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  Table of Contents  
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 582-586

The outcome effect of double-hormonal therapy in premenopausal breast cancer patients with high nodal-status: Result of a prospective randomized trial

1 Department of General Surgery, Turkish Ministry of Health Izmir Bozyaka Research and Training Hospital, Izmir, Turkey
2 Department of Pathology, Turkish Ministry of Health Izmir Bozyaka Research and Training Hospital, Izmir, Turkey
3 General Surgery, Turkish Ministry of Health Izmir Tepecik Research and Training Hospital, Izmir, Turkey

Date of Web Publication1-Feb-2016

Correspondence Address:
B Zengel
Department of General Surgery, Turkish Ministry of Health Izmir Bozyaka Research and Training Hospital, Izmir
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.175301

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 » Abstract 

Purpose: The combination of taxanes and anthracyclines has proven efficacy in node-positive (N+) premenopausal primary breast cancer patients. Ovarian ablation is also associated with better survival outcomes in premenopausal hormone-receptor positive (HR+) patients. Therefore, this trial aims to determine the superiority of combined hormonal treatment of ovarian ablation with tamoxifen (TMX) versus TMX alone, in premenopausal N+, HR + patients receiving adjuvant chemotherapy (AC) with taxane and anthracycline. Materials And Methods: Premenopausal women who had surgically removed breast cancer with histologically confirmed N + and HR+ were included in the trial. The AC consisted of six cycles of taxotere, adriamycin, cytoxan or taxotere, epirubicin and cytoxan with the completion of radiation therapy. Patients were randomly assigned to receive TMX 20 mg/day for 5 years or up to menopause or TMX 20 mg/day for 5 years plus goserelin (GOS) 3.6 mg injection per month for 2 years. The primary end point was disease-free survival (DFS). Results: Between 2003 and 2011, 101 consecutive patients were allocated to TMX (51 patients) and TMX/GOS (50 patients) groups. The mean follow-up period was 52.4 ± 2.8 months. DFS was 43.0 ± 3.6 months versus 49.9 ± 4.22 months (P = 0.13) and overall survival was 51.1 ± 3.8 months versus 53.1 ± 4.2 months (P = 0.50) in the TMX and TMX/GOS groups, respectively. The results showed 9% absolute risk reduction with respect to DFS in favor of the TMX/GOS group.Conclusion: This study group was comprised of stage II and III disease patients with high nodal status. The TMX/GOS combination reduced absolute risk of developing first locoregional or distant relapse by almost 9%. Longer follow-up is required to justify this protocol for routine use.

Keywords: Breast cancer, goserelin, hormonal therapy, tamoxifen

How to cite this article:
Uslu A, Zengel B, Akpinar G, Postaci H, Yetis H, Corumlu B, Kebapci E, Aykas A. The outcome effect of double-hormonal therapy in premenopausal breast cancer patients with high nodal-status: Result of a prospective randomized trial. Indian J Cancer 2014;51:582-6

How to cite this URL:
Uslu A, Zengel B, Akpinar G, Postaci H, Yetis H, Corumlu B, Kebapci E, Aykas A. The outcome effect of double-hormonal therapy in premenopausal breast cancer patients with high nodal-status: Result of a prospective randomized trial. Indian J Cancer [serial online] 2014 [cited 2021 Jul 24];51:582-6. Available from: https://www.indianjcancer.com/text.asp?2014/51/4/582/175301

