Yonago Acta medica 2013;56:51–56

Original Article

Effect of Chemotherapy for Luminal A Breast Cancer
Naotaka Uchida,*† Takako Suda† and Kiyosuke Ishiguro†*Clinic of Surgery, Tottori Prefectural Kosei Hospital, Kurayoshi 682-0804, Japan and †Clinical Department of Mammoendocrinology, Tottori University Hospital, Yonago 683-8504, Japan

ABSTRACTInternational Breast Cancer Conference held in 2011
showed that the luminal A subtype was fairly unresponsive to chemotherapy and said that node positivity per se
was not an indication for use of chemotherapy, althougha large majority of physicians would use it if more than
3 axillary lymph nodes were involved.4 However, theleast benefit of chemotherapy in all patients with luminal A breast cancer is controversial. The 11th St. Gallen
Conference held in 2009 presented the relative indications for using endocrine therapy alone or a combinationof chemotherapy and endocrine therapy for luminal A
breast cancer.5 The clinicopathological risk factors forprognosis included lymph node status, tumor size, presence of lymphovascular invasion, histological grade, andproliferative status. Therefore, it is essential to clarify thesignificance of chemotherapy for patients with these risk
factors and luminal A breast cancer. In this report, weanalyzed the significance of chemotherapy for patientswith luminal A breast cancer who underwent surgery
and received postoperative endocrine therapy.

Background

The addition of chemotherapy to endocrine therapy for luminal A breast cancer generally
provides little benefit. However, the least benefit of chemotherapy in all patients with luminal A breast cancer iscontroversial.
Methods This was a retrospective study of 140 patients with luminal A breast cancer who underwent
surgery at Tottori University Hospital between 2001 and2010. Luminal A breast cancer was defined as positivefor estrogen receptors and/or progesterone receptors andnegative for human epidermal growth factor 2. Postoperative endocrine therapy was given to all patients. The
prognostic values of age, tumor size, presence of lymphovascular invasion and lymph node status were evaluated. In addition, the prognostic value of chemotherapy
for patients with identified risk factors affecting relapsefree survival and overall survival was evaluated.
Results
Tumor size greater than 2 cm and positive
lymph node status were factors significantly affecting
relapse-free survival. There were no factors significantly
affecting overall survival. There was no significant difference in the relapse-free survival of patients with tumor size greater than 2 cm and/or positive lymph node
status who either received chemotherapy or not. However, the relapse event was earlier in patients with tumor
size greater than 2 cm and positive lymph node status
who did not receive chemotherapy than in those who received chemotherapy.
Conclusion Chemotherapy could provide little benefit
to patients with luminal A breast cancer. However, chemotherapy may bring them longer relapse-free periods.

SUBJECTS AND METHODSPatients

A total of 140 patients with initial luminal A primaryinvasive breast cancers who underwent surgery in our
department at Tottori University Hospital between June
2001 and December 2010 were retrospectively investigated (Table 1). Men with breast cancer, women with insitu carcinoma, bilateral breast carcinoma or who underwent neoadjuvant chemotherapy or chemotherapy for
another disease were excluded from the study. Informed
consent was obtained from every patient. Patients weretreated with breast-conserving surgery or mastectomy.
All patients received post-operative endocrine therapy(Table 2). Most patients with breast-conserving surgery
received radiotherapy to the whole breast after surgery.
There were 24 patients who received chemotherapy (Table 2). Decisions regarding chemotherapy were made by
the treating physician on the basis of patient preference

Key words breast cancer; chemotherapy; luminal A

Luminal A breast cancers that express estrogen receptors (ERs) and/or progesterone receptors (PRs) and are
negative for human epidermal growth factor receptor 2(HER2) expressions respond well to endocrine therapy
and have a generally favorable prognosis. Patientswith luminal A breast cancers are not so sensitive topaclitaxel- and doxorubicin-containing preoperative
chemotherapy.1 Patients with node-positive luminal A
breast cancer gain little benefit from taxane therapy
administered.2, 3 Proceedings from the 12th St. Gallen

Corresponding author: Naotaka Uchida, MD, PhD
uchidana@pref.tottori.jp
Received 2013/01/09
Accepted 2013/03/08
Abbreviations: ER, estrogen receptor; HER2, human epidermal
growth factor receptor 2; IHC, immunohistochemistry; PR, progesterone receptor

51

N. Uchida et al.
Table 1. Patients characteristics
Median [range]

Number (%)

