Oncological outcomes in patients with residual triple-negative breast cancer after preoperative chemotherapy

Hyunki Park; Haeyoung Kim; Won Park; Won Kyung Cho; Nalee Kim; Tae Gyu Kim; Young-Hyuck Im; Jin Seok Ahn; Yeon Hee Park; Ji-Yeon Kim; Seok Jin Nam; Seok Won Kim; Jeong Eon Lee; Jonghan Yu; Byung Joo Chae; Sei Kyung Lee; Jai-Min Ryu

doi:10.3857/roj.2024.00087

Radiation Oncology Journal > Volume 42(3); 2024 > Article

Park, Kim, Park, Cho, Kim, Kim, Im, Ahn, Park, Kim, Nam, Kim, Lee, Yu, Chae, Lee, and Ryu: Oncological outcomes in patients with residual triple-negative breast cancer after preoperative chemotherapy

Original Article

Radiation Oncology Journal 2024; 42(3): 210-217.

Published online: September 20, 2024

DOI: https://doi.org/10.3857/roj.2024.00087

Oncological outcomes in patients with residual triple-negative breast cancer after preoperative chemotherapy

Hyunki Park¹, Haeyoung Kim¹

, Won Park¹, Won Kyung Cho¹, Nalee Kim¹, Tae Gyu Kim², Young-Hyuck Im³, Jin Seok Ahn³, Yeon Hee Park³, Ji-Yeon Kim³, Seok Jin Nam⁴, Seok Won Kim⁴, Jeong Eon Lee³, Jonghan Yu⁴, Byung Joo Chae⁴, Sei Kyung Lee⁴, Jai-Min Ryu⁴

¹Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

²Department of Radiation Oncology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea

³Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

⁴Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Correspondence: Haeyoung Kim Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea.
Tel: +82-2-3410-2612 E-mail: haeyoung0131.kim@samsung.com

Received January 25, 2024 Revised June 26, 2024 Accepted July 2, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

This study aimed to evaluate the clinical outcomes and prognostic implications of regional nodal irradiation (RNI) after neoadjuvant chemotherapy (NAC) in patients with residual triple-negative breast cancer (TNBC).

Materials and Methods

We analyzed 152 patients with residual TNBC who underwent breast-conserving surgery after NAC between December 2008 and December 2017. Most patients (n = 133; 87.5%) received taxane-based chemotherapy. Adjuvant radiotherapy (RT) was administered at a total dose of 45–65 Gy in 15–30 fractions to the whole breast, with some patients also receiving RT to regional nodes. Survival was calculated using the Kaplan–Meier method, and prognostic factors influencing survival were analyzed using the Cox proportional-hazards model.

Results

During a median follow-up of 66 months (range, 9 to 179 months), the 5-year disease-free survival (DFS) rate was 68.0%. The 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 83.6%, 72.6%, and 78.7%, respectively. In the univariate analysis, the cN stage, ypT stage, ypN stage, axillary operation type, and RT field were associated with DFS. Multivariate analysis revealed that higher ypT stage (hazard ratio [HR] = 2.0; 95% confidence interval [CI] 1.00–3.82; p = 0.049) and ypN stage (HR = 4.7; 95% CI 1.57–14.24; p = 0.006) were associated with inferior DFS. Among clinically node-positive patients, those who received RT to the breast only had a 5-year DFS of 73.7%, whereas those who received RNI achieved a DFS of 59.6% (p = 0.164). There were no differences between the DFS and RNI.

Conclusion

In patients with residual TNBC, higher ypT and ypN stages were associated with poorer outcomes after NAC. RNI did not appear to improve DFS. More intensive treatments incorporating systemic therapy and RT should be considered for these patients.

Keywords: Triple negative breast neoplasms, Neoadjuvant chemotherapy, Pathologic complete response, Treatment outcome, Lymphatic irradiations

Introduction

Breast cancer is the most common cancer in women worldwide, accounting for 11.7% of all cancer types [1]. Triple-negative breast cancer (TNBC), defined as the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is known to have a heterogeneous course, prognoses, sensitivities to therapy, and other diverse characteristics owing to the distinct genetic backgrounds [2]. Considering all breast cancer subtypes, TNBC has been associated with a higher rate of locoregional recurrence, distant metastasis (DM), and poorer prognosis than endocrine-sensitive tumors [3-5].

