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Goserelin plus tamoxifen compared to chemotherapy followed by tamoxifen in premenopausal patients with early stage-, lymph node-negative breast cancer of luminal A subtype
The Breast 30 (2016) 111e117
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Original article
Goserelin plus tamoxifen compared to chemotherapy followed by tamoxifen in premenopausal patients with early stage-, lymph node-negative breast cancer of luminal A subtype Mansoor Alramadhan 1, Jai Min Ryu 1, Musaed Rayzah, Seok Jin Nam, Seok Won Kim, Jonghan Yu, Se Kyung Lee, Soo Youn Bae, Sungmin Park, Hyun-June Paik, Jeong Eon Lee* Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 May 2016 Received in revised form 2 August 2016 Accepted 18 August 2016
Objectives: To study the outcomes of adjuvant goserelin combined with tamoxifen (GosTam) compared to chemotherapy followed by tamoxifen (ChemTam) in premenopausal patients with early stage, luminal A breast cancer. Methods: From 2008 until 2013, data were retrospectively collected for premenopausal patients who underwent surgery for invasive tumors that were 2.0 cm, node-negative, strongly positive for estrogen and progesterone receptors, HER-2-negative, and Ki-67 < 25%. The patients were divided into two groups according to adjuvant regimen, either GosTam or ChemTam. All patients who underwent different adjuvant regimens were excluded. Results: In total, 235 patients underwent GosTam and 171 patients underwent ChemTam. There were significantly more patients younger than 40 years in the GosTam group (32% GosTam vs. 22% ChemTam, p ¼ 0.031). Mean tumor size was significantly smaller (1.19 cm vs. 1.48 cm, p < 0.001), Ki-67 significantly lower (p ¼ 0.049), and nuclear grade was low in a significant number of patients in the GosTam group (2% vs. 13%, p < 0.001). After a median follow-up of 51.3 months, there was no mortality in either group. There was no significant difference in 5-year disease-free survival (DFS) between the two groups even after univariate analysis considering age, tumor size, nuclear grade, and P53% (GosTam ¼ 98.9% vs. ChemTam ¼ 95.7%, HR ¼ 0.404, 95% CI ¼ [0.073, 2.222], p ¼ 0.248). Conclusion: There was no difference between treatment groups, and neither chemotherapy nor ovarian suppression seemed to improve the outcome. Thus, tamoxifen alone might be a sufficient option for this low-risk patient population. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Chemotherapy Goserelin GnRH Tamoxifen
Introduction Breast cancer is one of the most common malignancies in women worldwide [1]. In Korea, the incidence of breast cancer has been increasing, and the patients are younger at diagnosis than typical Western patients. Seventy percent of patients are at an early stage at diagnosis, and more than 70% are hormone receptorpositive (HRþ) [2]. Young age is an independent risk factor of
* Corresponding author. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea. Fax: þ82 2 3410 6982. E-mail address: [email protected] (J.E. Lee). 1 These authors equally contributed to this work. http://dx.doi.org/10.1016/j.breast.2016.08.011 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
poor prognosis; however, adjuvant therapy plays a crucial role in improving patient outcome [3]. Patients with HRþ are considered to be highly responsive to endocrine therapy [4]. Tamoxifen play a crucial role in the management of these patients, and the additive effect of chemotherapy is minimal especially in low-risk patients [5e7]. On the other hand, ovarian function suppression (OFS) has been shown to improve the outcome of high-risk premenopausal patients if combined with tamoxifen, but this improvement was not obvious in a low-risk group [8]. Breast cancer patients with luminal A subtype respond well to endocrine therapy and generally have a good prognosis [3,4]. We hypothesized that, in premenopausal women with early stage, luminal A breast cancer with Ki-67 < 25%, neither chemotherapy
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nor OFS (using LHRH agonist) has an additive effect on the outcome over tamoxifen. Materials and methods This was a retrospective study conducted at Samsung Medical Center. Between January 2008 and December 2013, we consecutively collected and reviewed the medical records of premenopausal patients who underwent surgery for primary breast cancer (either breast-conserving surgery followed by adjuvant radiotherapy or mastectomy) followed by adjuvant treatment with either GosTam or ChemTam. Patients who were included had a tumor size less than or equal to 2 cm with no metastasis to regional lymph nodes or distant metastasis. All patients' tumors were strongly positive for estrogen and progesterone receptors, negative for human epidermal growth factor receptor-2 (HER-2), and had low Ki-67. We defined premenopause as regular menses without exogenous hormones during the prior 6 months and/or estradiol level in the premenopausal range. The pertinent tumor size in this study was final pathological tumor size. Nodal status was determined by sentinel lymph node biopsy in all patients. The sentinel node was identified using radioisotopes, patent blue dye, or a combination of these techniques. All patients underwent work up to rule out distant metastasis. This includes history and physical examination, complete blood count (CBC), liver function test (LFT), alkaline phosphatase (ALP), chest X-ray, abdominal CT scan, and bone scan. These are routine investigations for all patients with breast cancer. We defined a luminal A tumor as one that was estrogen receptor (ER)- and progesterone receptor (PR)-positive, HER-2-negative, and had a low Ki-67, according to the 14th St. Gallen International Breast Cancer Conference [9]. ER and PR were considered to be strongly positive if the Allred score was 7e8þ by immunohistochemistry (IHC). HER-2 was considered to be negative if the score was 0e1þ by IHC. In cases in which the result was equivocal (2þ), further study using silver in situ hybridization (SISH) was performed. If the SISH result was positive, the patient was excluded. We considered Ki-67 to be low if it was less than 25% according to IHC. The histological features of all tumors were reviewed in the hospital's laboratory, and no central review was conducted. All patients were followed-up post-operatively every 6 months for 5 years; each visit included history and physical examination, CBC, LFT, ALP, mammography, and breast ultrasound. Breast ultrasound is routinely performed for all patients because Asian women usually have dense breast tissue, which may obscure some lesions from detection on mammography. One year after surgery, all patients underwent additionally bone scan, chest X-ray, and abdominal CT scan. Abdominal CT scan and bone scan are routinely performed one year post-operatively. All patients with breast cancer are routinely followed in the same way. The primary outcome of our study was 5-year disease-free survival (DFS). The secondary outcome was 5-year overall survival (OS). DFS was defined as the period from surgical management until the date of any incident of local, regional, or distant recurrence, which was radiological or biopsy proven, or breast cancer-related death. Patients who did not have any events were censored at the date of their last outpatient clinic visit. OS was defined as the period from surgical management to the date of death or last outpatient clinic visit. Patient groupings The patient population was divided into two groups according to adjuvant therapy regimen. The first group included patients who underwent GosTam; the second group included patients who
underwent ChemTam. All patients who underwent another adjuvant regimen or those who underwent neoadjuvant therapy were excluded. The goserelin acetate (Zoladex, AstraZeneca Pharma International, UK) dose was 3.78 mg, administered as a subcutaneous injection on the anterior abdominal wall every 28 days for 2 years. The most common chemotherapy regimen (89.4%) was four cycles of AC (cyclophosphamide 600 mg/m2 þ D5W 100 mL mixed intravenous over 1 h, doxorubicin 60 mg/m2 þ D5W 100 mL mixed intravenous over 30 min), and 11.6% of the patients underwent four cycles of FAC (cyclophosphamide 500 mg/m2 þ D5W 100 mL mixed intravenous over 1 h, doxorubicin 50 mg/m2 þ D5W 100 mL mixed intravenous over 30 min, 5-fluorouracil 500 mg/m2 intravenous push). Tamoxifen (20 mg) was administered daily for 5 years to patients in both groups and was administered concurrently to goserelin in the GosTam group and sequentially to chemotherapy in the ChemTam group. The decision to administer adjuvant radiotherapy was made in conjunction with a radio-oncologist. Statistical analysis The Chi-square test and Spearman correlation coefficient were used to compare discrete variables. Student's t-test was used to compare the continuous variables. Survival analysis was performed using the Kaplan-Meier method. All p-values were two-tailed, and a p-value <0.05 was considered statistically significant. All statistical analyses were executed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R3.0.3 (Vienna, Austria; http://www.R-project. org). Results Patient stratification and characteristics A total of 3059 patients were diagnosed between 2008 until 2013 to have a tumor size 2 cm with regional lymph node negative and no distant metastasis (T1N0M0) (Fig. 1). Of these, 72 patients were excluded because they underwent neoadjuvant chemotherapy. All patients who were postmenopausal at the time of diagnosis were excluded (n ¼ 1120). In addition, we excluded all patients with ER or PR receptor negative or HER-2 positive. Patients with weak ER or PR receptor positivity with Allred score 6 or with Ki-67 25% were also excluded (n ¼ 1461). A total of 406 premenopausal patients with T1N0M0 tumors, strong ER and PR positivity with Allred score 7 or 8, HER2 negative, and Ki-67 less than 25% were ultimately included. These patients comprised 171 who underwent ChemTam and 235 who underwent GosTam (Table 1). The patients in the GosTam group tended to be younger than those in the ChemTam group (32% of patients <40 years vs. 22%, p ¼ 0.031). Patients in the ChemTam group tended to have a higher body mass index (BMI; BMI ¼ 23.04 ± 2.94 kg/m2 vs. 21.93 ± 2.58 kg/m2, p < 0.001). Breast-conserving surgery was the most commonly performed surgery, and there was no significant difference between groups with regard to the type of surgery performed (p ¼ 0.931). Tumor characteristics Tumor characteristics are illustrated in Table 1. The histopathological types of the tumors were identical, and invasive ductal carcinoma was the dominant type. Tumor size tended to be smaller in the GosTam group (mean tumor size ¼ 1.19 cm vs. 1.48 cm, p < 0.001). Furthermore, we found that most of the patients in the ChemTam group (81%) had a T1c tumor size >1 cm, compared to 67% in the GosTam group (p ¼ 0.002). Ki-67 tended to be slightly higher in the ChemTam group (ChemTam ¼ 11.7 ± 5.63,
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Fig. 1. Patients' stratification. ER: estrogen receptor, PR: progesterone receptor, HER-2: human epidermal growth factor receptor-2, ChemTam: chemotherapy followed by tamoxifen, GosTam: goserelin combined with tamoxifen.
