Favorable Locoregional Control in Clinically Node- Negative Hormone-receptor Positive Breast Cancer With Low 21-gene Recurrence Scores: a Single Institutional Study With 10-year Follow-up

doi:10.21203/rs.3.rs-1856157/v1

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Research Article

Favorable Locoregional Control in Clinically Node- Negative Hormone-receptor Positive Breast Cancer With Low 21-gene Recurrence Scores: a Single Institutional Study With 10-year Follow-up

https://doi.org/10.21203/rs.3.rs-1856157/v1

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Background: Recent studies have shown a lower likelihood of locoregional recurrences in patients with low 21-gene recurrence score (RS). In this single institutional study, we investigated any associations between different cut-off values of 21-gene RS and histopathological factors and outcome in patients with long-term follow-up.

Methods: Between February 2010 to February 2013, 61 patients with early stage clinically node-negative hormone receptor-positive and HER2-negative breast cancer tested for the 21-gene RS assay, were included into the study. Demographic, clinicopathological, treatment and outcome characteristics were analyzed.

Results: Median age was 48 (range, 29-72). Of those, 53 patients were diagnosed with Stage 1 (86.9%) and 8 patients were Stage 2 (13.1%) following surgery. Patients with high histologic grade (HG), or with Ki-67>25%were more likely to have intermediate/high RS based on RS >11 and >18. Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy. At a median follow-up of 112 months, 3 patients developed local recurrences (4.9%) treated with endocrine therapy alone. Among patients treated with endocrine treatment alone (n=42), the clinicopathological characteristics including age <40, age <50, high histologic or nuclear grade, high Ki67-scores (>20%, >25%, >30%), presence of lymphovascular invasion, luminal-A type, multifocality, lymph node positivity, tumor size more than 2 cm, RS>18 or RS>11 were not significantly found to be associated with 10-year locoregional recurrence free survival (LRRFS). However, patients with a RS >16 have significantly shown a poorer 10-year LRRFS compared to those with RS <16 (RS <16; 100% vs RS>16; 75%, p=0.039).

Conclusions: These results suggest that Oncotpe DX assay may be of little value in patients with high histologic grade or high Ki67 scores (>25%) as treatment decision criteria to determine any benefit from chemotherapy. Furthermore, patients with a RS >16 are more likely to benefit from adjuvant chemotherapies, whereas those with a RS <16 have an excellent outcome and local control on long term follow-up with endocrine treatment alone.

oncotype dx scores

Ki-67

breast cancer

histologic grade

locoregional recurrence

Multigene prognostic gene assays have emerged to decide on the benefit of adjuvant chemotherapy in addtion to endocrine treatment in early stage, estrogen receptor (ER)-positive, HER2-negative breast cancer to guide the personalized management in the contemporary era of breast cancer treatment (1–6). Of those, the 21-gene recurrence score (RS) assay (Oncoype DX™, Genomic Health, Redwood City, CA) has been recommended by the National Comprehensive Cancer Network (NCCN) 2022 guidelines as widely used in USA (7).

The utility of this genetic assay has been validated in numerous clinical studies including “The Trial Assigning Individualized Options for Treatment (TAILORx) and RxPONDER trials in clinically lymph node negative and positive patients (8, 9). The TAILORx trial reported no chemotherapy benefit in women who were older than 50 years of age; however, in women who were 50 years of age or younger, adjuvant chemotherapy improved outcomes if the recurrence score was at between 16 to 25 (8). Similarly, recent findings from RxPONDER trial indicated that premenopausal women with node-positive disease and a recurrence score of 25 or lower, were found to have a better outcome with endocrine treatment in addition to chemotherapy compared to those with endocrine-treatment alone, whereas postmenopausal women with similar clinicopathological features did not show any benefit from adjuvant chemotherapy (9).

Furthermore, previous studies demonstrated no benefit of adjuvant chemotherapy in patients with ER-positive/HER2-negative breast cancer classified as molecularly defined luminal-A or immunohistochemically classified luminal-A like tumors tumors having excellent prognosis based on low Ki-67 index and progesterone receptor positivity (10–12). However, due to the interobserver variability in assessment of Ki-67 score (13, 14), it’s utility has been limited and not world-wide accepted in tailoring the adjuvant treatment of early stage hormone-receptor-positive breast cancer.

