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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 2  |  Page : 409-415

Candidate biomarkers predictive of anthracycline and taxane efficacy against breast cancer


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 Publication8-Mar-2018

Correspondence Address:
Keiichi Kontani
Department of Thoracic, Breast and Endocrine Surgery, Kagawa University Faculty of Medicine, Kita-gun
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1053_16

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 > Abstract 


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 2019 Nov 12];14:409-15. Available from: http://www.cancerjournal.net/text.asp?2018/14/2/409/214512




 > Introduction Top


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.[1],[2] 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.[3] 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.[4],[5],[6],[7],[8] 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.[9],[10],[11],[12] Regarding chemotherapy responsiveness, patients with TIMP-1-negative tumors have been reported to respond favorably to epirubicin.[8],[13] whereas those with high TIPM-1 expression levels exhibited resistance to paclitaxel-based regimens.[6] 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.[7] 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.[4],[5],[8],[14],[15],[16] 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 Top


Patients

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.

Immunohistochemical study

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.[17] 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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Statistical analysis

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.[18] 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 Top


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.
Table 1: Characteristics of patients and tumors

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Treatment efficacy

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 2: Overall response to anticancer agents

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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 Top


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,[19] 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.[20],[21],[22] 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.[23] This discrepancy may be attributed to the fact that the earlier study investigated lung cancer responses to taxane in combination with carboplatin.


 > Conclusion Top


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 Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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