GosTam ¼ 10.6 ± 5.50, p ¼ 0.045). The number of patients with a high nuclear grade was higher in the ChemTam group (13% ChemTam vs. 2% GosTam, p < 0.001). There were no statistically significant differences between groups with regard to P53 value or histological grade. Recurrence and survival After a median follow-up of 51.3 ± 18.9 months, there was no mortality in either group of patients. There were 8 recurrences (Table 2), six in the ChemTam group and two in the GosTam group; however, there was no statistically significant difference in DFS between groups (GosTam ¼ 98.9% vs. ChemTam ¼ 95.7%, HR ¼ 0.404, 95% CI ¼ [0.073, 2.222], p ¼ 0.248) (Fig. 2). Three patients had distant metastasis to the bone, two of whom were treated with chemotherapy and one with radiotherapy. One patient had liver metastasis and was treated with chemotherapy. Three patients had contralateral breast cancer and were treated with surgery. One patient had recurrence to the axillary lymph nodes and was treated with axillary lymph node dissection followed by chemotherapy. Univariate analysis according to patient age (Fig. 3), BMI, histopathological type, tumor size, nuclear grade, histological grade, and P53 showed no significant effect on DFS (Table 3). Multivariate analysis could not be performed because no factors tested in univariate analysis showed any effect on DFS, and the number of events was too small to be analyzed. Discussion In premenopausal women with breast cancer, more aggressive management is generally needed to treat the aggressive features of
the cancer and prevent recurrence [10]. However, the optimal systemic therapy for these premenopausal women remains controversial [11]. Chemotherapy has been shown to decrease the rate of relapse and death and, overall, is a highly effective adjuvant modality. It has been reported to have superior outcomes in premenopausal women than postmenopausal women [12], The interpretation of this superior outcome is complicated by its endocrine effect in suppressing ovarian function, because of chemotherapy-induced amenorrhea (CIA) [13]. However, in young women with HRþ disease, chemotherapy might not be efficacious, and CIA is uncommon among patients younger than 35 years [11]. For this reason, many earlier trials studied the outcome of inducing amenorrhea by ovarian ablation (surgical, irradiation, or medical) and compared it to the outcome of chemotherapy in HRþ breast cancer, which has been shown to be equivalent in terms of recurrence and survival [14e16]. Therefore, if tamoxifen is prescribed with either chemotherapy or ovarian suppression, it has been shown to offer a better long-term result compared to chemotherapy or ovarian suppression alone in patients with HRþ breast cancer [5,17e20]. To our knowledge, there is no study in the literature comparing the outcomes of chemotherapy followed by tamoxifen versus the combination of ovarian suppression (LHRH) with tamoxifen. We conducted this retrospective study comparing the effect of GosTam to ChemTam as an adjuvant treatment in a premenopausal, lowrisk group of women with early stage breast cancer of the luminal A subtype that had not spread to the lymph nodes. Jakesz R. et al. found better outcomes for the GosTam regimen compared to chemotherapy alone [17]. Also, their multivariate analysis showed that patient age, tumor size, and nuclear grade significantly affected DFS and OS. However, in our study, these factors did not affect DFS.
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Table 1 Patients' and tumors' characteristics. Characteristics Age, year 40 41e55 BMI, kg/m2 Ki-67, % FHx Yes No Bilaterality Unilateral Bilateral OP Mastectomy BCS Histopathology IDC ILC Others Tumor size, cm T-stage T1mic þ T1a þ T1b T1c Multiplicity Yes No NG Low Intermediate High P53 Positive Negative HG Low Intermediate High Follow-up duration, months
ChemTam group (n ¼ 171)
GosTam group (n ¼ 235)
38 (22%) 133 (78%) 23.04 ± 2.94 11.7 ± 5.63
75 (32%) 160 (68%) 21.93 ± 2.58 10.6 ± 5.50
9 (5%) 162 (95%)
23 (10%) 212 (90%)
165 (96%) 6 (4%)
229 (97%) 6 (3%)
26 (15%) 145 (85%)
35 (15%) 200 (85%)
162 (95%) 6 (3%) 3 (2%) 1.48 ± 0.4
217 (92%) 5 (2%) 13 (6%) 1.19 ± 0.43
33 (19%) 137 (81%)
78 (33%) 157 (67%)
52 (30%) 119 (70%)
70 (30%) 165 (70%)
36 (21.1%) 113 (66.1%) 22 (12.9%)
105 (44.7%) 126 (53.6%) 4 (1.7%)
26 (15%) 145 (85%)
28 (12%) 207 (88%)
95 (55.6) 70 (40.9) 6 (3.5) 56.86 ± 18.97
147 (62.6) 81 (34.5) 7 (1.7) 47.31 ± 18.01
p-value 0.031
<0.0001 0.049 0.095
0.575
0.931
0.114
<0.0001 0.002
0.893
<0.0001
0.335
0.370
<0.0001
ChemTam: chemotherapy followed by tamoxifen, GosTam: goserelin combined with tamoxifen, BMI: body mass index, FHx: family history, op: operation type, BCS: breast conserving surgery, IDC: infiltrated ductal carcinoma, ILC: infiltrated lobular carcinoma, NG: nuclear grade, HG: histological grade.