Recent few reports have also shown a lower likelihood of locoregional recurrences in patients with low 21-gene RS (15–18). In this single institutional study, we investigated any associations of locoregional recurrence with higher 21-gene RS in patients with early-stage ER-positive disease on long-term follow-up as primary aim. As secondary aim, we also investigated any associations of traditional biomarkers and histopathologic factors with Oncotype-DX recurrence RS whether to determine any of those factors could omit using 21-gene assay as a cost-effective strategy.

Consecutive female patients with early stage clinicaly node-negative ER- positive breast cancer tested for the 21-gene RS assay and underwent a surgery for breast cancer at the Acibadem Maslak Hospital with a follow-up more than 5-year after surgery were included into the study. This prospectively maintained data was retrospectively analyzed. Demographic, clinicopathological, treatment and outcome characteristics were analyzed. The study was approved by local institutional ethics committee at the Acibadem University, Faculty of Medicine.

Selected representative paraffine sections of the index tumor patients were studied by Genomic Health (Redwood City, CA, USA) to assess the Oncotype DX recurrence score determined by the 21-gene reverse transcriptase polymerase chain reaction (RT-PCR) using the RNA isolated from formalin-fixed paraffin-embedded tissue as decribed before (19). RT-PCR expression analysis (16 cancer related genes and 5 reference genes) evaluates the expression of 16 cancer related genes normalized to the expression of five reference genes and yields a numeric variable of RS on a scale of 0 to 100. Risk categories were determined according to the Oncotype DX® Recurrence Score® as: a) low risk group for scores < 18, b) intermediate risk group for scores between 18–30 c) high risk group for scores ≥ 31 as previously reported (2). Alternatively, patients were also stratified into three risk categories based on different RS cut-off scores: low risk (RS ≤ 11), intermediate risk (RS 11–25), and high risk (RS ≥ 25), as suggested before (8).

The results of the 21-gene RS assay were prospectively incorporated in the treatment plan as recommended (2). Most low risk patients were treated with adjuvant endocrine therapy, whereas most high risk patients received a combination of endocrine therapy and chemotherapy. Treatment of patients with intermediate RS was variable depending on various clinicopathologic features and individual choices. RS was not routinely considered in the selection of locoregional therapy. Results were correlated with histopathologic factors including: tumor size (≤ 2 cm vs > 2 cm), nuclear grade (NG), histologic grade (HG), lymphovascular invasion (LVI) and different cut-off values of Ki67 (10%≤, 15%≤, 20%≤, or 25%<).

ER or PR positivity were considered for any nuclear immunohistochemistry (IHC) staining > 1%. HER2-positivity was determined by IHC and FISH findings, whereas Ki-67 scores were determined as suggested before (13). The tumor subtypes according to the IHC staining were defined as follows (20): luminal A; ER(+) or PR(+), HER2-neu (-), Ki67 < 20%; luminal B, ER(+) or PR(+), HER2-neu (+) and/or Ki67 ≥ 20%; non-luminal HER2-neu(+), ER (-) PR(-) HER2-neu (+); triple-negative, ER(-) PR (-) HER2-neu (-).

Correlations were assessed between Oncotype DX expressions of ER, or PR, or, HER2, and IHC expressions of ER, PR, or HER2. Clinicopathologic variables included patient age at breast cancer diagnosis, tumor size, histologic type of tumor, LVI, 21-gene RS result, local and systemic treatment, and clinical outcome. For multifocal/multicentric carcinomas, the size of the largest tumor and the highest RS result were recorded. For one patient with metachronous bilateral ER+/HER2 − breast carcinomas with low RS, only the data pertaining to the first tumor were included. The institutional database and electronic medical records were reviewed to record date of last follow-up, date of death, date and type of LRR and distant recurrence.

Statistical Analysis

The statistical software program SPSS 25 (Statistical Package for Social Sciences; SPSS, IBM Corp., Armonk, NY, USA) was used for the statistical analyses. To assess the differences between the groups, categorical variables were evaluated by Pearson Chi-Square, and Fisher's Exact Tests in two-tailed univariate analyses.

Overall survival was calculated from date of pathologic diagnosis of breast cancer to date of last follow-up, estimated using Kaplan-Meier methods and compared using the log-rank test. Kaplan-Meier analyses were used for the survival curves test, and log rank test was used to compare different prognostic including different RS values affecting outcome. Disease-free survival (DFS) was analysed based local and systemic metastases, and disease-specific survival (DSS) rates was analysed based on breast cancer-related mortality. LRR was defined as invasive breast cancer involving the ipsilateral breast parenchyma, axilla, regional lymph nodes, chest wall, identified more than six months from the initial diagnosis of breast cancer. Univariate association of RS score on LRR was also examined among the subset of women treated with endocrine therapy and chemotherapy using the methods described above. All nodal recurrences of the axillary and supraclavicular and mammaria interna region, along with breast and chest wall recurrences were accepted as local recurrence (LR), and local recurrence free survival was analysed by considering local metastases. P-values were two-sided, and a p-value equal or less than 0.05 was considered as statistically significant.

