The Characteristics of HER2 Low-Expressing Breast Cancer: a China Single-Center Real-World Data Analysis

Abstract

Aim: This study examined the characteristics of HER2-low breast cancer patients in our center. Methods: Data of HER2-negative breast cancer patients were collected, and the patients were divided into HER2-low and HER2-0 groups. The differences in clinicopathological features, prognosis and treatment were compared. Results: The proportion of patients in the HER2-low group who were over 50 years old, had invasive breast cancer of no special type, histological grade 1/2, ER-positive, PR-positive and Ki67 ≤30% was higher. Patients with HER2-low status had better breast cancer-specific survival and overall survival. Additionally, HER2-low status was not associated with the effectiveness of adjuvant chemotherapy and endocrine therapy. Conclusion: HER2-low breast cancer is less aggressive than HER2-0 and may represent a distinct subtype.

Keywords: :

• breast cancer
• chemotherapy
• endocrine therapy
• HER2-low
• prognosis

Human epidermal growth factor receptor-2 (HER2) is a receptor on the cell surface that is activated after receiving specific signals, transmits information into cells and regulates cell growth and proliferation. In breast cancer cells, HER2 also plays an important role in regulating cell proliferation, survival, differentiation and migration [1]. Slamon et al. first reported in 1987 that HER2 amplification was associated with poor prognosis of breast cancer [2]. HER2-targeted drugs such as trastuzumab have specific therapeutic effects on HER2-positive breast cancer by inhibiting HER2 activation [3]. Breast cancer patients were classified as HER2-positive, indicated by HER2 immunohistochemical (IHC) detection +3 or in situ hybridization (ISH) amplification, or HER2-negative, denoted by HER2 IHC 0, +1, +2/ISH not amplified. Recently, due to the development of antibody–drug conjugates (ADCs), the HER2-negative population has been further divided into HER2-low (HER2 IHC +1, +2/ISH not amplified) and HER2-0 (HER2 IHC 0) [4].

Trastuzumab deruxtecan (T-Dxd), an ADC drug comprising trastuzumab and topoisomerase I inhibitors, has been validated by several studies for its efficacy in treating HER2-low breast cancer. For example, in a phase IB clinical study involving 54 HER2-low breast cancer patients, the median progression-free survival (PFS) of patients treated with T-Dxd was 11.1 months, and the median overall survival (OS) was 29.4 months [5]. A phase III clinical study (DESTINY-Breast04) involving 557 breast cancer patients with HER2-low confirmed that T-Dxd significantly prolonged PFS and OS [6]. In DESTINY-Breast04 study, all patients had metastatic breast cancer, with 88.7% of hormone receptor-positive (HR+) and 11.3% of -negative. They had previously received one to two lines of chemotherapy, and patients with HR+ had undergone at least one line of endocrine therapy. It indicated that clinicians can no longer treat patients with HER2-low in the same way with HER2-0. Patients with HER2-low should be treated as a unique subgroup and receive tailored treatment accordingly. In the past, there was insufficient understanding of the clinicopathological and prognostic characteristics of HER2-low breast cancer patients in our region. Therefore, this study mainly used retrospective data from a single center to study the features of HER2-low in our region in the real world.