This is most likely because all patients in our study had favorable prognostic factors, and our study involved a relatively short period of follow-up with only a few cases of recurrence. The SOFT trial showed that addition of ovarian suppression to tamoxifen did not improve the outcome compared to tamoxifen alone; however, more than half of the patients in the SOFT trial underwent chemotherapy in addition to hormonal therapy [8]. Sub-analysis of the SOFT trial showed that patients who underwent chemotherapy
followed by tamoxifen had a worse outcome than those who underwent ovarian suppression plus tamoxifen without chemotherapy. Also, in sub-analysis by chemotherapy, the group of patients who underwent chemotherapy showed significant improvement in the outcome if ovarian suppression was added to tamoxifen compared to tamoxifen alone. This benefit was not observed in the group of patients who did not undergo chemotherapy. The explanation for these findings is that in patients who were treated without chemotherapy had favorable clinical and pathological features, and treating this group of patients with tamoxifen alone produced a good outcome and may have shown no value of adding ovarian suppression. This may also explain why we observed equivalent outcomes for both GosTam and ChemTam groups in our study (Fig. 2). It is most likely that treating this lowrisk population with tamoxifen alone is sufficient, and neither chemotherapy nor ovarian suppression is of added value. In a subgroup analysis by age, the SOFT trial showed a slight improvement in the outcomes of ovarian suppression plus tamoxifen compared to those of tamoxifen alone in younger patients [8]. Our study did not indicate a difference with regard to age group, which may indicate that, in patients with favorable clinical and pathological features, age does not affect the outcome (Fig. 3). Amye J. et al. randomized 345 patients with HRþ, tumor size 3 cm, and lymph node negative to either tamoxifen alone or tamoxifen in addition to ovarian suppression. No chemotherapy was administered to either group. They found that if ovarian suppression added to tamoxifen, it increased menopausal symptoms, reduced sexual activity, lowered health-related quality of life, and did not improve DFS or OS in this low-risk population [21]. At the 14th St Gallen International Breast Cancer Conference, most of the experts agreed that patients with luminal A breast cancer are less responsive to chemotherapy. Most of the expert panel agreed that no need to administer chemotherapy for low-risk patients with strongly positive hormone receptors, HER2 negative, small tumor, and 0e3 positive lymph nodes who can be treated safely with endocrine therapy alone, which consists of tamoxifen for 5 years. Also, most of the panel disagreed on administration of chemotherapy based on patient age. The panel agreed to prescribe ovarian suppression for only high-risk premenopausal women with HRþ breast cancer [22]. Furthermore, The American Society of Clinical Oncology (ASCO) guidelines recommend tamoxifen alone for low-risk, stage I patients who have HRþ tumor, who are not warranted to receive chemotherapy [23]. In our study, we treated part of our patient population with goserelin in addition to tamoxifen because, in the inclusion period (2008e2013), the role of adjuvant ovarian suppression in addition to tamoxifen was not yet determined in clinical trials. We used 2-year duration of goserelin treatment rather than the 5 years recommended by ASCO guidelines, because the national insurance company covers it only for 2
Table 2 Clinical characteristics of patients who have disease recurrent. Case ChemTam group 1 38 2 43 3 31 4 47 5 48 6 46 GosTam group 1 43 2 49
Surgery
Recurrence
Tx after recurrence
Recurrence site
RFI (months)
Alive or death
FU duration (months)
BCS BCS BCS BCS BCS BCS
DM CBC DM CBC DM CBC
CTx OP CTx OP CTx OP
Liver Contralateral breast Bone Contralateral breast Bone Contralateral breast
39 38 92 80 57 59
Alive Alive Alive Alive Alive Alive
71 66 92 80 67 59
BCS BCS
DM LR
RTx OP, CTx
Bone Axilla
12 36
Alive Alive
48 49
BCS, breast conserving surgery; CTx, chemotherapy; FU, follow-up; CBC, contralateral breast cancer; DM, distant metastasis; LR, locoregional recurrence; RFI, recurrence free interval; OP, operation; RTx, radiotherapy; Tx, treatment.
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Fig. 2. KaplaneMeier curve of disease free survival of ChemTam vs. GosTam.
Fig. 3. KaplaneMeier curve of disease free survival of ChemTam vs. GosTam after univariate analysis by age <40 years.
years. Although the ASCO guideline recommends a 5-year duration for the use of OFS, there is no alternative data on a comparative period [23]. Our study has both advantages and limitations. First, it had a relatively small sample size that limited the power to draw a definitive conclusion. Second, there was a relatively short follow-up duration, thereby preventing the detection of later recurrences or breast cancer-related deaths; we observed only 8 recurrences and no breast cancer-related deaths (Table 2). Third, goserelin was
administered for 2 years only, different from the recommended period by the guidelines. Finally, this retrospective study had an inherent selection bias. Patients who were treated with chemotherapy tended to be older, have larger tumor sizes, and have tumors with a higher nuclear grade (Table 1). Despite these limitations, this study is of great value. To our knowledge, it is the first report comparing the outcome of LHRH plus tamoxifen to chemotherapy followed by tamoxifen in young patients with nodenegative, early stage, luminal A breast cancer and thus the first to
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Table 3 Factors affecting recurrence according to ChemTam, GosTam groups univariate analysis. Variable Age, year 40 41e55 BMI, kg/m2 Bilaterality Unilateral Bilateral Histopathology IDC ILC Others Tumor size, cm T-stage T1mic þ T1a þ T1b T1c Multiplicity Yes No NG P53 Positive Negative HG
HR
95% CI Lower
95% CI Upper
p value
1.00 2.12 0.96
0.26 0.73
17.60 1.26
0.4869 0.7533
1.00 7.70
0.92
64.17
0.0593 0.3618
1.00 0.00 4.67 1.20
0.00 0.56 0.23
38.91 6.16
0.9937 0.1539 0.8281
1.00 0.92
0.18
4.75
0.9215
1.00 1.00 0.59
0.19 0.16
5.17 2.17
0.9976 0.4237
1.00 1.01 0.56
0.12 0.12
8.41 2.57
0.991 0.4559
BMI: body mass index, FHx: family history, op: operation type, BCS: breast conserving surgery, IDC: infiltrated ductal carcinoma, ILC: infiltrated lobular carcinoma, NG: nuclear grade, HG: histological grade.
show equivalent results of the treatment modalities. This may confirm the finding in clinical trials in which patients with low-risk luminal A breast cancer may not benefit from either chemotherapy or OFS and can be treated safely with tamoxifen alone with good disease control in order to avoid the side effects of OFS and chemotherapy. In conclusion, in our patient population with low risk of recurrence, there was no difference between treatment groups, and we found neither chemotherapy nor ovarian suppression to improve the outcome. Thus, tamoxifen alone might be a good option for such low-risk patients. Ethical approval The need for informed consent was waived because of the low risk posed by this investigation. This study adhered to the ethical tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Samsung Medical Center in Seoul, Korea (IRB number: 2015-12-121-001). Conflict of interest statement The authors declare that they have no conflict of interest in this manuscript, including financial, consultant, institutional, or other relationships that might lead to bias. Acknowledgements Part of this work was presented as a poster presentation at the 2016 Global Breast Cancer Conference and at the 12th Asian Oncology Summit. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01057585) and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418).