Between February 2010 to February 2013, 61 consecutive female patients with early stage breast cancer with clinically node negative disease were included into the study. Median age was 48 (range, 29–72). Of those, 53 patients were diagnosed with Stage 1 (86.9%), and 8 patients were Stage 2 (13.1%) following surgery. The majority of patients had breast-conserving surgery (= BCS, n = 40; 65.6%) and sentinel lymph node biopsy (= SLNB, N = 21, 34.4%). Of 61 patients, 7 had (11.5%) axillary lymph node positivity and 6 patients underwent axillary dissection following SLNB. The demographic and clinicopathological characteristics of patients were shown in Tables 1 and 2.

Table 1

Clinicopathological characteristics of patients with clinically node negative hormone receptor positive HER2-neu-negative breast cancer tested for 21-gene recurrence score assay
Clinicopathological Characteristics	N (%)
Median Age (range, min-max)	48 (range, 29–72)
Premenopausal	35 (57.4%)
Postmenopausal	26 (42.6%)
Breast Surgery:
Breast conservation	40 (65.6%)
Mastectomy	21 (34.4%)
Axillary Surgery:
SLNB	55 (90.2%)
SLNB&ALND	6 (9.8%)
Type of axillary metastasis
Isolated tumor cell (pN0_ITC)	4 (0%)
Micrometastasis (pN_mic)	3 (42.9%)
Macrometastasis (pN₁)	4 (57.1%)
pT1	49 (80.3%)
pT2	12 (19.7%)
pN0	54 (88.5%)
pN1	7 (11.5%)
TNM Stage (7th vs 8th version)
Stage 1	44 (72.1%) vs 53 (86.9%)
Stage 2	17 (27.9%) vs 8 (13.1%)
Histopathology:
Invasive ductal carcinoma	53 (86.9%)
Invasive lobular carcinoma	5 (8.2%)
Musinous & tubular carcinoma	3 (4.9%)
ER positivity	61 (100%)
PR positivity	59 (96.7%)
Median Ki67 index (%, range)	15 (range, 1–57)
Luminal-A (by IHC)	42 (68.9%)
Median Follow-up	112 (range, 54–154)
Adjuvant Chemotherapy	19 (31.1%)
Postmastectomy radiation	2 (9.5%)

Table 2

Correlation of 21-gene Recurrence score (RS) including different cut-off values with Ki 67 scores and histopathologic factors
Characteristics	RS > 11	p-value	RS ≥ 18	p-value	RS > 25	p-value	RS > 31	p-value
pT1(n = 49) vs pT2 (n = 12)	39/49 (79.6%) vs 7/12 (58.3%)	0.147	20/49 (40.8%) vs 5/12 (41.7%)	0.999	5/49 (10.2%) vs 2/12 (16.7%)	0.615	4/49 (8.2%) vs 0/12 (0%)	0.576
HG low&intermediate (n = 51) vs high HG (n = 10)	36/51(71%) vs 10/10 (100%)	0.05	16/51(31%) vs 9/10 (90%)	0.001	3/51 (5.9%) vs 4/10 (40%)	0.011	2/51 (3.9%) vs 2/10 (20%)	0.122
NG low& intermediate (n = 45) vs high HG (n = 15)	32/45 (71.1%) vs 13/16 (81.25%)	0.313	15/45 (33.3%) vs 9/15 (60%)	0.126	1/45 (2.2%) vs 5/15 (33.3%)	0.003	1/45 (2.2%)vs 3/45 (6.7%)	0.045
LVI (-) (n = 49) vs LVI(+) (n = 10)	35/49 (71.4%) vs 9/10 (90%)	0.426	17/49 (34.7%) vs 6/10 (60%)	0.166	5/49 (10.2%) vs 1/10 (10%)	0.999	3/49 (6.1%)vs 1/10 (10%)	0.534
Ki67 < 15% (n = 29) vs ≥ 15% (n = 32)	20/29 (69%) vs 26/32 (81.25%)	0.374	11/29 (37.9%) vs 14/32 (43.75%)	0.795	1/29 (3.4%) vs 8/32 (25%)	0.106	1/29 (3.4%) vs 3/32 (9.4%)	0.615
Ki67 < 20% (n = 42) vs ≥ 20% (n = 19)	31/42 (7.4%) vs 15/19 (79%)	0.757	15/42 (35.7%) vs 10/19 (52.6%)	0.266	3/42 (7.1%) vs 4/19 (21%)	0.190	2/42 (4.8%) vs 10/19 (52.6%)	0.266
Ki67 < 25% (n = 50) vs ≥ 25% (n = 11)	37/50 (74%) vs 9/11 (81.8%)	0.716	17/50 (34%) vs 8/11 (72.7%)	0.038	3/50 (6%) vs 4/11 (36.4%)	0.016	2/50 (4%) vs 2/11 (18.2%)	0.146
Ki67 < 30% (n = 53) vs ≥ 30% (n = 8)	39/53 (73.6%) vs 7/8 (87.5)	0.666	18/53 (34%) vs 7/8 (87.5%)	0.006	3/53 (5.7%) vs 4/8 (50%)	0.004	2/53 (3.8%) vs 2/8 (25%)	0.08
Recurrence score = RS