Patients & methods

Patients

This study was approved by the Ethics Committee of the First Hospital of Jiaxing. All patients signed a written informed consent to participate in the study at the time of first admission. Figure 1 shows the patient selection process in this study. The clinicopathological data of breast cancer patients treated in the First Hospital of Jiaxing from 1 January 2012 to 31 December 2019, were collected. Inclusion criteria were as follows: pathological diagnosis of primary invasive breast cancer; pTNM stage I–III; HER2 IHC 0, +1, +2/fluorescence in situ hybridization (FISH) not amplified; age ≥18 years; female; undergoing radical surgery (including but not limited to modified radical mastectomy, breast-conserving radical mastectomy, etc.); complete clinical and pathological data. Exclusion criteria were as follows: breast carcinoma in situ; minimally invasive carcinoma; ipsilateral supraclavicular lymph node metastasis; distant metastasis; HER2 IHC +2 without FISH; IHC of the primary tumor showed heterogeneity; synchronous double primary breast cancer; patient received preoperative neoadjuvant chemotherapy or neoadjuvant endocrine therapy; previous history of malignant tumor or concurrently suffering from other malignancies. All patients received postoperative adjuvant therapy. The indication criteria for adjuvant chemotherapy were lymph node metastases (except for pN1mi), invasive tumors of >2 cm, ER/PR negative or age of <35 years. For patients with lymph node metastasis, the chemotherapy regimen was four cycles of epirubicin + cyclophosphamide (EC) followed by four cycles of docetaxel (T). For patients without lymph node metastasis, the chemotherapy regimen was four cycles of EC or four cycles of docetaxel + cyclophosphamide (TC). The indication criterion for adjuvant endocrine therapy was estrogen receptor (ER) or progesterone receptor (PR) positivity. For postmenopausal patients, endocrine therapy was aromatase inhibitors (AI), and the course of treatment was 5 years (for patients with lymph node negative) or 10 years (for patients with lymph node positive). For premenopausal patients, endocrine therapy was tamoxifen (TAM) for 5 years (for patients with lymph node negative) or ovarian function suppression (OFS, Goserelin / Leuprorelin) + AI / TAM for 5 years, followed by TAM for 5 years (for patients with lymph node positive). The indication criteria for adjuvant radiotherapy were breast-conserving surgery, lymph node positivity, ≥5 cm maximum diameter of the primary tumor and tumor invasion of the breast skin or chest wall.

Figure 1. Flowchart for patient selection.

FISH: Fluorescence in situ hybridization.

Methods

This retrospective observational study comprehensively documented the detection results of HER2, ER, PR and Ki-67 in the pathological reports. HER2 was detected by IHC and FISH. HER2-0: IHC no staining or ≤10% of infiltrating cancer cells exhibit incomplete, weak membrane staining. HER2-low: IHC >10% of invasive cancer cells showed incomplete and weak cell membrane staining; IHC >10% of invasive cancer cells showed weak-moderate intensity, complete cell membrane staining or ≤10% infiltrating cancer cells with strong and intact membrane staining, and FISH not amplified [7]. ER and PR were detected by IHC, and finding a proportion of positive cells ≥1% was considered positive [8,9]. Ki-67 was detected by IHC, and the proportion of positive cells in all tumor cells was estimated visually [10]. The cut-off value for Ki-67 was set at 30%, which was suitable for patients treated at our center and has been previously discussed [11].

Prognostic indicators included relapse-free survival (RFS), disease-free survival (DFS), breast cancer-specific survival (BCSS) and OS. RFS was defined as the time from radical surgery to any of the following events: invasive ipsilateral breast tumor recurrence / progression, local invasive recurrence / progression, regional invasive recurrence / progression, appearance / occurrence of metastases / distant recurrence, ipsilateral DCIS and any cause of death. Those who did not experience the above events were counted until the time of the last follow-up. DFS was defined as the time from radical surgery to any termination event, including termination events described for RFS as well as invasive contralateral breast cancer, second primary invasive cancer (nonbreast cancer), and contralateral DCIS. BCSS was defined as the span of time from radical surgery to death due to breast cancer recurrence or metastasis. OS was defined as the span of time from radical surgery to death from any cause [12,13].

Statistical analysis

SPSS 22.0 and GraphPad Prism 8.0.2 software were utilized for data processing and graph creation. The count data were analyzed by Pearson's chi-square test. The Kaplan–Meier method was used for survival analysis, and the log-rank test was used to test the difference in survival curves between groups. All statistical tests were bilateral tests, and the differences were statistically significant at p < 0.05.

Results

Patients

A total of 786 patients were enrolled, including 579 patients with HER2-low (73.7%) and 207 patients with HER2-0 (26.3%). The mean age of the patients was 54.9 ± 10.4 years, and the median age was 54 [48, 62] years. There were 382 (48.6%) premenopausal patients and 404 (51.4%) postmenopausal patients. The pathological type was invasive breast cancer of no special type (NST) in 654 (83.2%) cases, mucinous carcinoma in 38 (4.8%) cases, lobular carcinoma in 23 (2.9%) cases, and other types in 71 (9.0%) cases. There were 527 (67.0%) cases of histological grade 1/2 and 259 (33.0%) cases of grade 3. Based on ER and PR, we identified 623 cases (79.3%) of HR+, and 163 cases (20.7%) of triple-negative breast cancer (TNBC). Ki-67 ≤30% occurred in 540 (68.7%) cases, and Ki-67 >30% occurred in 246 (31.3%) cases. The average primary tumor diameter was 2.1 ± 1.2 cm, including 481 (61.2%) cases with tumor diameters ≤2 cm and 305 (38.8%) cases with tumor diameters >2 cm. Axillary lymph nodes were negative in 505 (64.2%) cases and positive in 281 (35.8%) cases. There were 376 (47.8%) cases of pTNM stage I, 311 (39.6%) cases of stage II and 99 (12.6%) cases of stage III. Patients received postoperative adjuvant therapy according to the treatment guidelines; 56.4% of patients received adjuvant chemotherapy, 77.6% received adjuvant endocrine therapy, and 57.1% received adjuvant radiotherapy. The average follow-up time was 6.1 ± 2.4 years, and the median follow-up time was 5.9 years. During the follow-up period, there were 72 (9.2%) cases of RFS events, 111 (14.1%) cases of DFS events, 15 (1.9%) cases of BCSS events, and 24 (3.1%) cases of OS events.