Although TNBC is known to exhibit aggressive behavior, it paradoxically demonstrates high sensitivity to cytotoxic chemotherapy, which is termed the triple-negative paradox [6]. The standard therapeutic approach for TNBC involves a sequential regimen of neoadjuvant chemotherapy (NAC), followed by surgical resection (OP) and adjuvant radiotherapy (RT) [7]. The importance of achieving pathological complete response (pCR) in determining patient outcomes has been established previously [8,9]. Patients with residual disease (non-ypCR) after NAC have a 20%–30% risk of relapse [10]. In recent years, efforts have been made to improve patient outcomes by enhancing pCR rates. Randomized trials have demonstrated that the addition of platinum-based chemotherapy or bevacizumab to TNBC therapy can enhance pCR rates and survival outcomes [11-14]. Notably, the KEYNOTE522 trial [15], which combined pembrolizumab with NAC, showed improved pCR and survival outcomes. The CREATE-X study enriched the paradigm for TNBC patients with residual disease by introducing capecitabine (Xeloda; Roche, Basel, Switzerland) as a systemic therapy option to potentially enhance outcomes [16]. Although systemic therapy with capecitabine has been established for patients with residual disease, the optimal approach to radiotherapy remains uncertain. In particular, the application of regional nodal irradiation (RNI) lacks definite guidance [17,18].

In the current study, we aimed to evaluate the prognosis of patients with residual disease (non-ypCR) and determine how prognosis varies based on RT patterns.

Materials and Methods

1. Patients

We retrospectively reviewed the medical records of 152 patients who underwent breast-conserving surgery and had residual TNBC post-NAC at the Samsung Medical Center in Seoul, Korea between December 2008 and December 2017. All patients received adjuvant RT. Residual TNBC was defined as the presence of residual invasive cancer at the primary site or lymph nodes. Most patients (n = 133; 87.5%) received taxane-based chemotherapy, while non-taxane-based NAC regimens comprised doxorubicin/carboplatin or gemcitabine/cisplatin. For adjuvant RT, a total dose of 45–65 Gy was delivered in 15–30 fractions, and most patients (94.2%) were treated using the 3D conformal RT technique. Among these patients, 98 patients (61.5%) received RNI, including the axillary level 3, supraclavicular node (SCN), and internal mammary node (IMN). According to our institutional policy, RNI was administered to patients with any of the following risk factors: cT3-4, cN+, breast tumor > 5 cm at pre-NAC evaluation, ypN1-3, or ypT3-4 (Table 1).

2. Immunohistochemistry

Immunohistochemical analysis was performed to examine expression levels of receptors, including ER, PR, and HER2, on the surface of tumor cells, from the initial tumor prior to NAC. Silver-enhanced in situ hybridization (SISH) was used to evaluate equivocal HER2 signals, and only SISH-negative patients were included. Ki-67 staining was performed using a Ventana Discovery Autostainer (Surplus Solution, Woonsocket, RI, USA), with the antibody MIB-1 (Agilent Technologies, Santa Clara, CA, USA), and expression was graded by pathologists. For semi-quantitative analysis, Ki-67 signals were graded as follows: 0%–25%, 1+; 25%–50%, 2+; 50%–75%, 3+; and >75%, 4+.

3. Clinical outcome assessment

Locoregional recurrence (LRR) was defined as the initial occurrence of failure in the ipsilateral breast or regional lymph nodes. Disease-free survival (DFS) was calculated as the period between the first day of NAC and the date of clinical or pathological diagnosis of recurrence, metastasis, or death related to breast cancer. Overall survival (OS) was defined as the duration from the first day of NAC to death from any cause.

4. Statistical analysis

Prognostic factors for DFS were calculated using the Kaplan–Meier method and the Cox proportional-hazards model. Multivariate analyses were performed to identify significant prognostic factors for DFS using the Cox proportional-hazards regression model, considering variables with p-values <0.10 from the univariate analysis. All analyses were conducted using SPSS Statistics for Windows version 27 (IBM, Armonk, NY, USA).