Age (yr)		
60.5[34–86]
Menstruation status
Premenopause			39
Postmenopause			
101
Surgical procedure
Mastectomy			
39
Breast-conserving surgery			
101
Tumor size (cm)		
1.7[0.5–5.3]
ER positivity proportion (%) 		
90[15–95]
PR positivity proportion (%) 		
60[0–95]
Lymphovascular invasion
Negative			37
Positive			
101
Unkown			2
Nuclear grade
Grade 1 			
52
Grade 2 			
54
Unkown			34
Ki67< 14%			
18Unknown			
122
Lymph node metastasis status Negative			
103
Positive			37
Lymph node metastasis number*2[1–18]* Number in 37 positive cases.
ER, estrogen receptor; PR, progesterone receptor.

and risk factors. In principle, the chemotherapy regimen
was as follows: FEC (fluorouracil 500 mg/m2, epirubicin
60 mg/m2 and cyclophosphamide 500 mg/m2) alone on
day 1 every 3 weeks for 4 cycles or FEC (fluorouracil
500 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide
500 mg/m2) on day 1 every 3 weeks for 4 cycles followed by docetaxel (60 mg/m2) on day 1 every 3 weeks
for 4 cycles or paclitaxel (80 mg/m2) on day 1 and 8 every 3 weeks for 4 cycles.

(28%)
(72%)
(28%)
(72%)

(27%)
(72%)
(1%)
(37%)
(39%)
(24%)
(13%)
(87%)
(74%)
(26%)

or nuclear grade were determined,
the luminal A subtype was also
defined as low Ki-67 labeling index (< 14%) and/or nuclear grade
1 or 2. ER and PR positivity wasconfirmed by immunohistochemistry (IHC); greater than 10%
of tumors cells staining positivewas considered positive. HER2negative-status was confirmed by
IHC (with 0, 1+, 2+ scores indicating no cells with staining, < 10%of cells with membrane staining,or > 10% of cells with low or medium membrane staining, respectively). Tumors that were 2+ by
IHC were also examined by fluorescence in situ hybridization (withan amplification ratio < 2.0 indicating negative status). The Ki-67
labeling index was determined by
IHC.

Statistics

Relapse-free survival was defined as the period fromthe date of operation to the date of the first confirmation of relapse (i.e., local relapse or metastasis) or deathfrom any cause, whichever came first. Overall survival
was defined as the period from the date of operation
to the date of death from any cause. Relapse-free andoverall survival periods were estimated with the KaplanMeier method and compared with the log-rank test andWilcoxon test. The Mann-Whitney U test was used forcomparisons of continuous outcomes, while the chisquare test, for comparisons of categorical variables.
Risk factors affecting prognosis were estimated withunivariate and multivariate analyses. Cox’s proportionalhazards model was applied in multivarate analysis. Differences were considered significant when the P value
was < 0.05.

Histopathological and immunohistochemical evaluations

All histopathological and immunohistopathologicaldiagnoses were determined by several pathologists at
our facilities or at another laboratory facility within ourpartnership. Surgical specimens were embedded in paraffin, sectioned and stained with hematoxylin and eosin.
Luminal A subtype was defined as ER and/or PR positive and HER2 negative. If the Ki-67 labeling index and/
Table 2. Adjuvant systemic therapy

Number(%)

Endocrine therapy [n = 140]

Tamoxifen ± LH-RH agonist
Aromatase inhibitor
Tamoxifen ± LH-RH agonist Aromatase inhibitor
Aromatase inhibitor Tamoxifen
Toremifene citrate

48
75
15
1
1

(34%)
(54%)
(10%)
(1%)
(1%)

Chemotherapy [n = 24]

Anthracyclin
Anthracyclin + Taxane

19
5

(79%)
(21%)

LH-RH, luteinizing hormone-releasing hormone.