HER2-low breast cancer was less aggressive than HER2-0

Compared with HER2-0 patients, those in the HER2-low group were more frequently older than 50 years. Additionally, a higher proportion of patients in this group had invasive breast cancer of no special type (NST), histological grade 1/2, ER / PR positive, and Ki-67 ≤30% (Table 1). The above characteristics suggested that the tumor malignancy of HER2-low might be lower than that of HER2-0.

Table 1. Clinicopathological features of breast cancer patients with HER2-low status.

		All			HR+			TNBC
		HER2-0 (n = 207)	HER2-low (n = 579)	p-value	HER2-0 (n = 139)	HER2-low (n = 484)	p-value	HER2-0 (n = 68)	HER2-low (n = 95)	p-value
Age	≤50	96 (46.4%)	198 (34.2%)	0.002	61 (43.9%)	166 (34.3%)	0.038	35 (51.5%)	32 (33.7%)	0.023
	>50	111 (53.6%)	381 (65.8%)		78 (56.1%)	318 (65.7%)		33 (48.5%)	63 (66.3%)
Menstruation	Premenopausal	112 (54.1%)	270 (46.6%)	0.065	74 (53.2%)	230 (47.5%)	0.235	38 (55.9%)	40 (42.1%)	0.083
	Postmenopausal	95 (45.9%)	309 (53.4%)		65 (46.8%)	254 (52.5%)		30 (44.1%)	55 (57.9%)
Pathological type	NST	154 (74.4%)	500 (86.4%)	<0.001	99 (71.2%)	420 (86.8%)	<0.001	55 (80.9%)	80 (84.2%)	0.541
	Mucinous	21 (10.1%)	17 (2.9%)		21 (15.1%)	17 (3.5%)		0 (0.0%)	0 (0.0%)
	Lobular	6 (2.9%)	17 (2.9%)		6 (4.3%)	16 (3.3%)		0 (0.0%)	1 (1.1%)
	Other	26 (12.6%)	45 (7.8%)		13 (9.4%)	31 (6.4%)		13 (19.1%)	14 (14.7%)
Grade	1/2	123 (59.4%)	404 (69.8%)	0.007	112 (80.6%)	379 (78.3%)	0.564	11 (16.2%)	25 (26.3%)	0.124
	3	84 (40.6%)	175 (30.2%)		27 (19.4%)	105 (21.7%)		57 (83.8%)	70 (73.7%)
ER	Negative	70 (33.8%)	106 (18.3%)	<0.001	2 (1.4%)	11 (2.3%)	0.743	0 (0.0%)	0 (0.0%)
	Positive	137 (66.2%)	473 (81.7%)		137 (98.6%)	473 (97.7%)		0 (0.0%)	0 (0.0%)
PR	Negative	77 (37.2%)	136 (23.5%)	<0.001	9 (6.5%)	41 (8.5%)	0.445	0 (0.0%)	0 (0.0%)
	Positive	130 (62.8%)	443 (76.5%)		130 (93.5%)	443 (91.5%)		0 (0.0%)	0 (0.0%)
Ki-67	≤30%	127 (61.4%)	413 (71.3%)	0.008	116 (83.5%)	384 (79.3%)	0.283	11 (16.2%)	29 (30.5%)	0.036
	>30%	80 (38.6%)	166 (28.7%)		23 (16.5%)	100 (20.7%)		57 (83.8%)	66 (69.5%)
Tumor diameter	≤2 cm	125 (60.4%)	356 (61.5%)	0.781	95 (68.3%)	305 (63.0%)	0.248	30 (44.1%)	51 (53.7%)	0.228
	>2 cm	82 (39.6%)	223 (38.5%)		44 (31.7%)	179 (37.0%)		38 (55.9%)	44 (46.3%)
Lymph node	Negative	135 (65.2%)	370 (63.9%)	0.735	92 (66.2%)	306 (63.2%)	0.521	43 (63.2%)	64 (67.4%)	0.584
	Positive	72 (34.8%)	209 (36.1%)		47 (33.8%)	178 (36.8%)		25 (36.8%)	31 (32.6%)

Bold values are significant.