Results

1. Patients and tumor characteristics

The median age of the study population was 45 years (range, 24 to 72), and the primary pathological type was invasive ductal carcinoma (96.7%). Regarding clinical TNM staging, 76.3% of the patients had lymph node metastasis, with 53.9% exclusively presenting with axillary lymph node (ALN) involvement. Furthermore, 63.8% patients had no lymph node metastasis after NAC (ypN0), and among ypN+ patients, two patients had non-ALN involvement. Ki-67 >3+ was detected in 57.3% of patients, and 59.2% of tumors were located on the lateral side of the breast. Other patient and tumor characteristics are shown in Table 1.

2. Clinical outcomes

The median follow-up time was 66 months (range, 9 to 179), and the 5-year DFS, LRR-free survival, DM-free survival, and OS rates were 68.0%, 83.6%, 72.6%, and 78.7%, respectively (Figs. 1, 2). The univariate analysis identified cN stage (hazard ratio [HR] = 3.9; 95% confidence interval [CI] 1.54–9.79; p = 0.004), ypT stage (HR = 1.8; 95% CI 1.02–3.30; p = 0.039), ypN stage (HR = 6.8; 95% CI 2.54–18.25; p < 0.001), ypStage (HR = 3.6; 95% CI 1.85–7.07; p < 0.001), Axillary OP (HR = 2.4; 95% CI 1.26–4.50; p = 0.006), and RT field (HR = 2.1; 95% CI 1.08–3.94; p = 0.029) as significant factors. The multivariate analysis revealed that ypT stage (HR = 2.0; 95% CI 1.00–3.82; p = 0.049) and ypN stage (HR = 4.7; 95% CI 1.57–14.24; p = 0.006) were associated with DFS (Table 2). Regarding cN stage, the 5-year DFS rates for cN0 and cN+ patients were 86.1% and 62.5%, respectively (Fig. 3). For cN+ patients, the 5-year DFS and OS were 73.7% and 83.9% when RT was only administered to the whole breast (WB)/chest wall (CW), and 59.6% and 100% on including regional nodes (p = 0.164, p = 0.353) (Table 3). Conversely, for cN0 patients, the 5-year DFS and OS were 83.9% and 93.5% when RT was administered only to the WB/CW and 100% on adding RNI (p = 0.353, p = 0.567). Additionally, 5-year DFS with RNI was 61.5%, and 79.5% without RNI in the overall cohort (p = 0.026) (Fig. 4). However, the 5-year DFS rate by RT field did not differ regardless of the ypN stage (p = 0.089) (Table 4).

3. Patterns of first failure

Among the 152 patients with residual TNBC, 49 (32.2%) experienced recurrence (Table 3). The recurrence rate was higher in clinically lymph node-positive (cN+) patients. The LRR rate for cN0 was 2.8%, and the DM only rate was 13.9%. Patients without ALN invasion had higher recurrence rates than those without ALN invasion. ALN+ and non-ALN+ patients had LRR rates of 7.3% and 14.7%, and DM rates of 14.6% and 23.5%, respectively. The most common sites of LRR were the ipsilateral breast, IMN, and SCN, whereas the most common DM sites were the lungs, followed by the bones and brain.

4. Patterns of failure by RT field

RNI was performed in five cN0 patients (13.9%) and 92 cN+ patients (79.3%). Recurrence occurred in 16.7% of cN0 patients who received WB or CW irradiation alone, whereas none of the RNI-administered cN0 patients experienced recurrence. The overall recurrence rates of cN+ (ALN) patients were 7.3% and 24.4% in the WB/CW-only and WB/CW plus RNI groups, respectively. For cN+ (non-ALN) patients, the overall recurrence rates were 20.5% in the WB/CW plus SCN group, 8.8% in the WB/CW plus IMN group, and 20.6% in the WB/CW plus SCN and IMN groups, respectively (Table 3). In the ypN+ (ALN) patient group, 49 (92.5%) patients received RNI, while the four patients who did not receive RNI were ypT1mi or had a tumor size ≤1 cm or ypN1mi patients. Among ypN+ (ALN) patients, there was no difference in recurrence rates or sites by the RT field (Table 4).

Discussion and Conclusion

The current study, involving 152 patients with residual TNBC who underwent NAC followed by OP and adjuvant RT, showed that the ypT and ypN stages were significant prognostic factors for TNBC.