 » Introduction Top

The patterns of adjuvant therapy for breast cancer have changed dramatically during the last two decades. The first change saw cyclophosphamide, methotrexate and 5-fluorouracil (CMF), the so-called "Milan protocol" gradually vanish from routine practice as the superiority of both standard and escalated doses of anthracycline-based polychemotherapy over CMF was demonstrated in 5 years survival outcomes.[1],[2] From early 2000, the standard adjuvant chemotherapy (AC) protocol in node-positive (N +) primary breast cancer (PBC) patients, consisted of four cycles of anthracycline (A) plus cyclophosphamide (C) followed by four cycles of paclitaxel (T) at 3 weeks intervals. Two pivotal studies disclosed a potential benefit of additional paclitaxel (T) to conventional cyclophosphamide (C) (600 mg/m 2) plus doxorubicin (A) (60, 75, 90 mg/m 2) with regard to disease-free survival (DFS) and observed reduction in hazard ratio (HR) ranging from 17% to 28% in that triple chemotherapy group.[3],[4] There is now compelling evidence to induce amenorrhea (preferably reversible ovarian function suppression [OFS]) for better prognosis in premenopausal women with hormone-receptor positive (HR +) PBC. Current chemotherapy protocols have the potential to induce temporary amenorrhea. The prevalence of amenorrhea ranged between 10% and 48% in premenopausal women aged <40 years following the administration of CMF, cytoxan, adriamycin, 5-fluorouracil (CAF), cytoxan, epirubicin, 5-fluorouracil (CEF) or AC regimens.[5] Further improvement was observed in women with (N +) cancer on the National Surgical Adjuvant Breast and Bowel Project NSABP B-30 trial, in which amenorrhea occurred in 58% and 70% of the premenopausal patients receiving taxotere, adriamycin, cytoxan (TAC) and AC followed by (T) regimens, respectively.[6] These results indicate that polychemotherapy alone is insufficient for inducing menopause and are convincing enough to designate a protocol including single or double hormonal therapy using tamoxifen (TMX) (with or without medical ovarian ablation) in combination with a current polychemotherapy regimen for premenopausal (N +) and (HR +) PBC patients.

Mainstay of the protocol

The primary objective of this trial is to determine the superiority of combined hormonal therapy to TMX alone, in premenopausal (N +) and (HR +) patients receiving AC of proven efficacy. The primary end point was DFS, which was defined as the period of time from allocation to the occurrence of relapse either locally, in the contralateral breast or in a remote organ. Parallel-group method was used for randomization in which participants were arbitrarily allocated to receive the antracycline plus taxane combination followed by TMX for 5 years or TMX with the same schedule, plus goserelin (GOS) for 24 months. Endocrine treatment started after completion of AC.

None of the investigators in this study participated in the assignment procedure. The allocation and randomization was performed by a third party and the participants did not obtain any information about the type of hormonal intervention until it was begun.

 » Materials and Methods Top

Premenopausal women with histologically confirmed primary infiltrating ductal (IDC), infiltrating lobular (ILC) or mixed carcinoma (IDC + ILC) of the breast with positive axillary lymph nodes and hormone receptor status (estrogen receptor positive [ER +], progesterone receptor positive [PR +], or both +) were included. Patients who had undergone surgery with R0 resection and had at least 10 lymph nodes evaluated, were screened for the clinical trial. Exclusion criteria included previous oophorectomy; a history of malignancy in any other organ; presence of bilateral or node-negative breast cancer; documented history of recent cardiac ejection fraction rate <50%, which might preclude the use of taxanes and anthracyclines; impaired renal function (clearance of serum creatinine (SCr) <40 ml/min/m 2) and history of neoadjuvant chemoradiotherapy for the present breast tumor.

ER and/or PR content of the tumor were quantitatively measured by immunohistochemistry. Values ≥10% were considered as positive and eligible for recruitment into the study.

The National Health Service (SGK) of Turkey granted approval for trastuzumab (Herceptin) in 2003 for the treatment of patients with metastatic breast cancer and revised this prior approval in 2009 for the use of trastuzumab in an adjuvant setting. However, irrespective of human epidermal growth factor receptor 2 status, both patients who were accrued from 2003 to 2009 or from 2009 until 2011 were not treated with trastuzumab in this study.

The randomized patients unexceptionally received luteinizing hormone-releasing hormone (LHRH) analog, GOS for medical ovarian ablation. The options of AC consisted of TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) or taxotere, epirubicin and cytoxan (TEC) (docetaxel 75 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 500 mg/m2) administered in 3 weeks intervals for six cycles. G-CSF support was given for 5 consecutive days during the administration of TAC/TEC.

Following the completion of chemotherapy cycles, patients were randomly assigned to receive TMX 20 mg/day for 5 years or up to menopause or TMX 20 mg/day and for 5 years plus GOS 3.6 mg injection per month for 2 years. The minimum duration of endocrine therapy was determined as 5 years. Those who promoted to menopausal state during TMX-only therapy were switched to anastrozole or letrozole to complete the remaining ablation period. Menopausal status was defined as the cessation of cycles at least for 6 months with relevant luteinizing hormone and estradiol levels measured in the last 2 consecutive months.