52

Chemotherapy for luminal A breast cancer
Table 3. Comparion between chemotherapy and non-chemotherapy groups
FactorNumber of lymph node metastasis
Tumor size (cm)Lymphovascular invasion
Age (yr)
Event

Chemotherapy groupn = 24
Median [range]
1.5 [0–18]
Median [range]
2.5 [1.2–4.5]
Positive: number (%)23(96%)
Negative: number (%)1(4%)
Unknown: number (%)			
Median [range]
52[34–74]
Relapse: number (%)4(16%)
Death: number (%)2(8%)

Non-chemotherapy groupn = 116

P value

0
1.5
78
36
2
62
6
3

< 0.01< 0.01< 0.01[0–8][0.5–5.3]
(67%)
(31%)
(2%)
[37–86](5%)(2.5%)< 0.01
0.06
0.2

pre- to post-menopausal in 9 patients, patient preference
to continue endocrine therapy after 5 years of treatment
with 1 type of therapy in 3, thrombosis in 1, uterine endometrial hypertrophy in 1, and uterine cancer in 1 patients. One patient changed from the aromatase inhibitor
to tamoxifen because of joint pain.
A total of 24 patients received chemotherapy. Chemotherapy was performed more frequently to patientswith metastases involving several lymph nodes, large
tumor size, positive lymphvascular invasion and youngerage (Table 3). Relapse events were 4 (16%) in the chemotherapy group and 6 (5%) in the non-chemotherapy
group, and intergroup difference was not significant (P =0.06) (Table 3). Death events, 2 (8%) in the chemotherapy group and 3 (2.5%) in the non-chemotherapy group,
showed no significance (P = 0.20) (Table 3). Of 24
chemotherapy-based patients, 19 (79%) patients received
anthracycline alone, and the remaining 5 (21%) received
anthracycline and taxane (Table 2). Chemotherapy that
included taxane was adopted more frequently in patientswith metastases involving several lymph nodes: median
number of involved nodes (range) was 1 (0–13) when theagent was anthracycline, and 11 (3–18) when taxane wascoadministered.

RESULTS
Patient characteristics

Table 1 shows the characteristics of 140 luminal A
breast cancer patients. The median patient age was 60.5
years (range: 34–86 years). Menstruation status of 39(28%) patients was premenopausal and that of 101 (72%)
patients was postmenopausal. There were 101 (72%)
patients receiving breast-conserving surgery and 39(28%) patients receiving mastectomy. The median tumor
size was 1.7 cm (range: 0.5–5.3 cm), and 103 patients(74%) were free of axillary lymph node metastasis. In
37 patients with axillary lymph node metastasis, themedian number of involved lymph nodes was 2 (range:
1–18). Median ER and PR positivity proportions of tumor cells in each tumor were 90% (range: 15–95%) and
60% (range: 0–95%) respectively. There were 101 (72%)
patients positive for lymphovascular invasion. There
were 52 (37%) and 54 (39%) patients with nuclear-grade
tumors of 1 and 2, respectively. The median follow-up
period was 40 months (range: 3–113 months).
Adjuvant systemic therapy

Table 2 lists the post-operative systemic therapies. All
patients received some type of endocrine therapy. A totalof 48 (34%) patients received tamoxifen and/or a luteinizing hormone-releasing hormone agonist, and 75 (54%)
patients received an aromatase inhibitor. There were 15(10%) patients who changed from tamoxifen and/or luteinizing hormone-releasing hormone agonist to the aromatase inhibitor for the following reasons: change from

Risk factors associated with relapse and death

Relapse or death risk factors were investigated by univariate analysis among positive lymph node status, tumor size > 2 cm, positive lymphovascular invasion andage < 40 years old. As the result, positive lymph node
status and tumor size > 2 cm were significant relapse

Table 4. Relapse-free survival and overall survival in 140 patients with luminal A breast cancer (univariate analysis)
Relapse-free survival		
Univariate analysis		Hazard
95% ConfiP
ratio
dence interval
value
Lymph node status (positive versus negative)
8.08
Tumor size (> 2 cm versus ≤ 2 cm)
3.68
Lymphovascular invasion (positive versus negative) 1.98
Age (< 40 yr versus ≥ 40 yr)
0.35

2.02–32.2
1.01–13.3
0.43–9.04
0.01–8.04

53< 0.01
0.04
0.37
0.51

Overall survival
Univariate analysis
Hazard
95% Confiratio
dence interval

P
value

4.68
1.73
1.57
0.35

0.11
0.56
0.65
0.72

0.66–32.7
0.26–11.3
0.21–11.5
0.001–122.9

N. Uchida et al.
Table 5. Relapse-free survival and overall survival in 140 patients with luminal A breast cancer (multivariate analysis)
Relapse-free survival		
Multivariate analysis		Hazard
95% Confidence P
ratio
interval
value
Lymph node status (/1 involved node)
0.95
Tumor size (/1 cm)
0.88
Lymphovascular invasion (positive versus negative) 0.84
Age (/1 yr)
1.01

0.88–1.03
0.68–1.15
0.56–1.26
0.99–1.02

Fig. 1. Relapse-free survival in patients with tumor sizes > 2 cm.
There is no difference between groups undergoing chemotherapy
or not.