In the RT field, RNI failed to improve the DFS rate in the present study. Noh et al. [19] reported that nodal relapse is more common in patients with TNBC than in those without it. Regarding RNI (IMN or SCN), the administration of RT to IMN or SCN does not benefit survival [20,21]. Kim et al. [22] analyzed 353 breast cancer patients with SCN and/or IMN involvement who were treated with NAC, followed by surgery and adjuvant RT, reporting clinical outcomes similar to those observed in the current study. The 5-year DFS and OS rates were 57.8% and 75.1%. Considering non-CR patients, those who received higher RT doses to the SCN (≥54 Gy) experienced failure more frequently than those who received lower RT doses (<54 Gy) (25.0% vs. 2.3%; p = 0.005). Although IMN RT was associated with low IMN failure, no survival benefits were observed. Given that DM is responsible for most treatment failures, RNI may fail to substantially impact DFS or OS. Likewise, the lack of a survival benefits with RNI in the current study may be due to patients receiving RNI already having a worse disease profile. Further studies are required to confirm the efficacy of RNI in the treatment of TNBC.

In the CREATE-X trial, the addition of adjuvant capecitabine therapy was found to improve DFS and OS in patients with HER2-negative breast cancer who had residual invasive disease, subsequently established as the standard of care [16]. However, the current study analyzed patients treated between 2008 and 2017, with capecitabine administered to only a small number of patients. Studies evaluating the role of RNI in this population must consider the heterogeneity of treatment approaches and their effects on outcomes. Therefore, there are inherent limitations in determining the role of RNI in the current standard of care.

Patients with TNBC without a pCR following NAC experience substantially higher LRR rates than those with other subtypes, even after surgery and adjuvant RT. All LRRs occurred in or near the RT field [23]. Tissues adjacent to TNBC are reportedly enriched with cancer stem cells, which may be more radioresistant and cause a higher LRR rate in patients with non-pCR [24]. Consequently, a higher ypT stage may be associated with poorer DFS. Our findings corroborate the existing literature documenting a compelling relationship between the ypT stage and adverse prognostic outcomes in TNBC. Patients with advanced ypT stages exhibited a propensity toward higher rates of disease recurrence, DM, and mortality, reflecting the aggressive biological behavior inherent to this disease entity. This observation aligns with previous studies highlighting the prognostic significance of tumor size in TNBC, wherein a larger tumor burden portends worse clinical outcomes [25-27]. The underlying mechanisms driving the association between the ypT stage and poor prognosis in TNBC are multifaceted, encompassing both tumor-related factors and treatment response dynamics. Advanced tumor stages are frequently associated with increased tumor aggressiveness, characterized by enhanced proliferative capacity, invasiveness, and metastatic potential, thereby predisposing patients to disease dissemination and therapeutic resistance. Additionally, the presence of residual disease following neoadjuvant therapy signifies an incomplete treatment response, indicative of intrinsic tumor resistance mechanisms and a heightened risk of disease relapse.

This study had a few limitations. The current study found no survival benefit by the RT field, which differs from the previously reported findings of radiation oncologists that observe that RNI elicits a survival benefit. However, the retrospective nature of the study, short median follow-up, and small number of patients need to be considered; hence, further studies on survival by the RT field are warranted. Moreover, the Ki-67 test results at our institution were only reported as quartiles, and a continuous value would have been preferable.

In conclusion, the ypT and ypN stages were associated with poor treatment outcomes in patients with residual TNBC following NAC. Given the importance of locoregional control in preventing future DM, more intensive therapy for TNBC patients with high ypT and ypN stages may be necessary. The RNI did not appear to improve DFS. Identifying TNBC subgroups that are potentially resistant to RT, and further intensive RT incorporating systemic therapy should be considered for these patients.

Statement of Ethics

This study was conducted in accordance with the 1964 Declaration of Helsinki. This study was approved by the Institutional Review Board of Samsung Medical Center (Approval No. 2023-07-010). The requirement for informed consent was waived due to the retrospective nature of the study.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author Contributions

Conceptualization, HK; Resources, HP; Writing of the original draft, HP; Writing of the review and editing, HK; Formal analysis, HP; Data curation, NK.

Data Availability Statement

Data availability is limited owing to institutional data protection laws and the confidentiality of patient data.

Fig. 1.

Overall survival (OS) and disease-free survival (DFS) of entire cohort.

Fig. 2.