Irrespective of pathological subgroups, all patients received adjuvant radiotherapy except two patients who had prolonged chemotherapy-induced side-effects.

The sequence of treatment protocol was AC followed by adjuvant radiotherapy and single or double hormonotherapy for both groups.

The study protocol was approved by the Ethics Committee of the Turkish Ministry of Health İzmir Teaching and Research Hospital. All patients received information about safety-efficacy and side-effect profile of AC and signed written informed consent. All authors have no conflicts of interest in this study.

Statistical analysis

We assumed to obtain 10% absolute difference in the DFS rate at 5 years between the two groups. In order to achieve this goal, we have targeted to recruit 190 patients (95 patients for each group) with 90% statistical power and 5% alpha error level. As the number of participants of each group was equally distributed at all periods of the study, we used paired samples t-test to evaluate the difference in means. For detecting group differences using frequency data, we used 2-by-2 table analysis and calculated Chi-square test with Yates' correction. P values less than 0.05 was considered as significant. Kaplan-Meier survival curves were drawn to describe the survival characteristics. In addition, absolute risk reduction (ARR) values with respect to DFS and overall survival (OS) were derived from 2-by-2 table analysis. All statistical analyses were two-sided and performed using SPSS version 15.0 (SPSS, Chicago, IL, USA).

 » Results Top

Between April 2003 and January 2011, 101 consecutive patients were allocated to the TMX (51 pts.) and TMX/GOS (50 pts.) groups. Because of both the slow accrual of patients and our observation of a higher frequency of local relapse and remote organ metastasis in the TMX group, we decided to report a final analysis.

The demographic data, histopathological features and stages of the patients were well balanced. The only significant differences were the younger age of the patients in the TMX/GOS group [Table 1].
Table 1: Demographic and histopathological data of the groups

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The mean follow-up was 52.4 ± 2.8 months (mo). After randomization, no patient was lost to follow-up or excluded due to severe side-effects of treatment or non-compliance. No death unrelated to breast cancer has been observed. Furthermore, none of the patients required cardiac intervention during TAC/TEC treatment.

A total of 13 patients in the TMX group presented with distant metastasis between 11 and 84 months after mastectomy. Among these, there were three liver, three multiple osseous and one patient each with pleural, cerebral, isolated bony, pulmonary, pleural + pulmonary, liver + bone and liver + pulmonary + bone metastases. During treatment, a total of 7 patients were died in this group. The pathological stage was 3C in five patients and 3A and 2B in one patient each. Six patients are already receiving second or third-line chemotherapy and/or endocrine treatment for systemic disease.

As a DFS event, locoregional failure was only observed in two patients (one ipsilateral and one contralateral axillary lymph node metastasis) and distant metastasis occurred in six patients in the TMX/GOS group. There were two liver, three multiple osseous and one pulmonary metastasis. Three patients in this group died during treatment. The pathological stage was 3C in one and 3A in two patients. One patient with solitary bone metastasis and another with biopsy proven solitary liver metastasis demonstrated complete response to radiotherapy + aromatase inhibitor and second line chemotherapy and are alive with no evidence of metastasis at 6 and 56 months after treatment, respectively. The last patient with multiple liver metastasis is already receiving second line chemotherapy and alive with stable disease at 24 months following treatment.