The majority of the patients had invasive ductal carcinoma (81.6%), low or intermediate nuclear (= NG, n = 45, 73.8%) or histologic grade (= HG, n = 51, 83.6%) tumors and all tumors were hormone-receptor positive and HER2-negative and the majority had no lymphovascular invasion (n = 49, 80.3%). Median Ki-67 score was 15% (range, 1%-57%). The associations between histopathological variables and different RS cut-off scores were shown in Table 2. Patients with high HG were more likely to have a RS > 11 or ≥ 18 or > 25, whereas patients with high NG were more likely to have a RS > 25 or > 31. Similarly, patients with Ki-67 ≥ 25 or > 31 were more likely to have a RS ≥ 18 or > 25. Briefly, patients with high HG (RS > 11; 100% vs 71%, p = 0.05, RS ≥ 18, 90% vs 31%, p = 0.001), or with Ki-67 ≥25% (RS ≥ 18; 73% vs 34%, p = 0.038) were more likely to have intermediate/high RS based on RS > 11 and ≥ 18 (Table 2). The other associations did not reach the statistical significance.

Outcome

Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy, and 2 patients had postmastectomy radiation (9.5%). At a median follow-up of 112 months (range, 60–160 months), 3 patients developed local recurrences (4.9%) treated with endocrine therapy alone. The clinicopathological characteristics of patients were shown in Table 3. Of those, two patients had locoregional recurrences including axillary and supraclavicular region with adjuvant radiation to the chest wall. The other patient had a local recurrence in breast at the previously operated region of the primary tumor despite adjuvant radiation to the breast following surgery. All patients had unifocal tumors with a IHC classification as luminal A having a ER and PR-positivity > 50%, and Ki-67 < 20%, and developed local recurrences at a median time of 105 month (range, 96–107 months) on long term follow-up. Interestingly, all patients had a RS > 16 which is an intermediate score between 11–25 according to the TAILOR-X and RxPONDER trials.

Table 3

Clinicopathological characteristics of patients with locoregional recurrence treated with endocrine therapy alone decision made by the 21-gene RS to omit adjuvant chemotherapy
Characteristics	Patient 1	Patient 2	Patient 3
LR type	Breast recurrence	SupraclavicularLN metastasis	Axillary LN metastasis
Family history	No	No	No
Age	50	52	29
Surgery type	BCS&SLNB	BCS&SLNB	Mastectomy&SLNB
Surgical margin distance	10 mm	10 mm	4 mm
Tumor size/ pTNM	1.1 cm/ pT1N0	3 cm/ pT2N0	2 cm/ pT1N0
Histopathology	IDC	IDC	IDC
Histological/ Nuclear Grade	2/2	2/2	2/2
LVI	No	No	No
Multifocality/ extensive intraductal component	No/No	No/No	No/Yes
ER rate /PR rate	100%/100%	95%/30%	95%/70%
Ki67 score	10%	11%	18%
21-gene RS	21	17	17
Adjuvant Radiotherapy	Yes	Yes	Yes
Adjuvant Chemotherapy	No	No	No
Type of endocrine therapy	Tamoxifen/leuprolide acetate	letrazol	Tamoxifen/leuprolide acetate
LR time after surgery	98 months	107 months	105 months