Locoregional recurrence-free survival (LRFS) and distant metastasis (DM)-free survival of entire cohort.

Fig. 3.

Clinical outcome of disease-free survival by clinical node stage.

Fig. 4.

Clinical outcome of disease-free survival by regional nodal irradiation. CW, chest wall; RLN, regional lymph node.

Table 1.

Patient characteristics (n = 152)

Characteristic	Value
Age (yr)	45 (24–72)
<45	74 (48.7)
≥45	78 (51.3)
Histologic type of tumor
IDC	147 (96.7)
Others	5 (3.3)
Tumor subtype
ER−/PR−/HER2−	105 (69.1)
ER−/PR−/HER2 1+	38 (25.0)
ER−/PR−/HER2 2+	9 (5.9)
Ki-67 of breast tumor
1+	46 (30.3)
2+	19 (12.5)
3+	34 (22.4)
4+	53 (34.9)
Initial tumor location
Medial	30 (19.7)
Central	32 (21.1)
Lateral	90 (59.2)
cT stage
cT1-2	133 (87.5)
cT3-4	19 (12.5)
cN stage
cN0	36 (23.7)
cN1-2	82 (53.9)
cN3	34 (22.4)
Involved node level
Axillary lymph node only	82 (53.9)
Non-axillary lymph node	34 (22.4)
N0	36 (23.7)
ypT stage
ypTis/1	115 (75.7)
ypT2	35 (23.0)
ypT3	2 (1.3)
Is/No residual tumor	14 (9.3)
ypN stage
ypN0	97 (63.8)
ypN1-2	49 (32.2)
ypN3	6 (3.9)
ypStage
ypStage I-II	137 (90.1)
ypStage III	15 (9.9)
Types of breast surgery
Breast-conserving surgery	152 (100)
Type of axillary surgery
SLNBx	66 (43.4)
ALND	86 (56.6)
Number of dissected lymph nodes	11 (2–34)
NAC regimen, taxane-based	133 (87.5)
Adjuvant CTx
None	131 (86.2)
Capecitabine	8 (5.3)
Other agents	13 (8.6)
RT modality
3D conventional	147 (94.2)
IMRT	9 (5.8)
RT field in all patients
Breast or CW	54 (35.5)
Breast or CW + RLN	98 (64.5)
RT field in cN+ patients
Breast or CW	23 (19.8)
Breast or CW + RLN	93 (80.2)
Last treatment end to RT interval (day)	30 ± 9.7 (20–129)
≤30	91 (59.9)
>30	61 (40.1)

Values are presented as median (range) or number (%) or mean ± standard deviation.

IDC, invasive ductal carcinoma; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; SLNBx, sentinel lymph node biopsy; ALND, axillary lymph node dissection; NAC, neoadjuvant chemotherapy; CTx, chemotherapy; CW, chest wall; RLN, regional lymph node; RT, radiotherapy; 3D, three dimensional; IMRT, intensity-modified radiation therapy.

Table 2.

Prognostic factors for disease-free survival (DFS)