DFS was 43.0 ± 3.6 month versus 49.9 ± 4.2 month (P = 0.13) and OS was 51.1 ± 3.8 month versus 53.1 ± 4.2 month (P = 0.5) in the TMX and TMX/GOS groups, respectively. Thirteen of the 51 patients in the TMX and 8 of the 50 patents in the TMX/GOS group demonstrated local or distant failure (P = 0.35). There was a 9.5% ARR (95% confidence interval [CI]: 8.1-24.6) for DFS in favour of the TMX/GOS group. Comparison of Kaplan-Meier survival curves, with regard to DFS, revealed HR = 0.55 for the TMX/GOS group with a P = 0.23 [Figure 1]. In order to prevent treatment bias in TMX-only patients who were switched to anastrozole or letrozole after menopause, we restricted the analysis of TAM versus TAM + GOS only to patients who received TAM alone without switching to an aromatase inhibitor. After excluding seven patients who received an aromatase inhibitor in the TAM-only group, we calculated DFS of TAM versus TAM + GOS patients with Wilcoxon two-sample test. There was no statistically significant difference between the two groups (P = 0.21). There was no difference in the OS curves of both groups reflected by a HR = 0.93 [Figure 2]. Although the risk of developing first locoregional or distant relapse was reduced by nearly 45% in the TMX/GOS group (95% CI: 0.24-1.41), this has not yet reached statistical significance.
Figure 1: Kaplan-Meier disease-free survival curves of Group I tamoxifen (TMX) and Group II (TMX/goserelin)

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Figure 2: Kaplan-Meier overall survival curves of Group I tamoxifen (TMX) and Group II (TMX/goserelin)

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Finally; with a mean follow-up of 57 months, the DFS and OS rates in the TMX and TMX/GOS groups were 76% versus 86% and 83% versus 93%, respectively.

 » Discussion Top

The choice of AC for treatment of (N +) (PBC) patients is of prime importance to both medical and surgical oncologists. A meta-analysis in 2005 revealed the efficacy of 6-8 courses of anthracycline-based triple chemotherapy in this group, demonstrating a 38% decrease in cancer-related deaths in women younger than 50 years of age.[2] The emergence of taxanes and AC with anthracycline plus taxane drugs provided better survival outcomes in (N +) premenopausal women with (PBC).[7] The Breast Cancer International Research Group (BCIRG) 001 trial compared TAC with 5-fluorouracil, adriamycin, cytoxan (FAC) in (N +) premenopausal patients and reported significant improvement both in DFS (HR = 0.72, P = 0.001) and OS (HR = 0.70, P = 0.008), regardless of hormone-receptor status. The major difference between our study and BCIRG 001, is the lower percentage of patients with ≥4 pathologically involved lymph nodes (30% in both groups), which indicates lower nodal status in the BCIRG 001 trial.[8] There is clear evidence that chemotherapy alone is insufficient to induce amenorrhea in premenopausal women with ER(+) tumors, which mandates additional use of TMX with or without LHRH analogue.[9] This concept has been reinforced by the results of the ZEBRA trial; in which GOS successfully induced amenorrhea in more than 95% of the premenopausal patients with N + breast cancer, was non-inferior to CMF for OS and displayed equivalence to CMF for DFS.[10] As it is stated later in the literature,[5] during the initiation of our clinical trial, there was no forthcoming data evaluating the composite effect of anthracycline + taxane chemotherapy with TMX ± medical ovarian ablation in premenopausal (N +) and (HR +) patients. In our study, almost 60% of the patients had stage III disease with the number of pathologically involved lymph nodes were average seven, indicating higher nodal status (high-risk) breast cancer in both groups. Therefore, the principle treatment regimen had to be systemic chemotherapy followed by single or double hormonal ablation. In a similarly designed study, CAF alone was compared with CAF + GOS versus CAF + GOS + TMX in premenopausal (N +), (HR +) patients. With a median follow-up of 9 years, the addition of TMX to CAF + GOS resulted in a significant DFS advantage reflected by 57% versus 60% versus 68% in the three groups, respectively.[11] Three different clinical trials investigated the additional benefit of systemic chemotherapy added to OFS/ablation and 5 years of TMX in premenopausal (N +) and (HR +) patients. The first one is the Premenopausal Endocrine Responsive Chemotherapy trial in 2003, which was prematurely closed within 3 years due to accrual of only 29 patients.[12] The second one was International Breast Cancer Study Group (IBCSG) trial 11-93, which was launched in 1993 and suspended because of the low accrual reflected by the enrollment of less than 25% of the targeted patient population. In this study, the sequence of treatment was optimal hormonal blockade (defined as ovarian ablation and TMX) followed by four cycles of AC chemotherapy. There was no difference between the two randomized groups (optimal hormonal blockade versus optimal hormonal blockade followed by AC chemotherapy) for DFS and OS. However, the IBCSG trial 11-93 was comprised of low-risk endocrine responsive PBC patients with 97% having 1-3 positive nodes and 55% with only one positive node. In addition, 88% of the patients had both ER and PR positivity. These histopathologic features represent low-risk of recurrence and eliminating chemotherapy in one arm may not potentially cause a detrimental effect.[13] In TEXT (IBCSG 25-02), premenopausal women with endocrine-responsive early breast cancer were randomly assigned to receive OFS plus either TMX (20 mg/day) or exemestane (25 mg/day) for 5 years. The use of chemotherapy was determined according to center's choice. Thus, chemotherapy was administered in 88% of patients with N + disease compared with 46% with N-disease. This clearly indicates that the majority of cancer centers prefer giving chemotherapy to N + premenopausal early breast cancer patients even if they are having endocrine-responsive tumors.[14]