0.26
0.37
0.40
0.14

Overall survival
Multivariate analysis
Hazard
95% Confidence P
ratio
interval
value
0.94
0.89
0.86
1.01

0.88–1.01
0.69–1.15
0.57–1.30
0.99–1.02

0.14
0.39
0.49
0.12

Fig. 2. Relapse-free survival in patients with axillary lymph nodemetastasis. There is no difference between groups undergoing
chemotherapy or not.

risk factors (Table 4). Meanwhile, there were no significant death risk factors (Table 4). In multivariate analysis,
there were no significant relapse and death risk factors(Table 5).
Relapse-free survival

The relapse-free survival rates of patients with significant
risk factors were estimated for patients with or without
chemotherapy. In 44 patients with tumor size > 2 cm, 16
patients received chemotherapy. The 5-year relapse-freesurvival rate of the patients undergoing chemotherapy
was estimated at 78.7%, whereas for those not undergoing chemotherapy it was estimated at 86.6%. The difference was not significant (P = 0.40) (Fig. 1).
In 37 patients with positive lymph node status, 21
patients received chemotherapy. The 5-year relapse-freesurvival rate of the patients undergoing chemotherapy
was estimated at 82.5%, whereas for those not undergoing chemotherapy it was estimated at 83.3%. The difference was also not significant (P = 0.45) (Fig. 2).
In 20 patients with positive lymph node status andtumor size > 2 cm, 14 patients received chemotherapy.
The 5-year relapse-free survival rate of the patients undergoing chemotherapy was estimated at 78.7%, whereas

Fig. 3. Relapse-free survival in patients with tumor sizes > 2 cm
and axillary lymph node metastasis. There is no difference between groups undergoing chemotherapy or not. But chemotherapy
brings a longer relapse-free period.

for those not undergoing chemotherapy it was estimatedat 33.3%. The difference was also not significant on logrank analysis (P = 0.21), but significant on Wilcoxon’s
analysis (P = 0.02) (Fig. 3). These suggest earlier relapse
54Chemotherapy for luminal A breast cancer

were more frequent in non-chemotherapy group thanchemotherapy group.

of anthracycline treatment has improved the diseasefree and OS of patients with node-positive early breast
cancer.13, 14 However, patients with luminal A breast
cancer benefit less from treatment with a taxane whenadministered after anthracycline, even if lymph nodes
are involved.2, 3 In our study, chemotherapy had no beneficial effects on relapse in patients with lymph node involvement. The effects on relapse in patients with large
tumor size and lymph node involvement were also notbeneficial. Multivariate analysis revealed that endocrine
therapy alone sufficiently removed relapse and death risk
from patients with luminal A breast cancer.
The following reasons could explain why, in ourstudy, patients with larger tumors and lymph node involvement did not benefit from chemotherapy. First, microarray analysis has shown that nodal status and tumor
size cannot be correlated with biologically distinct diseases.15 These findings suggest that biological characteristics, not node positivity, are indications for the use of
chemotherapy.4 Therefore, in our study, luminal A breast
cancer in patients with larger tumors and lymph node
involvement may exhibit lower malignant potential. Second, the chemotherapy regimen used in this study was at
the lower limit of standard regimens in regard to dosages(epirubicin: 60–100 mg/m2, docetaxel: 60–100 mg/m2,
paclitaxel: 80–100 mg/m2). A less-efficacious regimen
might be the reason that we did not detect a significant
effect in the chemotherapy group. Third, the size of thisstudy is a limitation. Our study is retrospective, and thechemotherapy group contained 24 patients. We cannot
draw a conclusion using such a small dataset. Fourth,
unknown cases regarding nuclear grade and/or Ki-67
could affect the results. In our study, nuclear grade in
34 patients was unknown because the grading is generally used in patients with invasive ductal carcinoma andthere is no consensus to decide nuclear grade in patientswith special types of breast cancer. Ki-67 in 122 patientswas unknown because it was introduced in May 2009,
and the confidence for specimens embedded in paraffin and preserved for long time is not established. Ki-67
and/or nuclear grade are important factors to distinguishluminal A and luminal B (HER2 negative type) in the
12th St. Gallen International Breast Cancer Conference
held in 2011. Among them, the cases belonging to luminal B (HER2 negative type) could be included and it
may influence the result in patients with large tumor sizeand lymph node involvement.
In conclusion, chemotherapy could provide little
benefit to patients with luminal A breast cancer, eventhose with high relapse risk factors including large tumor
size and many positive nodes. However, chemotherapy
may bring patients longer relapse-free periods. Prospec-