Characteristic	n	5-yr DFS (%)	Univariate		Multivariate
Characteristic	n	5-yr DFS (%)	HR (95% CI)	p-value	HR (95% CI)	p-value
Age (yr)
<45	74	64.4	1.4 (0.79–2.42)	0.259	-
≥45	78	71.2	-		-
Histologic type
IDC	147	67.5	1.1 (0.26–4.46)	0.921	-
Others	5	80.0	-		-
Subtype of tumor
ER−/PR−/HER2−	105	66.7	0.9 (0.46–1.58)	0.608	-
ER−/PR−/HER2 1+/2+	47	71.0	-		-
Ki-67
≤2+	65	74.5	1.6 (0.91–2.93)	0.098	-
≥3+	87	63.0	-		1.0 (0.57–1.83)	0.947
Tumor location
Lateral	90	65.6	0.7 (0.41–1.31)	0.283	-
Medial/Central	62	71.6	-		-
cT stage
cT1-2	133	68.5	1.2 (0.55–2.48)	0.695	-
cT3-4	19	66.0	-		-
cN stage
cN0	36	86.1	-	0.011	-	0.067
cN1-2	82	68.1	2.1 (0.88–5.20)	0.093	1.7 (0.61–4.85)	0.306
cN3	34	51	3.9 (1.54–9.79)	0.004	3.6 (1.05–12.25)	0.042
ypT stage
ypT0/is or T1	115	73.1	1.8 (1.02–3.30)	0.039	-
ypT2-4	37	52.5	-		2.0 (1.00–3.82)	0.049
ypN stage
ypN0	97	80.6		< 0.001		0.016
ypN1 or N2	49	50.5	2.9 (1.58–5.15)	< 0.001	2.1 (0.98–4.66)	0.055
ypN3	6	16.7	6.8 (2.54–18.25)	< 0.001	4.7 (1.57–14.24)	0.006
ypStage
≤Stage 2	137	71.8	-	< 0.001	-
>Stage 2	15	33.3	3.6 (1.85–7.07)		-
NAC regimen, taxane-based	133	67.1	1.7 (0.68–4.48)	0.242	-
Adjuvant CTx
No	131	66.5	0.8 (0.35–1.82)	0.595	-
Yes	21	76.2	-		-
Axillary OP
SLNBx	66	79.5	2.4 (1.26–4.50)	0.006	-
ALND	86	59.4	-		0.7 (0.31–1.45)	0.312
RT field
Breast or CW	54	79.5	2.1 (1.08–3.94)	0.029	-
Breast or CW + RLN	98	61.5	-		0.6 (0.25–1.53)	0.300
RT field in cN+
Breast or CW	23	73.7	-	0.171	-
Breast or CW + RLN	93	59.6	-		-
Last treatment to RT interval (day)
≤30	91	69.3	-		-
>30	61	66.5	-		-

IDC, invasive ductal carcinoma; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; NAC, neoadjuvant chemotherapy; CTx, chemotherapy; axillary OP, axillary surgery; SLNBx, sentinel lymph node biopsy; ALND, axillary lymph node dissection; ALN, axillary lymph node; CW, chest wall; RLN, regional lymph node; RT, radiotherapy; HR, hazard ratio; CI, confidence interval.

Table 3.

Outcomes according to clinically involved lymph node levels and radiation field

	cN0 (n = 36)			cN+/ALN (n = 82)			cN+/non-ALN (n = 34)
	Breast	Breast/SCN	p-value	Breast	Breast/SCN	p-value	Breast/SCN	Breast/IMN	Breast/SCN/IMN	p-value
5-yr DFS (%)	55.9	100	0.353	73.7	66.0	0.458	44.4	40.0	28.6	0.986
Patterns of failures
LRR only	1 (2.8)	0 (0)	0.684	3 (3.7)	3 (3.7)	0.214	3 (8.8)	0 (0)	2 (5.9)	0.549
DM only	5 (13.9)	0 (0)	0.333	2 (2.4)	10 (12.2)	0.342	3 (8.8)	1 (2.9)	4 (11.8)	0.845
LRR + DM	0 (0)	0 (0)	-	1 (1.2)	7 (8.5)	0.303	1 (2.9)	2 (5.9)	1 (2.9)	0.105

Values are presented as number (%).

DFS, disease-free survival; ALN, axillary lymph node; SCN, supraclavicular node; IMN, internal mammary node; LRR, locoregional recurrence; DM, distant metastasis; LRR, locoregional recurrence.

Table 4.

Outcomes according to pathologically involved lymph node levels and radiation field

	ypN0 (n = 97)					ypN+/ALN (n = 53)				ypN+/non-ALN (n = 2)
	Breast (n = 50)	Breast/SCN (n = 33)	Breast/IMN (n = 5)	Breast/SCN/IMN (n = 9)	p-value	Breast (n = 4)	Breast/SCN (n = 42)	Breast/SCN/IMN (n = 7)	p-value	Breast/SCN (n = 1)	Breast/SCN/IMN (n = 1)	p-value
5-yr DFS (%)	82.0	87.9	40.0	77.8	0.089	50.0	44.3	57.1	0.813	0	0	0.317
Patterns of failures
LRR only	3 (6.0)	0 (0)	0 (0)	0 (0)	0.406	1 (25.0)	6 (14.3)	2 (28.6)	0.658	0 (0)	0 (0)	-
DM only	6 (12.0)	3 (9.1)	1 (20.0)	1 (11.1)	0.905	1 (25.0)	10 (23.8)	2 (28.6)	0.697	0 (0)	1 (100)	-
LRR + DM	1 (2.0)	1 (3.0)	2 (40.0)	1 (11.1)	0.002	0 (0)	7 (16.7)	0 (0)	0.327	0 (0)	0 (0)	-

Values are presented as number (%).