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Original article
Goserelin plus tamoxifen compared to chemotherapy followed by tamoxifen in premenopausal patients with early stage-, lymph node-negative breast cancer of luminal A subtype Mansoor Alramadhan 1, Jai Min Ryu 1, Musaed Rayzah, Seok Jin Nam, Seok Won Kim, Jonghan Yu, Se Kyung Lee, Soo Youn Bae, Sungmin Park, Hyun-June Paik, Jeong Eon Lee* Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 May 2016 Received in revised form 2 August 2016 Accepted 18 August 2016
Objectives: To study the outcomes of adjuvant goserelin combined with tamoxifen (GosTam) compared to chemotherapy followed by tamoxifen (ChemTam) in premenopausal patients with early stage, luminal A breast cancer. Methods: From 2008 until 2013, data were retrospectively collected for premenopausal patients who underwent surgery for invasive tumors that were 2.0 cm, node-negative, strongly positive for estrogen and progesterone receptors, HER-2-negative, and Ki-67 < 25%. The patients were divided into two groups according to adjuvant regimen, either GosTam or ChemTam. All patients who underwent different adjuvant regimens were excluded. Results: In total, 235 patients underwent GosTam and 171 patients underwent ChemTam. There were significantly more patients younger than 40 years in the GosTam group (32% GosTam vs. 22% ChemTam, p ¼ 0.031). Mean tumor size was significantly smaller (1.19 cm vs. 1.48 cm, p < 0.001), Ki-67 significantly lower (p ¼ 0.049), and nuclear grade was low in a significant number of patients in the GosTam group (2% vs. 13%, p < 0.001). After a median follow-up of 51.3 months, there was no mortality in either group. There was no significant difference in 5-year disease-free survival (DFS) between the two groups even after univariate analysis considering age, tumor size, nuclear grade, and P53% (GosTam ¼ 98.9% vs. ChemTam ¼ 95.7%, HR ¼ 0.404, 95% CI ¼ [0.073, 2.222], p ¼ 0.248). Conclusion: There was no difference between treatment groups, and neither chemotherapy nor ovarian suppression seemed to improve the outcome. Thus, tamoxifen alone might be a sufficient option for this low-risk patient population. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Chemotherapy Goserelin GnRH Tamoxifen
Introduction Breast cancer is one of the most common malignancies in women worldwide [1]. In Korea, the incidence of breast cancer has been increasing, and the patients are younger at diagnosis than typical Western patients. Seventy percent of patients are at an early stage at diagnosis, and more than 70% are hormone receptorpositive (HRþ) [2]. Young age is an independent risk factor of
* Corresponding author. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea. Fax: þ82 2 3410 6982. E-mail address: [email protected] (J.E. Lee). 1 These authors equally contributed to this work. http://dx.doi.org/10.1016/j.breast.2016.08.011 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
poor prognosis; however, adjuvant therapy plays a crucial role in improving patient outcome [3]. Patients with HRþ are considered to be highly responsive to endocrine therapy [4]. Tamoxifen play a crucial role in the management of these patients, and the additive effect of chemotherapy is minimal especially in low-risk patients [5e7]. On the other hand, ovarian function suppression (OFS) has been shown to improve the outcome of high-risk premenopausal patients if combined with tamoxifen, but this improvement was not obvious in a low-risk group [8]. Breast cancer patients with luminal A subtype respond well to endocrine therapy and generally have a good prognosis [3,4]. We hypothesized that, in premenopausal women with early stage, luminal A breast cancer with Ki-67 < 25%, neither chemotherapy
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nor OFS (using LHRH agonist) has an additive effect on the outcome over tamoxifen. Materials and methods This was a retrospective study conducted at Samsung Medical Center. Between January 2008 and December 2013, we consecutively collected and reviewed the medical records of premenopausal patients who underwent surgery for primary breast cancer (either breast-conserving surgery followed by adjuvant radiotherapy or mastectomy) followed by adjuvant treatment with either GosTam or ChemTam. Patients who were included had a tumor size less than or equal to 2 cm with no metastasis to regional lymph nodes or distant metastasis. All patients' tumors were strongly positive for estrogen and progesterone receptors, negative for human epidermal growth factor receptor-2 (HER-2), and had low Ki-67. We defined premenopause as regular menses without exogenous hormones during the prior 6 months and/or estradiol level in the premenopausal range. The pertinent tumor size in this study was final pathological tumor size. Nodal status was determined by sentinel lymph node biopsy in all patients. The sentinel node was identified using radioisotopes, patent blue dye, or a combination of these techniques. All patients underwent work up to rule out distant metastasis. This includes history and physical examination, complete blood count (CBC), liver function test (LFT), alkaline phosphatase (ALP), chest X-ray, abdominal CT scan, and bone scan. These are routine investigations for all patients with breast cancer. We defined a luminal A tumor as one that was estrogen receptor (ER)- and progesterone receptor (PR)-positive, HER-2-negative, and had a low Ki-67, according to the 14th St. Gallen International Breast Cancer Conference [9]. ER and PR were considered to be strongly positive if the Allred score was 7e8þ by immunohistochemistry (IHC). HER-2 was considered to be negative if the score was 0e1þ by IHC. In cases in which the result was equivocal (2þ), further study using silver in situ hybridization (SISH) was performed. If the SISH result was positive, the patient was excluded. We considered Ki-67 to be low if it was less than 25% according to IHC. The histological features of all tumors were reviewed in the hospital's laboratory, and no central review was conducted. All patients were followed-up post-operatively every 6 months for 5 years; each visit included history and physical examination, CBC, LFT, ALP, mammography, and breast ultrasound. Breast ultrasound is routinely performed for all patients because Asian women usually have dense breast tissue, which may obscure some lesions from detection on mammography. One year after surgery, all patients underwent additionally bone scan, chest X-ray, and abdominal CT scan. Abdominal CT scan and bone scan are routinely performed one year post-operatively. All patients with breast cancer are routinely followed in the same way. The primary outcome of our study was 5-year disease-free survival (DFS). The secondary outcome was 5-year overall survival (OS). DFS was defined as the period from surgical management until the date of any incident of local, regional, or distant recurrence, which was radiological or biopsy proven, or breast cancer-related death. Patients who did not have any events were censored at the date of their last outpatient clinic visit. OS was defined as the period from surgical management to the date of death or last outpatient clinic visit. Patient groupings The patient population was divided into two groups according to adjuvant therapy regimen. The first group included patients who underwent GosTam; the second group included patients who
underwent ChemTam. All patients who underwent another adjuvant regimen or those who underwent neoadjuvant therapy were excluded. The goserelin acetate (Zoladex, AstraZeneca Pharma International, UK) dose was 3.78 mg, administered as a subcutaneous injection on the anterior abdominal wall every 28 days for 2 years. The most common chemotherapy regimen (89.4%) was four cycles of AC (cyclophosphamide 600 mg/m2 þ D5W 100 mL mixed intravenous over 1 h, doxorubicin 60 mg/m2 þ D5W 100 mL mixed intravenous over 30 min), and 11.6% of the patients underwent four cycles of FAC (cyclophosphamide 500 mg/m2 þ D5W 100 mL mixed intravenous over 1 h, doxorubicin 50 mg/m2 þ D5W 100 mL mixed intravenous over 30 min, 5-fluorouracil 500 mg/m2 intravenous push). Tamoxifen (20 mg) was administered daily for 5 years to patients in both groups and was administered concurrently to goserelin in the GosTam group and sequentially to chemotherapy in the ChemTam group. The decision to administer adjuvant radiotherapy was made in conjunction with a radio-oncologist. Statistical analysis The Chi-square test and Spearman correlation coefficient were used to compare discrete variables. Student's t-test was used to compare the continuous variables. Survival analysis was performed using the Kaplan-Meier method. All p-values were two-tailed, and a p-value <0.05 was considered statistically significant. All statistical analyses were executed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R3.0.3 (Vienna, Austria; http://www.R-project. org). Results Patient stratification and characteristics A total of 3059 patients were diagnosed between 2008 until 2013 to have a tumor size 2 cm with regional lymph node negative and no distant metastasis (T1N0M0) (Fig. 1). Of these, 72 patients were excluded because they underwent neoadjuvant chemotherapy. All patients who were postmenopausal at the time of diagnosis were excluded (n ¼ 1120). In addition, we excluded all patients with ER or PR receptor negative or HER-2 positive. Patients with weak ER or PR receptor positivity with Allred score 6 or with Ki-67 25% were also excluded (n ¼ 1461). A total of 406 premenopausal patients with T1N0M0 tumors, strong ER and PR positivity with Allred score 7 or 8, HER2 negative, and Ki-67 less than 25% were ultimately included. These patients comprised 171 who underwent ChemTam and 235 who underwent GosTam (Table 1). The patients in the GosTam group tended to be younger than those in the ChemTam group (32% of patients <40 years vs. 22%, p ¼ 0.031). Patients in the ChemTam group tended to have a higher body mass index (BMI; BMI ¼ 23.04 ± 2.94 kg/m2 vs. 21.93 ± 2.58 kg/m2, p < 0.001). Breast-conserving surgery was the most commonly performed surgery, and there was no significant difference between groups with regard to the type of surgery performed (p ¼ 0.931). Tumor characteristics Tumor characteristics are illustrated in Table 1. The histopathological types of the tumors were identical, and invasive ductal carcinoma was the dominant type. Tumor size tended to be smaller in the GosTam group (mean tumor size ¼ 1.19 cm vs. 1.48 cm, p < 0.001). Furthermore, we found that most of the patients in the ChemTam group (81%) had a T1c tumor size >1 cm, compared to 67% in the GosTam group (p ¼ 0.002). Ki-67 tended to be slightly higher in the ChemTam group (ChemTam ¼ 11.7 ± 5.63,
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Fig. 1. Patients' stratification. ER: estrogen receptor, PR: progesterone receptor, HER-2: human epidermal growth factor receptor-2, ChemTam: chemotherapy followed by tamoxifen, GosTam: goserelin combined with tamoxifen.