ER: Estrogen receptor; HER2: Human epidermal growth factor receptor-2; HR: Hormone receptor; NST: No special type; PR: Progesterone receptor; TNBC: Triple-negative breast cancer.

HER2-low breast cancer has a better prognosis than HER2-0

The BCSS and OS of breast cancer patients with HER2-low were better than those of HER2-0 patients, while the RFS and DFS were similar between the two groups (Figure 2). In the HR+ subgroup, both BCSS and OS were superior in HER2-low compared with HER2-0, while in the TNBC subgroup, there was no association between HER2 and BCSS, OS, RFS or DFS (Figure 3).

Figure 2. Relationship between HER2 and prognosis.

(A) The BCSS of HER2-low was better than HER2-0; (B) The OS of HER2-low was better than HER2-0; (C) The RFS was not associated with HER2; (D) The DFS was not associated with HER2.

BCSS: Breast cancer-specific survival; DFS: Disease-free survival; HER2: Human epidermal growth factor receptor-2; m: Months; OS: Overall survival; RFS: Relapse-free survival.

Figure 3. Relationship between HER2 and prognosis in HR+ or TNBC subtypes.

(A) The BCSS of HER2-low was better than HER2-0 in HR+ subgroup; (B) The BCSS was not associated with HER2 in TNBC subgroup; (C) The OS of HER2-low was better than HER2-0 in HR+ subgroup; (D) The OS was not associated with HER2 in TNBC subgroup; (E) The RFS was not associated with HER2 in HR+ subgroup; (F) The RFS was not associated with HER2 in TNBC subgroup; (G) The DFS was not associated with HER2 in HR+ subgroup; (H) The DFS was not associated with HER2 in TNBC subgroup.

BCSS: Breast cancer-specific survival; DFS: Disease-free survival; HER2: Human epidermal growth factor receptor-2; HR: Hormone receptor; m: Months; OS: Overall survival; RFS: Relapse-free survival; TNBC: Triple-negative breast cancer.

HER2-low was not associated with the effectiveness of adjuvant therapy

The guidelines for adjuvant chemotherapy and endocrine therapy after surgery were clear. There was no statistically significant difference in the distribution of chemotherapy and radiotherapy between the HER2-low and HER2-0 groups, but there was a statistically significant difference in the distribution of endocrine therapy between the two groups (Table 2). Patients in HER2-low had a higher proportion of receiving endocrine therapy, which was attributed to the higher proportion of HR+ in HER2-low. An analysis of the relationship between HER2-low and DFS among patients who received the same chemotherapy or endocrine therapy revealed that HER2-low did not affect DFS (Figures 4 & 5). This may imply that when administering postoperative adjuvant chemotherapy or endocrine therapy according to current guidelines, it is unnecessary to customize the treatment regimen based on the patient's HER2-low status.

Table 2. Relationship between HER2 and the effectiveness of adjuvant therapy.

