-tub, 27.3% ± 28.4% vs. 24.0% ± 27.6%, P = 0.349; TOP2A, 6.6% ± 9.2% vs. 14.9% ± 20.9%, P = 0.481; TIMP-1, 15.2% ± 24.0% vs. 6.4% ± 11.7%, P = 0.444, [Table 4]. For further analysis, patients were divided into subgroups according to HR (positive vs. negative) or HER2 status (overexpressing vs. normal), and the proportions of cancer cells positive for the candidate molecules were compared between responders and nonresponders to taxane or anthracycline within these subgroups. Among both HR subgroups, the proportions of B-tub-positive cancer cells did not differ between taxane responders and nonresponders [HR-positive group, 24.5% ± 28.2% vs. 27.5% ± 32.8%, P = 0.82; HR-negative group, 22.4% ± 26.1% vs. 17.3% ±22.7%, P = 0.594, [Table 7]. Similarly, the proportions of B-tub-positive cancer cells did not differ between taxane responders and nonresponders in the HER-normal group (23.9% ±26.9% vs. 23.8% ±27.8%, P = 0.989); however, patients with HER2-overexpressing tumors were administered taxane in combination with trastuzumab, and therefore, data regarding the efficacy of taxane alone were unavailable.
|Table 7: Comparison of the proportions of cancer cells positive for B-tub expression between taxane responders and nonresponders among patients stratified according to hormone receptor or human epidermal growth factor receptor 2 status|
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Further comparison of patients in the HR-positive subgroup found that the proportions of TOP2A- or TIMP-1-positive cancer cells did not differ between anthracycline responders and nonresponders [TOP2A, 6.4% ± 8.4% vs. 9.4% ± 15.4%, P = 0.718; TIMP-1, 13.4% ± 18.5% vs. 16.7% ± 21.9%, P = 0.765, [Table 8]. However, among HR-negative patients, although TIMP-1 expression did not differ between anthracycline responders and nonresponders (24.6% ± 34.5% vs. 13.2% ±17.8%, respectively, P = 0.407), TOP2A positivity was significantly more frequent among the responders than among the nonresponders (15.4% ± 17.5% vs. 2.0% ± 2.4%, respectively, P = 0.048).
|Table 8: Comparison of the proportions of cancer cells positive for topoisomerase-II alpha and tissue inhibitor of metalloprotease-1 expression between anthracycline responders and nonresponders among patients stratified according to hormone receptor or human epidermal growth factor receptor 2 status|
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Finally, the responders and nonresponders were compared with respect to the proportions of patients in whom B-tub-, TOP2A-, or TIMP-1-positive cells accounted for ≥10%, ≥5%, or ≤20% of all tumors cells, respectively. Although the proportions of patients with ≥5% TOP2A- or ≤20% TIMP-1-positive cells did not differ between responders and nonresponders [TOP2A, 46.4% vs. 18.2%, P = 0.123; TIMP-1, 80.0% vs. 67.8%, P = 0.365, [Table 9], responders included a significantly higher proportions of patients with ≥10% B-tub positivity as compared with nonresponders (72.4% vs. 37.5%, respectively, P = 0.023). Notably, the proportion of patients with either ≥5% TOP2A or ≤20% TIMP-1 positivity was higher among responders than among nonresponders, whereas this difference was not statistically significant (86.7% vs. 61.5%, respectively, P = 0.066).
|Table 9: Proportions of patients with target molecule expressions between responders and nonresponders|
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| > Discussion|| |
The biological characteristics and genetic heterogeneity associated with breast cancer have been reported to influence variations in tumor progression, responses to treatment, and patient prognosis. Recent systems have allowed the classification of breast cancers into several subtypes, according to hormone sensitivity, HER2 status, and proliferation ability, in an attempt to gain a better understanding of clinical behaviors. Since each breast cancer subtype exhibits particular clinical behaviors, specific treatment strategies must be developed for each.
In this study, we aimed to determine whether the expression of key molecules that serve as targets of chemotherapeutic agents or are closely involved in tumor sensitivity to these agents, such as B-tub, TOP2A, and TIMP-1, could predict clinical responses to treatment in 70 tumors from 68 patients who had locally advanced, metastatic, or recurrent breast cancer and were treated with anthracycline or taxane. We selected an immunohistochemical method that could be completed in 2 days because the ability to rapidly predict responses to chemotherapy is crucial to the development of a novel strategy for predicting treatment efficacy.