GosTam ¼ 10.6 ± 5.50, p ¼ 0.045). The number of patients with a high nuclear grade was higher in the ChemTam group (13% ChemTam vs. 2% GosTam, p < 0.001). There were no statistically significant differences between groups with regard to P53 value or histological grade. Recurrence and survival After a median follow-up of 51.3 ± 18.9 months, there was no mortality in either group of patients. There were 8 recurrences (Table 2), six in the ChemTam group and two in the GosTam group; however, there was no statistically significant difference in DFS between groups (GosTam ¼ 98.9% vs. ChemTam ¼ 95.7%, HR ¼ 0.404, 95% CI ¼ [0.073, 2.222], p ¼ 0.248) (Fig. 2). Three patients had distant metastasis to the bone, two of whom were treated with chemotherapy and one with radiotherapy. One patient had liver metastasis and was treated with chemotherapy. Three patients had contralateral breast cancer and were treated with surgery. One patient had recurrence to the axillary lymph nodes and was treated with axillary lymph node dissection followed by chemotherapy. Univariate analysis according to patient age (Fig. 3), BMI, histopathological type, tumor size, nuclear grade, histological grade, and P53 showed no significant effect on DFS (Table 3). Multivariate analysis could not be performed because no factors tested in univariate analysis showed any effect on DFS, and the number of events was too small to be analyzed. Discussion In premenopausal women with breast cancer, more aggressive management is generally needed to treat the aggressive features of
the cancer and prevent recurrence [10]. However, the optimal systemic therapy for these premenopausal women remains controversial [11]. Chemotherapy has been shown to decrease the rate of relapse and death and, overall, is a highly effective adjuvant modality. It has been reported to have superior outcomes in premenopausal women than postmenopausal women [12], The interpretation of this superior outcome is complicated by its endocrine effect in suppressing ovarian function, because of chemotherapy-induced amenorrhea (CIA) [13]. However, in young women with HRþ disease, chemotherapy might not be efficacious, and CIA is uncommon among patients younger than 35 years [11]. For this reason, many earlier trials studied the outcome of inducing amenorrhea by ovarian ablation (surgical, irradiation, or medical) and compared it to the outcome of chemotherapy in HRþ breast cancer, which has been shown to be equivalent in terms of recurrence and survival [14e16]. Therefore, if tamoxifen is prescribed with either chemotherapy or ovarian suppression, it has been shown to offer a better long-term result compared to chemotherapy or ovarian suppression alone in patients with HRþ breast cancer [5,17e20]. To our knowledge, there is no study in the literature comparing the outcomes of chemotherapy followed by tamoxifen versus the combination of ovarian suppression (LHRH) with tamoxifen. We conducted this retrospective study comparing the effect of GosTam to ChemTam as an adjuvant treatment in a premenopausal, lowrisk group of women with early stage breast cancer of the luminal A subtype that had not spread to the lymph nodes. Jakesz R. et al. found better outcomes for the GosTam regimen compared to chemotherapy alone [17]. Also, their multivariate analysis showed that patient age, tumor size, and nuclear grade significantly affected DFS and OS. However, in our study, these factors did not affect DFS.
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Table 1 Patients' and tumors' characteristics. Characteristics Age, year 40 41e55 BMI, kg/m2 Ki-67, % FHx Yes No Bilaterality Unilateral Bilateral OP Mastectomy BCS Histopathology IDC ILC Others Tumor size, cm T-stage T1mic þ T1a þ T1b T1c Multiplicity Yes No NG Low Intermediate High P53 Positive Negative HG Low Intermediate High Follow-up duration, months
ChemTam group (n ¼ 171)
GosTam group (n ¼ 235)
38 (22%) 133 (78%) 23.04 ± 2.94 11.7 ± 5.63
75 (32%) 160 (68%) 21.93 ± 2.58 10.6 ± 5.50
9 (5%) 162 (95%)
23 (10%) 212 (90%)
165 (96%) 6 (4%)
229 (97%) 6 (3%)
26 (15%) 145 (85%)
35 (15%) 200 (85%)
162 (95%) 6 (3%) 3 (2%) 1.48 ± 0.4
217 (92%) 5 (2%) 13 (6%) 1.19 ± 0.43
33 (19%) 137 (81%)
78 (33%) 157 (67%)
52 (30%) 119 (70%)
70 (30%) 165 (70%)
36 (21.1%) 113 (66.1%) 22 (12.9%)
105 (44.7%) 126 (53.6%) 4 (1.7%)
26 (15%) 145 (85%)
28 (12%) 207 (88%)
95 (55.6) 70 (40.9) 6 (3.5) 56.86 ± 18.97
147 (62.6) 81 (34.5) 7 (1.7) 47.31 ± 18.01
p-value 0.031
<0.0001 0.049 0.095
0.575
0.931
0.114
<0.0001 0.002
0.893
<0.0001
0.335
0.370
<0.0001
ChemTam: chemotherapy followed by tamoxifen, GosTam: goserelin combined with tamoxifen, BMI: body mass index, FHx: family history, op: operation type, BCS: breast conserving surgery, IDC: infiltrated ductal carcinoma, ILC: infiltrated lobular carcinoma, NG: nuclear grade, HG: histological grade.