		All			HR+			TNBC
		HER2-0 (n = 207)	HER2-low (n = 579)	p-value	HER2-0 (n = 139)	HER2-low (n = 484)	p-value	HER2-0 (n = 68)	HER2-low (n = 95)	p-value
Chemotherapy	No	94 (45.4%)	286 (49.4%)	0.291	88 (63.3%)	275 (56.8%)	0.424	6 (8.8%)	11 (11.6%)	0.86
	EC	22 (10.6%)	47 (8.1%)		3 (2.2%)	22 (4.5%)		19 (27.9%)	25 (26.3%)
	TC	28 (13.5%)	57 (9.8%)		6 (4.3%)	23 (4.8%)		22 (32.4%)	34 (35.8%)
	EC to T	63 (30.4%)	189 (32.6%)		42 (30.2%)	164 (33.9%)		21 (30.9%)	25 (26.3%)
Endocrine therapy	No	68 (32.9%)	95 (16.4%)	<0.001	0 (0%)	0 (0%)	0.671	0 (0%)	0 (0%)
	TAM	37 (17.9%)	114 (19.7%)		37 (26.6%)	114 (23.6%)		0 (0%)	0 (0%)
	OFS + TAM	3 (1.4%)	13 (2.2%)		3 (2.2%)	13 (2.7%)		0 (0%)	0 (0%)
	AI	64 (30.9%)	249 (43.0%)		64 (46.0%)	249 (51.4%)		0 (0%)	0 (0%)
	OFS + AI	35 (16.9%)	108 (18.7%)		35 (25.2%)	108 (22.3%)		0 (0%)	0 (0%)
Radiotherapy	No	91 (44.0%)	246 (42.5%)	0.713	62 (44.6%)	205 (42.4%)	0.637	29 (42.6%)	41 (43.2%)	0.948
	Yes	116 (56.0%)	333 (57.5%)		77 (55.4%)	279 (57.6%)		39 (57.4%)	54 (56.8%)

Bold values are significant.

AI: Aromatase inhibitor; EC: Epirubicin + cyclophosphamide; HER2: Human epidermal growth factor receptor-2; HR: Hormone receptor; OFS: Ovarian function suppression; T: Docetaxel; TAM: Tamoxifen; TC: Docetaxel + cyclophosphamide; TNBC: Triple-negative breast cancer.

Figure 4. Relationship between HER2 and the effectiveness of adjuvant chemotherapy.

(A) The DFS was not associated with HER2 in the EC subgroup. (B) The DFS was not associated with HER2 in the TC subgroup. (C) The DFS was not associated with HER2 in the EC to T subgroup.

DFS: Disease-free survival; EC: Epirubicin + cyclophosphamide; HER2: Human epidermal growth factor receptor-2; m: Months; T: Docetaxel; TC: Docetaxel + cyclophosphamide.

Figure 5. Relationship between HER2 and the effectiveness of adjuvant endocrine therapy.

(A) The DFS was not associated with HER2 in the AI subgroup. (B) The DFS was not associated with HER2 in the TAM subgroup. (C) The DFS was not associated with HER2 in the OFS + AI subgroup. (D) The DFS was not associated with HER2 in the OFS + TAM subgroup.

AI: Aromatase inhibitor; DFS: Disease-free survival; HER2: Human epidermal growth factor receptor-2; m: Months; OFS: Ovarian function suppression; TAM: Tamoxifen.

Discussion

In this study, the clinicopathological data of more than 500 HER2-low breast cancer patients who were followed up for more than 5 years were retrospectively analyzed. To the best of our knowledge, this is the first report on breast cancer patients with HER2-low in our region. In our study, compared with HER2-0 patients, HER2-low patients were more commonly older than 50 years and more commonly exhibited invasive breast cancer of NST, histological grade 1/2, ER or PR positivity, and Ki-67 ≤30%; this was similar to the research results from Shanghai, Italy and Greece, indicating that HER2-low breast cancer patients may have lower tumor malignancy than HER2-0 patients [14–17].

The BCSS and OS of HER2-low breast cancer patients were better than those of HER2-0 patients, which was consistent with lower tumor malignancy in the former. However, there was no significant difference in RFS and DFS between the two groups. From an examination of the survival curve (Figure 2), the RFS and DFS curves of the two groups were noted to be separate after the start of follow-up. The curve of HER2-low was above that of HER2-0, and it crossed through the curve of HER2-0 at approximately 9 years of follow-up, which could result in there being no statistically significant difference in RFS and DFS in Kaplan–Meier analysis. Studies from Guangzhou and South Korea also showed similar prognostic characteristics [18–20].

We stratified patients into HR+ and TNBC subgroups according to ER and PR status. In the HR+ subgroup, the BCSS and OS of patients with HER2-low were better than those of HER2-0 patients, and there were no significant differences in RFS and DFS between the two groups. In the TNBC subgroup, HER2 was not associated with BCSS, OS, RFS or DFS (Figure 3). This was similar to the findings of Li et al. [21]. However, Xu et al. found that in the ER-positive subgroup, HER2 status was not related to DFS, and landmark analysis found that there was no significant difference in DFS between the two groups within 60 months after surgery; but the DFS of patients with HER2-low was better 60 months after surgery [22]. Mutai et al. detected the Oncotype DX score in the ER-positive subgroup and found that HER2-low patients with scores of RS >25 experienced better OS and DFS, while HER2 was not associated with prognosis in patients with scores of RS ≤25, suggesting that ER-positive, HER2-low patients may be heterogeneous [23]. However, the results of some studies indicated that the prognosis of patients with HER2-low status was similar to that of HER2-0 patients [16,17,24,25].