We observed higher than expected overall anthracycline and taxane response rates of 70.5% and 67.2%, respectively [Table 2]; these high rates were attributed to the fact that either agent was administered to most of the patients as either the first or second of chemotherapy (data not shown). When we assessed tumor responses to these agents according to the subtype, we noted a low response rate for TN cancer as compared to that for other types of cancer [Table 3]. However, the response rates did not significantly differ among the groups (data not shown). Our data suggest that these chemotherapeutic agents exhibited strong activity against breast cancer when used at an early stage of treatment regardless of subtype.
Regarding the tumor expression of the three molecules of interest, chemotherapy responders and nonresponders did not differ with respect to the proportions of cancer cells positive for B-tub, TOP2A, and TIMP-1 expressions [Table 4]. In further analysis of tumor responses or molecular expression according to the HR or HER2 status, we found that, although chemotherapeutic responses did not differ according to HR or HER2 status, TOP2A expression was significantly higher among anthracycline responders than among nonresponders with HR-negative tumors [Table 8]. These data were compatible with the findings of previous reports.,, However, TOP2A expression did not differ between the anthracycline responders and nonresponders in the HR-positive group, and TIMP-1 expression did not differ regardless of HR status. Therefore, another biomarker may indicate sensitivity to anthracycline in HR-positive breast cancers.
Although the proportion of cancer cells expressing TIMP-1 was significantly lower in patients with HER2-overexpressing tumors than in patients with HER2-normal tumors, tumor responses to anthracycline did not differ by HER2 status and were not found to be associated with intratumoral TIMP-1 expression [Table 4] and [Table 6]. However, as shown in [Table 9], the combined TOP2A and TIMP-1 status, indicating high TOP2A/low TIMP-1 expression, was expected to be useful for predicting tumor responses to anthracycline. Similarly, neither taxane efficacy nor B-tub expression appeared to be affected by the HR or HER2 status in this study [Table 7]. However, the overall proportion of patients with a proportion of B-tub-positive cells ≥ 10% was significantly higher among taxane responders than among nonresponders [Table 9]. These data contradicted an earlier report by Huang et al. in which patients expressing high tumor levels of B-tub exhibited resistance to taxane. This discrepancy may be attributed to the fact that the earlier study investigated lung cancer responses to taxane in combination with carboplatin.
| > Conclusion|| |
Immunohistochemical analysis of TOP2A, TIMP-1, and B-tub may yield biomarkers predictive of responses to chemotherapy for breast cancer. Overall, these biomarkers are expected to become available for clinical predictions of anthracycline and taxane efficacy. However, a prospective study involving a large number of patients is needed to confirm the correlation between tumor responses and molecular expression.
Financial support and sponsorship
This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (Nos. 10671249, 13671380, 14571262, and 15591340).
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Yamashita H, Iwase H, Toyama T, Takahashi S, Sugiura H, Yoshimoto N, et al.
Estrogen receptor-positive breast cancer in Japanese women: Trends in incidence, characteristics, and prognosis. Ann Oncol 2011;22:1318-25.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.
Freedman LS, Edwards DN, McConnell EM, Downham DY. Histological grade and other prognostic factors in relation to survival of patients with breast cancer. Br J Cancer 1979;40:44-55.
Hertel PB, Tu D, Ejlertsen B, Jensen MB, Balslev E, Jiang S, et al.
TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients. Breast Cancer Res Treat 2012;132:225-34.
Ejlertsen B, Jensen MB, Nielsen KV, Balslev E, Rasmussen BB, Willemoe GL, et al.
HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients. J Clin Oncol 2010;28:984-90.
Zhu D, Zha X, Hu M, Tao A, Zhou H, Zhou X, et al.
High expression of TIMP-1 in human breast cancer tissues is a predictive of resistance to paclitaxel-based chemotherapy. Med Oncol 2012;29:3207-15.
Munro AF, Bartels A, Balslev E, Twelves CJ, Cameron DA, Brünner N, et al.
Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial? Breast Cancer Res 2013;15:R31.
Willemoe GL, Hertel PB, Bartels A, Jensen MB, Balslev E, Rasmussen BB, et al.
Lack of TIMP-1 tumour cell immunoreactivity predicts effect of adjuvant anthracycline-based chemotherapy in patients (n=647) with primary breast cancer. A Danish Breast Cancer Cooperative Group Study. Eur J Cancer 2009;45:2528-36.
Dechaphunkul A, Phukaoloun M, Kanjanapradit K, Graham K, Ghosh S, Santos C, et al.
Prognostic significance of tissue inhibitor of metalloproteinase-1 in breast cancer. Int J Breast Cancer 2012;2012:290854.
Neri A, Megha T, Bettarini F, Tacchini D, Mastrogiulio MG, Marrelli D, et al.
Is tissue inhibitor of metalloproteinase-1 a new prognosticator for breast cancer? An analysis of 266 cases. Hum Pathol 2012;43:1184-91.
Kuvaja P, Hulkkonen S, Pasanen I, Soini Y, Lehtonen S, Talvensaari-Mattila A, et al.
Tumor tissue inhibitor of metalloproteinases-1 (TIMP-1) in hormone-independent breast cancer might originate in stromal cells, and improves stratification of prognosis together with nodal status. Exp Cell Res 2012;318:1094-103.
Jørgensen CL, Bjerre C, Ejlertsen B, Bjerre KD, Balslev E, Bartels A, et al.
TIMP-1 and responsiveness to gemcitabine in advanced breast cancer; results from a randomized phase III trial from the Danish breast cancer cooperative group. BMC Cancer 2014;14:360.
Schrohl AS, Look MP, Meijer-van Gelder ME, Foekens JA, Brünner N. Tumor tissue levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and outcome following adjuvant chemotherapy in premenopausal lymph node-positive breast cancer patients: A retrospective study. BMC Cancer 2009;9:322.
Würtz SO, Schrohl AS, Mouridsen H, Brünner N. TIMP-1 as a tumor marker in breast cancer – An update. Acta Oncol 2008;47:580-90.
Di Leo A, Desmedt C, Bartlett JM, Piette F, Ejlertsen B, Pritchard KI, et al.
HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: A meta-analysis of individual patient data. Lancet Oncol 2011;12:1134-42.
O'Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Bramwell VH, et al.
Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 2009;101:644-50.
Sorensen IV, Fenger C, Winther H, Foged NT, Lademann U, Brünner N, et al.
Characterization of anti-TIMP-1 monoclonal antibodies for immunohistochemical localization in formalin-fixed, paraffin-embedded tissue. J Histochem Cytochem 2006;54:1075-86.
Elashoff RM, Lee JJ, Afifi AA. A note on confidence limits for quartiles with right censored data. Stat Med 1989;8:1269-76.
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ; Panel Members. Strategies for subtypes – Dealing with the diversity of breast cancer: Highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011;22:1736-47.
Nikolényi A, Sükösd F, Kaizer L, Csörgo E, Vörös A, Uhercsák G, et al.
Tumor topoisomerase II alpha status and response to anthracycline-based neoadjuvant chemotherapy in breast cancer. Oncology 2011;80:269-77.
Susini T, Berti B, Carriero C, Tavella K, Nori J, Vanzi E, et al.
Topoisomerase II alpha and TLE3 as predictive markers of response to anthracycline and taxane-containing regimens for neoadjuvant chemotherapy in breast cancer. Onco Targets Ther 2014;7:2111-20.
Wang J, Xu B, Yuan P, Zhang P, Li Q, Ma F, et al.
TOP2A amplification in breast cancer is a predictive marker of anthracycline-based neoadjuvant chemotherapy efficacy. Breast Cancer Res Treat 2012;135:531-7.
Huang CL, Kadota K, Liu D, Ueno M, Nakasima N, Ishikawa S, et al.
Expression of ERCC1 and class III ß-tubulin is associated with the survival of resected stage III non-small cell lung cancer patients treated with induction chemoradiotherapy using carboplatin-taxane. Exp Ther Med 2010;1:445-51.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]