The 10-year disase free survival (DFS) and locoregional recurrence free survival (LRRFS) rates were 92.8% in the present cohort. Patients with a RS ≥ 16 were found to have a poorer 10-year LRRFS as 88% compared to those with RS < 16 as 100% (p = 0.149, Fig. 1a). Among patients treated with endocrine treatment alone (n = 42), the clinicopathological characteristics including age < 40, age < 50, high histologic or nuclear grade, high Ki67-scores (≥ 20%, > 25%, > 30%), presence of lymphovascular invasion, luminal A type, multifocality, lymph node positivity, tumor size more than 2 cm, RS ≥ 18 or RS > 11 were not significantly found to be associated with 10-year LRRFS. However, patients with a RS ≥ 16 have significantly shown a poorer 10-year LRRFS (RS < 16; 100% vs RS ≥ 16; 75%, p = 0.039) as demonstrated in Table 4 (Fig. 1b).

Table 4

Clinicopathologic factors and 21-gene Recurrence Score (= RS) associated with disease free survival (DFS) and locoregional recurrence free survival free survival (= LRRFS). (DFS is equal to LRRFS since none of the patients developed distant metastases)
Factors	10- year LRRFS = 10-year DFS	p-value
Total (N = 61)
RS ≤ 11 vs RS > 11	100% vs 90.2%	0.292
RS < 16 vs RS ≥ 16	100% vs 88%	0.149
RS < 18 vs RS ≥ 18	91.6% vs 94.1%	0.808
Without Adjuvant Chemotherapy (n = 42)
RS ≤ 11 vs RS > 11	100% vs 83%	0.180
RS < 16 vs RS ≥ 16	100% vs 75%	0.039
RS < 18 vs RS ≥ 18	91.3% vs 75%	0.274

Among various multigene prognostic gene assays, the 21-gene RS assay has been more widely used in patients recommended in AJCC TNM 8th edition to be classified as early stage, ER+/HER2- breast cancer or to be spared from unnecessary adjuvant chemotherapies as recommended by NCCN guidelines when detected with a low RS (7). The 21-gen RS assay was initially developed to assess the distant recurrence risk as validated in patient samples from the from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials B-14 and B-20 (2). However, its clinical utility to estimate the locoregional recurrence risk is relatively less studied so far, and not well established in patients with long-term follow-up. In this single institutional study with 10-year follow-up, we demonstrated that patients with early stage ER-positive HER2(-) breast cancer having a RS < 16, and mostly presented with lymph node-negative breast cancer, have shown an excellent prognosis with endocrine treatment alone without any locoregional recurrence. However, patients with a RS > 16 were found to have a poorer 10-year DFS and LRRFS treated with endocrine treatment alone similar to the findings in the recently published TAILORx study (8). In the TAILORx-study included only lymph-node negative patients, associations between various RS cut-off values and benefit from chemotherapy to improve the DFS have demonstrated some benefit of chemotherapy in patients ≤ 50 years with a RS in the range of 16 to 25 with a 9-year DFS rate of 83.3% in the patient subgroup treated with endocrine treatment alone (8).

Mamounas et al.first studied the association of locoregional recurrence with 21-gene RS assay scores in tamoxifen-treated patients with node-negative, ER-positive breast cancer of NSABP B-14 and B-20 studies (15). Of 895 tamoxifen-treated patients, significant associations were found between RS and LRR in patient cohorts of both trials, and RS was also demonstrated as an independent significant predictor of LRR in multivariate analysis. Similarly, Turashvili et al further investigated the relationship between 21-gene RS and LRR risk among 2326 patients with node-negative, ER+/HER2- breast cancer treated at the Memorial Sloan Kettering Cancer Center from 2008 to 2013 (16). At a median follow-up of 53 months. Patients with intermediate and high RS were more liklely to have LRR compared to the patients with low RS with a hazard ratio of 2.81 ( 95% CI 1.41–5.56, p < 0.01) and a hazard ratio of 4.61, (95% CI 1.90-11.19, p < 0.01), respectively. A recent report from the same institution also indicated that extremely low rates of LRR were observed as 0.7% (8/1184) among patients with a low RS < 18 treated with endocrine therapy alone (17).