DFS, disease-free survival; ALN, axillary lymph node; SCN, supraclavicular node; IMN, internal mammary node; LRR, locoregional recurrence; DM, distant metastasis; LRR, locoregional recurrence.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.

2. Wang Q, Xu M, Sun Y, et al. Gene expression profiling for diagnosis of triple-negative breast cancer: a multicenter, retrospective cohort study. Front Oncol 2019;9:354.

3. Kumar P, Aggarwal R. An overview of triple-negative breast cancer. Arch Gynecol Obstet 2016;293:247–69.

4. Sharma P. Biology and management of patients with triple-negative breast cancer. Oncologist 2016;21:1050–62.

5. Holleczek B, Stegmaier C, Radosa JC, Solomayer EF, Brenner H. Risk of loco-regional recurrence and distant metastases of patients with invasive breast cancer up to ten years after diagnosis: results from a registry-based study from Germany. BMC Cancer 2019;19:520.

6. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13:2329–34.

7. Harbeck N, Gluz O. Neoadjuvant therapy for triple negative and HER2-positive early breast cancer. Breast 2017;34 Suppl 1:S99–103.

8. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164–72.

9. Huang M, O’Shaughnessy J, Zhao J, et al. Association of pathologic complete response with long-term survival outcomes in triple-negative breast cancer: a meta-analysis. Cancer Res 2020;80:5427–34.

10. Kuroi K, Toi M, Ohno S, et al. Prognostic significance of subtype and pathologic response in operable breast cancer; a pooled analysis of prospective neoadjuvant studies of JBCRG. Breast Cancer 2015;22:486–95.

11. von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014;15:747–56.

12. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 2015;33:13–21.

13. von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012;366:299–309.

14. Earl HM, Hiller L, Dunn JA, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol 2015;16:656–66.

15. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810–21.

16. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017;376:2147–59.

17. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 2015;373:317–27.

18. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med 2015;373:307–16.

19. Noh JM, Choi DH, Huh SJ, et al. Patterns of recurrence after breast-conserving treatment for early stage breast cancer by molecular subtype. J Breast Cancer 2011;14:46–51.

20. Park HJ, Shin KH, Cho KH, et al. Outcomes of positron emission tomography-staged clinical N3 breast cancer treated with neoadjuvant chemotherapy, surgery, and radiotherapy. Int J Radiat Oncol Biol Phys 2011;81:e689–95.

21. Chen RC, Lin NU, Golshan M, Harris JR, Bellon JR. Internal mammary nodes in breast cancer: diagnosis and implications for patient management: a systematic review. J Clin Oncol 2008;26:4981–9.

22. Kim K, Jeong Y, Shin KH, et al. Impact of regional nodal irradiation for breast cancer patients with supraclavicular and/or internal mammary lymph node involvement: a multicenter, retrospective study (KROG 16-14). Cancer Res Treat 2019;51:1500–8.

23. Zhang C, Wang S, Israel HP, et al. Higher locoregional recurrence rate for triple-negative breast cancer following neoadjuvant chemotherapy, surgery and radiotherapy. Springerplus 2015;4:386.

24. Atkinson RL, Yang WT, Rosen DG, et al. Cancer stem cell markers are enriched in normal tissue adjacent to triple negative breast cancer and inversely correlated with DNA repair deficiency. Breast Cancer Res 2013;15:R77.

25. Zarotti C, Papassotiropoulos B, Elfgen C, et al. Biomarker dynamics and prognosis in breast cancer after neoadjuvant chemotherapy. Sci Rep 2022;12:91.

26. Walsh EM, Shalaby A, O’Loughlin M, et al. Outcome for triple negative breast cancer in a retrospective cohort with an emphasis on response to platinum-based neoadjuvant therapy. Breast Cancer Res Treat 2019;174:1–13.

27. Kern P, Von Minckwitz G, Puetter C, et al. Prognostic impact of residual disease after neoadjuvant chemotherapy in 648 patients with triple-negative breast cancer. Anticancer Res 2015;35:5479–84.