This study investigated the predictive responsiveness of NACT to tumors and identified factors related to NACT using the BCT score in HR+/HER2- BC with metastatic LN. We demonstrated that the high-response group could predict pCR and PR for NACT in HR+/HER2- BC with metastatic LN.
Although NACT has been established as a standard treatment option for HER2 + and triple-negative BC (TNBC) subtypes, many oncologists still have difficulty determining NACT in HR + BC because of the low rate of pCR and limited benefit of NACT for HR + BC4. As the application of ACOSOG Z0011 and AMAROS to axillary treatment has expanded and pCR rate has increased in the HER2 and TNBC subtypes in NACT, axillary de-escalation is increasing in patients with positive axillary LN11–13. Ironically, although luminal type breast cancers show favorable biologic characteristics compared with HER2 and TNBC subtypes, axillary LN dissection continues in terms of axillary treatment in the luminal subtype14. Therefore, many efforts are being made to predict the responsiveness of NACT in HR + BC using various modalities such as multigene assay and clinicopathologic scale.
Recently, attempts have been made to predict the responsiveness of NACT using multigene assays in HR+/HER2- BC. The BCT score was developed to predict the risk of distant metastasis and responsiveness of chemotherapy using five proliferation-related genes, one immune response-related gene, and clinical information such as tumor size and nodal status15,16. Through this study, it was shown that concordant results were obtained when comparing the predictive power of pCR with existing gene tests in predicting NACT responsiveness (Table 5)8,9,17−22.
Table 5
Comparison table of multigene assay for predicting NACT responsiveness in hormone receptor-positive breast cancer.
Strongly ER + patients (n = 79)
|
Univariate
|
Multivariate
|
Parameter
|
OR (95% C.I.)
|
p-value
|
OR (95% C.I.)
|
p-value
|
BCT score (low versus high)
|
5.33 (1.87–16.96)
|
0.003
|
4.18 (1.34–14.28)
|
0.016
|
cT stage (cT1 or 2 versus cT3 or 4)
|
0.44 (0.17–1.07)
|
0.074
|
0.58 (0.20–1.65)
|
0.303
|
cN stage (cN1 versus cN2 or 3)
|
1.08 (0.40–3.03)
|
0.876
|
0.89 (0.28–2.93)
|
0.847
|
Ki-67 (1 + versus > 1+)
|
3.81 (1.50-10.16)
|
0.006
|
2.74 (0.99–7.79)
|
0.054
|
|
Multigene assay
|
Sample (no.)
|
pCR (%)
|
pCR or PR (%)
|
Age
(mean)
|
cT1 or 2 (%)
|
cT3+ (%)
|
cN0 (%)
|
cN+ (%)
|
Tumor grade 1 (%)
|
Tumor grade 2/3 (%)
|
Ki-67 > 1+
|
Odds Ratio
|
A.M.Pease
et al. (2019)
|
Oncotype Dx®
|
989
|
42 (4.3)
|
N/A
|
54.6
|
882 (89.2)
|
107 (10.8)
|
757 (76.5)
|
232 (23.5)
|
123 (12.4)
|
866
(87.6)
|
N/A
|
4.87 [2.01–11.82]
|
H. Iwata
et al. (2019)
|
Oncotype Dx®
|
295
|
N/A
|
133
(45.1)
|
63.0
|
295
(100)
|
0
(0)
|
295
(100)
|
0
(0)
|
195
(66.1)
|
86
(29.2)
|
184
(62.4)
|
0.06 [0.01–0.18]
|
J.A.Pardo
et al. (2021)
|
Oncotype Dx®
|
158
|
10
(6.3)
|
N/A
|
N/A
|
158
(100)
|
0
(0)
|
0
(0)
|
158
(100)
|
105
(66.5)
|
53
(33.5)
|
N/A
|
3.16 [1.06–9.45]
|
T. Sella et al. (2021)
|
Oncotype Dx®
|
76
|
10
(13.2)
|
N/A
|
35.9
|
51
(67.1)
|
25
(32.9)
|
20
(26.3)
|
56
(73.7)
|
4
(5.3)
|
71
(93.4)
|
N/A
|
4.80 [0.95–24.34]
|
A.M.Ohara (2019)
|
Prosigna™
(PAM50)
|
124
|
12
(9.7)
|
N/A
|
51.3
|
98
(79.0)
|
26
(21.0)
|
41
(33.1)
|
83
(66.9)
|
25
(20.2)
|
99
(79.8)
|
59
(47.6)
|
6.98 [1.17-133.97]
|
F.Bertucci
et al.(2014)
|
EndoPredict®
|
553
|
64
(11.6)
|
N/A
|
49.0
|
40
(7.2)
|
512
(92.6)
|
183
(33.1)
|
336
(60.8)
|
47
(8.50)
|
464
(83.9)
|
N/A
|
1.13 [1.04–1.24]
|
P.C.Dubsky
et al.(2020)
|
EndoPredict®
|
134
|
N/A
|
N/A
|
N/A
|
116
(86.6)
|
18
(13.4)
|
69
(51.5)
|
63
(47.0)
|
1
(0.7)
|
121
(90.3)
|
N/A
|
1.44 [1.20–1.74]
|
M.C.Mathieu, el al. (2012)
|
Breast Cancer IndexSM
|
150
|
22
(14.7)
|
N/A
|
51.0
|
97
(64.7)
|
53
(35.3)
|
70
(46.7)
|
76
(50.7)
|
16
(10.7)
|
132
(88.0)
|
N/A
|
26.25 [3.19-216.24]
|
Present study
|
GenesWell™ BCT
|
88
|
6
(6.8)
|
50
(56.8)
|
N/A
|
53
(60.2)
|
35
(39.8)
|
0
(0)
|
87 (98.9)
|
18
(20.5)
|
67
(76.1)
|
54 (61.4)
|
4.18 [1.34–14.28]
|
According to the latest ASCO/CAP guidelines, only 1%-10% of ER expression by IHC is divided by low positive ER23. Low ER has a property similar to basal-like gene expression profiles as shown in the TNBC subtype; thus, it is emerging as an important prognostic factor for consideration of NACT24,25. Moreover, in the case of the strongly ER + group in this study, the predictive power of pCR and PR was higher in the BCT high response group than in the all-patient group. In other words, the response to NACT was high even in the BCT low-response group in the case of the weakly ER + group. Therefore, our results demonstrate that the BCT score clearly predicts tumor response and is an independent factor for predicting tumor response in NACT, especially in strongly ER + patients.
Although this study is a retrospective, single-center study with a small sample size, it is significant as it predicted the NACT response from the core biopsy sample for the first time using the BCT score. In addition, efforts have also been made to predict the responsiveness of neoadjuvant endocrine therapy (NET) by multigene assay21,26. Further studies are needed to prove the predictive potential of the BCT score response to NET in Asian patients with BC because many multigene assays have been developed with a focus on the Western population27,28. Although the number of patients with pCR was so small that we could not show the BCT score as a tool to determine surgical de-escalation, the BCT score might be a helpful gene test for determining the surgical treatment plan after NACT if larger populations are included.
In conclusion, we demonstrated that the BCT score predicts NACT responsiveness in HR+/HER2- BC with LN metastasis. The BCT score might be an early surrogate of prognostic signatures for predicting the response of NACT in HR+/HER2- BC with LN metastasis. Therefore, the BCT score might be a helpful tool for predicting NACT responsiveness in HR+/HER2- BC with LN metastasis. Further validation using the BCT score and prospective studies is needed to increase the accuracy of the prediction of the NACT response.