DISCUSSION
Using complementary DNA microarrays representing
8102 human genes, Perou et al. defined 4 breast cancer
subtypes (luminal/ER, HER2-overexpressing, basal-likeand normal), based on gene expression patterns.6 Carley
et al. subsequently classified 5 subtypes based on immunohistochemical staining of various markers as follows:
luminal A (ER+ and/or PR+, HER2–), luminal B (ER+and/or PR+, HER2+), HER2 (ER–, PR–, HER2+), basallike (ER–, PR–, HER2–, CK5/6+ and/or HER1+) and an
unclassified type, and also demonstrated the applicability of this system to past classification systems based ongene microarray analysis.7 The clinical application ofgene expression profiling is limited because the procedure is technically difficult and expensive. Therefore,
the consensus of the 12th St. Gallen Conference defined
luminal A breast cancer as ER+ and/or PR+, HER2–
tumors with a Ki-67 labeling index of < 14%.4 However,there was a lack of complete consensus on the thresholdindication for administering chemotherapy to patientswith luminal A breast cancer.4 It has been reported that
Oncotype DX recurrence scores were high in 13% of patients with luminal A breast cancer.8 Among tamoxifentreated patients, patients with a low or intermediate
recurrence score on the 21-gene assay benefited fromtamoxifen, whereas patients with a high recurrence
score did not benefit.9 However, the 21-gene assay has
also demonstrated that chemotherapy provided a large
benefit when the recurrence score was high.10 These results suggest that chemotherapy is beneficial for patientswith potentially malignant luminal A breast cancer.
The value of chemotherapy for patients with large
luminal A breast tumors is unclear. The 21-gene recurrence score assay has shown that there is a significant association between increased tumor size and high recurrence score.10 Tumor size was prognostic for local anddistant relapse.11, 12 These findings suggest that the larger
the tumor the greater the association of gene expression
with malignant potential and that chemotherapy may
lead to a better prognosis. However, in our study, chemotherapy had no beneficial effects on relapse in patientswith tumors larger than 2 cm.
The value of chemotherapy for patients with lymph
node involvement of luminal A breast cancer is also not
clear. Generally speaking, the number of axillary lymph
node metastases is the most reliable prognostic factor
and an important indication for adjuvant therapy. The
addition of a paclitaxel protocol after the completion55

N. Uchida et al.

tive studies and additional subject recruitment are necessary to draw definitive conclusions.

in the Carolina Breast Cancer Study. JAMA. 2006;295:2492502. PMID: 16757721.
8 Ademuyiwa FO, Thorat MA, Jain RK, Nakshatri H, Badve S.
Expression of Forkhead-box protein A1, a marker of luminal
A type breast cancer, parallels low Oncotype DX 21-gene relapse scores. Mod Pathol. 2010;23:270-5. PMID: 19946260.
9 Sparano JA, Paik S. Development of the 21-gene assay and its
application in clinical practice and clinical trials. J Clin Oncol.
2008;26:721-8. PMID: 18258979.
10 Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene
expression and benefit of chemotherapy in women with nodenegative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-34. PMID: 16720680.
11 Sanpaolo P, Barbieri V, Genovesi D. Prognostic value of breast
cancer subtypes on breast cancer specific survival, distantmetastases and local relapse rates in conservatively managed
early stage breast cancer: a retrospective clinical study. Eur J
Surg Oncol. 2011;37:876-82. PMID: 21824742.
12 Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A
multigene assay to predict relapse of tamoxifen-treated, nodenegative breast cancer. N Engl J Med. 2004;351:2817-26.
PMID: 15591335.
13 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. PMID: 15897552.
14 Henderson IC, Berry DA, Demetri GD, Cirrincione CT,
Goldstein LJ, Martino S, et al. Improved outcomes fromadding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patientswith node-positive primary breast cancer. J Clin Oncol.
2003;21:976-83. PMID: 12637460.
15 Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM,
Jazaeri A, et al. Breast cancer classification and prognosis
based on gene expression profiles from a population-based
study. Proc Natl Acad Sci U S A. 2003;100:10393-8. PMID:
12917485.

The authors declare no conflict of interest.
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