However, some reports (21) could not find a correlation between ipsilateral breast tumor recurrence (IBTR) and RS, even though Ki-67 expression was significantly associated with both IBTR (p = .019) and the RS (p = .002). Furthermore, an increased risk of locoregional recurrences were also demonstrated in node-positive ER-positive patients with high RS that may justify postmastectomy radiation or more extensive radiation along with other known clinicopathologic factors including tumor size and LVI (22–25). Finally, a recent metaanalyses including 16 studies with 21,037 patients investigated the association of RS with LRR in ER+/HER2- breast cancer with a mean follow-up of 66.4 months (18). Patients with RS 18–30 and RS > 30 were significantly more likely to develop LRR than those with RS < 18 with an increased relative risk (RR) of 1.76 (95% confidence interval (CI): 1.32–2.37) and a RR of 3.45, (95% CI: 2.63–4.53), respectively. Similarly, by using TAILORx cut-offs, those with RS > 25 had an increased risk of LRR with a RR of 2.49 (95% CI: 0.68–9.39) compared to those with RS < 11. In the present report, our study cohort included mostly patients presented with luminal A type node negative disease having low Ki-67 index. In concordance with previous reports, our findings also have demonstrated that 21-gene RS > 16 was significantly associated with the 10-year LRRFS among patients with good clinicopathologic characteristics on long-term follow-up.

The findings in the present study also indicated that patients with high HG, or with Ki-67 ≥25% were more likely to have intermediate/high RS based on RS > 11 and ≥ 18 in concordance with previous studies that similarly demonstrated a significant association between increasing RS and higher Ki67 values (26–32). However, Ki-67 proliferation value is a major, but not the sole determinant of Oncotype Dx score (26). Therefore, some tumors with a low RS may reveal a surprisingly high Ki-67, whereas a small percentage of Luminal-A like tumors with low Ki-67 index have a RS > 25 for whom chemotherapy is recommended (27, 32). These findings suggest that immunohistochemical evaluation of markers of proliferation including Ki67 may provide useful prognostic information, at lower cost than 21-gene RS assay since IHC assessment of Ki-67 expression is less expensive than Oncotype Dx testing to make a decision, who will benefit from adjuvant chemotherapy. Ki-67 has the potential to support patient selection for genomic testing even though it may always not replace 21-gene assay and can help physicians to make an accurate decision on chemotherapy use. However, it’s clinical uitlity has been questioned due to the lack of consensus on scoring and has only “AJCC Level III” in the new AJCC edition. Therefore, alternative nomograms or alternative multivariable models called Magee Equations™ (ME) that can estimate oncotype score were developed (33, 34). These models use routinely reported histopathology and breast cancer biomarker data to provide a score similar to oncotype Magee Decision Algorithm™: use of Magee Equations™ and mitosis score (34). Other models alternatively included nomograms based on routine clinicopathologic variables including age, tumor size, tumor grade, PR status, lymph-vascular invasion (LVI), and histologic type of breast cancer are developed to to predict the 21-gene RS (33). However, whether these models could accurately replace 21-gene RS assay should be validated in further prospective studies.

In conclusion, our results here suggest that Oncotpe DX assay may be of little value in patients with high histologic grade or high Ki67 scores (> 25%) as treatment selection criteria to determine any benefit from chemotherapy. Considering the cost of these gene assays, careful selection of patients is needed. However, their clinical utility should be studied in prospective trials. Furthermore, patients with a RS ≥ 16 are more likely to benefit from adjuvant chemotherapies on long term follow-up to obtain excellent outcome and local control. Future prospective, randomized studies are required to further investigate the clinical utility of RS testing to estimate the LRR risk and to establish better locoregional control in high-risk cases.

Ethics approval and consent to participate

The study was approved by the ethical committee of Acibadem University, Medical Faculty in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration (2022-09/08). Informed consent was obtained from all individual participants included in the study.

Consent for publication: All authors have read and gave consent for publication.

Availability of data and material: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The following authors “CU, NC, FT, ÖE, HK, TK, NB, UI” have no conflict of interest.

Funding : None.

Authors’ contributions:

The study was designed by CU, and NC. The initial search, literature organization, analyses and manuscript writing were performed by NC and CU. Data acquisition was provided by CU, OE, NC, HK, TK, FT, UI, NB, Critical comments and typesetting corrections on the final version were made by CU, OE, NC, HK, TK, FT, UI, and NB All authors have read and revised the manuscript critically.

Acknowledgments: Not applicable

Authors Information (optional): Not applicable

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No competing interests reported.

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Favorable Locoregional Control in Clinically Node- Negative Hormone-receptor Positive Breast Cancer With Low 21-gene Recurrence Scores: a Single Institutional Study With 10-year Follow-up

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