As mentioned above, the relationship between HER2 and prognosis was inconsistent in various studies, which may be related to tumor heterogeneity and inconsistent HER2 detection methods. Through genetic testing, Liao et al. found that patients with HER2-low had significantly increased mutations involved in PI3K-Akt signaling, while patients with HER2-0 had more mutations in checkpoint factors [26]. Schettini et al. reviewed HER2 IHC slides of 100 cases from different hospitals and found that 35% of the diagnostic results were inconsistent, which may also be the reason for the discrepancy in the study [27]. In addition, the ethnic diversity may also be one of the reasons [28]. Therefore, investigating and reporting on HER2-low breast cancer in our region is crucial to gain a deeper understanding of the survival characteristics of these patients.

The main reason why HER2-low is of concern is the great success of T-Dxd in this subgroup of patients, and whether previous classic postoperative adjuvant therapy will have different effects on this subgroup of patients? To this end, we evaluated the prognostic value of HER2-low for postoperative adjuvant therapy. Although HER2-low did not affect the DFS of the entire group of patients, we still used DFS as the efficacy evaluation index of postoperative adjuvant therapy, because DFS is more sensitive to postoperative adjuvant therapy, while BCSS and OS are influenced by post-relapse treatment. The results showed that HER2-low did not change the DFS of patients who received the same adjuvant chemotherapy or adjuvant endocrine therapy regimen. Therefore, we believe that HER2-low does not need to be considered when formulating postoperative adjuvant chemotherapy and adjuvant endocrine therapy regimens for post-operative patients at this stage.

The biggest challenge faced by this study is the IHC result of HER2, because IHC is subjective and there may be differences in diagnosis between different laboratories and different doctors. Given that this is a retrospective study, all data, particularly the IHC results, are derived from medical records and have been tested by various technicians using different antibody batches over an extended period, and interpreted by different pathologists, which could introduce heterogeneity in the IHC results and potentially influence the study outcomes. In order to eliminate these effects, unified IHC detection and diagnosis of pathological specimens from all patients can be considered in the future, and ISH detection can be performed [29].

Conclusion

In conclusion, by reviewing the data of breast cancer patients in a single center, we found that compared with HER2-0 patients, HER2-low patients were older and more commonly exhibited invasive breast cancer of NST, histological grade 1/2, ER or PR positivity, and Ki-67 ≤30% while also experiencing better BCSS and OS. Therefore, we believe that HER2-low may be a group of breast cancer subtypes different from HER2-0, and it is worthy of further research. Since this article represents a retrospective study, there may be inconsistencies in the results of HER2 testing, which may affect the conclusion of the study. In the future, patients can be uniformly tested for HER2 to reduce bias.

Summary points

• This study retrospectively analyzed 786 primary breast cancers, including 579 HER2-low and 207 HER2-0.

• The TNM stage of all patients was 1–3.

• All patients received therapeutic surgery and appropriate postoperative adjuvant treatment.

• The median follow-up time was 5.9 years.

• Compared with HER2-0 patients, HER2-low patients were older and more commonly exhibited invasive breast cancer of no special type, histological grade 1/2, ER or PR positivity and Ki-67 ≤30%.

• Compared with HER2-0 patients, HER2-low patients had better breast cancer-specific survival and overall survival.

• Whether the patient was HER2-low or HER2-0 does not need to be considered when formulating postoperative adjuvant chemotherapy or endocrine therapy plans.

Financial disclosure

The authors disclosed receipt of the following financial support for the research, authorship and publication of this article: this study was funded by the Jiaxing Key Discipline of Medicine (Mastropathy, Innovation Subject, 2023-FC-001), and the Breast Cancer Precision Diagnosis and Treatment Center of the First Hospital of Jiaxing (2021-ZZZX-06), and the Provincial and Municipal Co-constructed and Cultivation Discipline of Jiaxing, General Surgery (Minimally Invasive Direction, 2023-PYXK-001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the Ethics Committee of the First Hospital of Jiaxing (2022-LY-385). All patients signed a written informed consent to participate in the study at the time of first admission.