This is most likely because all patients in our study had favorable prognostic factors, and our study involved a relatively short period of follow-up with only a few cases of recurrence. The SOFT trial showed that addition of ovarian suppression to tamoxifen did not improve the outcome compared to tamoxifen alone; however, more than half of the patients in the SOFT trial underwent chemotherapy in addition to hormonal therapy [8]. Sub-analysis of the SOFT trial showed that patients who underwent chemotherapy
followed by tamoxifen had a worse outcome than those who underwent ovarian suppression plus tamoxifen without chemotherapy. Also, in sub-analysis by chemotherapy, the group of patients who underwent chemotherapy showed significant improvement in the outcome if ovarian suppression was added to tamoxifen compared to tamoxifen alone. This benefit was not observed in the group of patients who did not undergo chemotherapy. The explanation for these findings is that in patients who were treated without chemotherapy had favorable clinical and pathological features, and treating this group of patients with tamoxifen alone produced a good outcome and may have shown no value of adding ovarian suppression. This may also explain why we observed equivalent outcomes for both GosTam and ChemTam groups in our study (Fig. 2). It is most likely that treating this lowrisk population with tamoxifen alone is sufficient, and neither chemotherapy nor ovarian suppression is of added value. In a subgroup analysis by age, the SOFT trial showed a slight improvement in the outcomes of ovarian suppression plus tamoxifen compared to those of tamoxifen alone in younger patients [8]. Our study did not indicate a difference with regard to age group, which may indicate that, in patients with favorable clinical and pathological features, age does not affect the outcome (Fig. 3). Amye J. et al. randomized 345 patients with HRþ, tumor size 3 cm, and lymph node negative to either tamoxifen alone or tamoxifen in addition to ovarian suppression. No chemotherapy was administered to either group. They found that if ovarian suppression added to tamoxifen, it increased menopausal symptoms, reduced sexual activity, lowered health-related quality of life, and did not improve DFS or OS in this low-risk population [21]. At the 14th St Gallen International Breast Cancer Conference, most of the experts agreed that patients with luminal A breast cancer are less responsive to chemotherapy. Most of the expert panel agreed that no need to administer chemotherapy for low-risk patients with strongly positive hormone receptors, HER2 negative, small tumor, and 0e3 positive lymph nodes who can be treated safely with endocrine therapy alone, which consists of tamoxifen for 5 years. Also, most of the panel disagreed on administration of chemotherapy based on patient age. The panel agreed to prescribe ovarian suppression for only high-risk premenopausal women with HRþ breast cancer [22]. Furthermore, The American Society of Clinical Oncology (ASCO) guidelines recommend tamoxifen alone for low-risk, stage I patients who have HRþ tumor, who are not warranted to receive chemotherapy [23]. In our study, we treated part of our patient population with goserelin in addition to tamoxifen because, in the inclusion period (2008e2013), the role of adjuvant ovarian suppression in addition to tamoxifen was not yet determined in clinical trials. We used 2-year duration of goserelin treatment rather than the 5 years recommended by ASCO guidelines, because the national insurance company covers it only for 2
Table 2 Clinical characteristics of patients who have disease recurrent. Case ChemTam group 1 38 2 43 3 31 4 47 5 48 6 46 GosTam group 1 43 2 49
Surgery
Recurrence
Tx after recurrence
Recurrence site
RFI (months)
Alive or death
FU duration (months)
BCS BCS BCS BCS BCS BCS
DM CBC DM CBC DM CBC
CTx OP CTx OP CTx OP
Liver Contralateral breast Bone Contralateral breast Bone Contralateral breast
39 38 92 80 57 59
Alive Alive Alive Alive Alive Alive
71 66 92 80 67 59
BCS BCS
DM LR
RTx OP, CTx
Bone Axilla
12 36
Alive Alive
48 49
BCS, breast conserving surgery; CTx, chemotherapy; FU, follow-up; CBC, contralateral breast cancer; DM, distant metastasis; LR, locoregional recurrence; RFI, recurrence free interval; OP, operation; RTx, radiotherapy; Tx, treatment.
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Fig. 2. KaplaneMeier curve of disease free survival of ChemTam vs. GosTam.
Fig. 3. KaplaneMeier curve of disease free survival of ChemTam vs. GosTam after univariate analysis by age <40 years.
years. Although the ASCO guideline recommends a 5-year duration for the use of OFS, there is no alternative data on a comparative period [23]. Our study has both advantages and limitations. First, it had a relatively small sample size that limited the power to draw a definitive conclusion. Second, there was a relatively short follow-up duration, thereby preventing the detection of later recurrences or breast cancer-related deaths; we observed only 8 recurrences and no breast cancer-related deaths (Table 2). Third, goserelin was
administered for 2 years only, different from the recommended period by the guidelines. Finally, this retrospective study had an inherent selection bias. Patients who were treated with chemotherapy tended to be older, have larger tumor sizes, and have tumors with a higher nuclear grade (Table 1). Despite these limitations, this study is of great value. To our knowledge, it is the first report comparing the outcome of LHRH plus tamoxifen to chemotherapy followed by tamoxifen in young patients with nodenegative, early stage, luminal A breast cancer and thus the first to
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Table 3 Factors affecting recurrence according to ChemTam, GosTam groups univariate analysis. Variable Age, year 40 41e55 BMI, kg/m2 Bilaterality Unilateral Bilateral Histopathology IDC ILC Others Tumor size, cm T-stage T1mic þ T1a þ T1b T1c Multiplicity Yes No NG P53 Positive Negative HG
HR
95% CI Lower
95% CI Upper
p value
1.00 2.12 0.96
0.26 0.73
17.60 1.26
0.4869 0.7533
1.00 7.70
0.92
64.17
0.0593 0.3618
1.00 0.00 4.67 1.20
0.00 0.56 0.23
38.91 6.16
0.9937 0.1539 0.8281
1.00 0.92
0.18
4.75
0.9215
1.00 1.00 0.59
0.19 0.16
5.17 2.17
0.9976 0.4237
1.00 1.01 0.56
0.12 0.12
8.41 2.57
0.991 0.4559
BMI: body mass index, FHx: family history, op: operation type, BCS: breast conserving surgery, IDC: infiltrated ductal carcinoma, ILC: infiltrated lobular carcinoma, NG: nuclear grade, HG: histological grade.
show equivalent results of the treatment modalities. This may confirm the finding in clinical trials in which patients with low-risk luminal A breast cancer may not benefit from either chemotherapy or OFS and can be treated safely with tamoxifen alone with good disease control in order to avoid the side effects of OFS and chemotherapy. In conclusion, in our patient population with low risk of recurrence, there was no difference between treatment groups, and we found neither chemotherapy nor ovarian suppression to improve the outcome. Thus, tamoxifen alone might be a good option for such low-risk patients. Ethical approval The need for informed consent was waived because of the low risk posed by this investigation. This study adhered to the ethical tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Samsung Medical Center in Seoul, Korea (IRB number: 2015-12-121-001). Conflict of interest statement The authors declare that they have no conflict of interest in this manuscript, including financial, consultant, institutional, or other relationships that might lead to bias. Acknowledgements Part of this work was presented as a poster presentation at the 2016 Global Breast Cancer Conference and at the 12th Asian Oncology Summit. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01057585) and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418).
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