In our study, the majority of patients (>66%) had stage III disease, was susceptible to local or distant failure and required a proper sequence of treatment beginning with systemic chemotherapy followed by hormonal ablation. The estimated relative risk of the occurrence of a first event in the TMX group was approximately twice as high as that of the TMX-GOS group over a 5 years follow-up period. Therefore, we feel justified in hoping that, with longer follow-up, this moderate improvement in terms of DFS might translate into a statistically significant survival outcome. All patients in this study received adjuvant radiotherapy irrespective of pathological subgroups. The benefit of this adjuvant practice was verified later in the 2005 Early Breast Cancer Trialists' Collaborative Group update, which indicated that radiation therapy was beneficial, regardless of the number of lymph nodes involved and in National Cancer Institute Breast Cancer Treatment Guideline 2013, which adjuvant radiation therapy postmastectomy is recommended in axillary N + tumors with more than four nodes or extranodal involvement.[15]

 » References Top

Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National cancer ınstitute of Canada clinical trials group. J Clin Oncol 1998;16:2651-8.  Back to cited text no. 1
Trudeau M, Charbonneau F, Gelmon K, Laing K, Latreille J, Mackey J, et al. Selection of adjuvant chemotherapy for treatment of node-positive breast cancer. Lancet Oncol 2005;6:886-98.  Back to cited text no. 2
Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976-83.  Back to cited text no. 3
Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol 2005;23:3686-96.  Back to cited text no. 4
Jonat W, Pritchard KI, Sainsbury R, Klijn JG. Trends in endocrine therapy and chemotherapy for early breast cancer: A focus on the premenopausal patient. J Cancer Res Clin Oncol 2006;132:275-86.  Back to cited text no. 5
Ganz PA, Land SR, Geyer CE Jr, Cecchini RS, Costantino JP, Pajon ER, et al. Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. J Clin Oncol 2011;29:1110-6.  Back to cited text no. 6
Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer:First report of ıntergroup trial C9741/cancer and leukemia group B trial 9741. J Clin Oncol 2003;21:1431-9.  Back to cited text no. 7
Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302-13.  Back to cited text no. 8
Aebi S, Gelber S, Castiglione-Gertsch M, Gelber RD, Collins J, Thürlimann B, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000;355:1869-74.  Back to cited text no. 9
Kaufmann M, Jonat W, Blamey R, Cuzick J, Namer M, Fogelman I, et al. Survival analyses from the ZEBRA study. goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer. Eur J Cancer 2003;39:1711-7.  Back to cited text no. 10
Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, et al. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol 2005;23:5973-82.  Back to cited text no. 11
Price KN, Goldhirsch A. International breast cancer study group. Clinical trial update: International breast cancer study group. Breast Cancer Res 2005;7:252-4.  Back to cited text no. 12
Thürlimann B, Price KN, Gelber RD, Holmberg SB, Crivellari D, Colleoni M, et al. Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of international breast cancer study group trial 11-93. Breast Cancer Res Treat 2009;113:137-44.  Back to cited text no. 13
Regan MM, Pagani O, Walley B, Torrisi R, Perez EA, Francis P, et al. Premenopausal endocrine-responsive early breast cancer: Who receives chemotherapy? Ann Oncol 2008;19:1231-41.  Back to cited text no. 14
Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087-106.  Back to cited text no. 15


  [Figure 1], [Figure 2]

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