Ten-Year Follow-up Clinical Outcomes and the Role of Adjuvant Chemotherapy in HER2-Positive Patients with Microinvasive Breast Cancer

Yeokyeong Shin; Soo-Young Lee; Hyehyun Jeong; Jin-Hee Ahn; Kyung Hae Jung; Sung-Bae Kim; Hee Jeong Kim; Jong Won Lee; Byung Ho Son; BeomSeok Ko; Ji Sun Kim; Il Yong Chung; Hee Jin Lee; Gyungyub Gong; Sae Byul Lee; Jae Ho Jeong

doi:10.4143/crt.2024.1120

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Original Article Breast cancer Ten-Year Follow-up Clinical Outcomes and the Role of Adjuvant Chemotherapy in HER2-Positive Patients with Microinvasive Breast Cancer: Yeokyeong Shin¹, Soo-Young Lee², Hyehyun Jeong¹, Jin-Hee Ahn¹, Kyung Hae Jung¹, Sung-Bae Kim¹, Hee Jeong Kim³, Jong Won Lee³, Byung Ho Son³, BeomSeok Ko³, Ji Sun Kim³, Il Yong Chung³, Hee Jin Lee⁴, Gyungyub Gong⁴, Sae Byul Lee³, Jae Ho Jeong¹; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2026;58(1):151-158.
DOI: https://doi.org/10.4143/crt.2024.1120
Published online: March 5, 2025

¹Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Department of Surgery, Inha University Hospital, Inha University College of Medicine, Incheon, Korea

³Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

⁴Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence: Jae Ho Jeong, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-3223 E-mail: jaeho.jeong@amc.seoul.kr

Co-correspondence: Sae Byul Lee, Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-1729 E-mail: newstar@amc.seoul.kr

^*Yeokyeong Shin, Soo-Young Lee, and Hyehyun Jeong contributed equally to this work.

• Received: November 22, 2024 • Accepted: March 3, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://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.

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Abstract

Purpose
Although human epidermal growth factor receptor 2 (HER2) positivity is prevalent in microinvasive breast cancer (MIBC), data focused on HER2-positive MIBC are limited. We investigated the clinical course and long-term outcomes of HER2-positive MIBC and evaluated the role of adjuvant chemotherapy.
Materials and Methods
The study included patients with curatively resected pT1mi pN0 HER2-positive breast cancer between January 2000 and January 2020. Treatments and survival outcomes, including invasive breast cancer-free survival (IBCFS), distant recurrence-free survival (DRFS), and overall survival (OS) were analyzed.
Results
The analysis included 799 female patients. The median age was 51 years (range, 23 to 79 years), and 51.6% (n=412) were premenopausal. Multifocality was confirmed in 17.3% (n=138), and estrogen receptor (ER) positivity in 29.8% (n=238). Adjuvant chemotherapy was administered to 17.5% (n=140), with doxifluridine in 96.4% of cases. One patient (0.1%) received trastuzumab. With a median follow-up of 119.0 months (95% confidence interval [CI], 114.0 to 127.0), the 8-year IBCFS, DRFS, and OS were 91.2% (95% CI, 89.1 to 93.3), 97.5% (95% CI, 96.4 to 98.7), and 98.8% (95% CI, 98.0 to 99.6), respectively. No significant differences were observed between patients with and without adjuvant chemotherapy. The lack of differences in IBCFS by chemotherapy was consistent across subgroups, including pre-/postmenopausal patients, grade 1-2/3 tumors, and ER-negative disease.
Conclusion
A clinically meaningful proportion of HER2-positive MIBC patients experience IBCFS events with long-term follow-up. Adjuvant chemotherapy did not improve survival, potentially due to the use of an outdated, ineffective regimen. The role of modern adjuvant regimens, particularly those incorporating HER2-targeted therapy, warrants further exploration.
Key words: HER2, Microinvasive breast cancer, Clinical outcomes

Introduction

Microinvasive breast cancer (MIBC) is defined as invasive carcinoma without any foci measuring greater than 1 mm. The American Joint Committee on Cancer Staging Manual categorizes this as “T1mic” in the TNM classification system [1]. MIBC has a rare incidence, accounting for 0.7% to 3.4% of all breast cancers [2,3]. However, its incidence has increased in parallel with the increasing incidence of ductal carcinoma in situ (DCIS), largely due to the introduction of breast cancer screening programs and more thorough sampling of breast tissue specimens [4,5].

The prognosis of MIBC is generally favorable, with 5-year overall survival (OS) rates ranging between 97% and 100% [6-8]. The prognosis and survival outcomes of MIBC occupy an intermediate position between those of DCIS and small invasive carcinomas [9].

MIBC has a higher likelihood of human epidermal growth factor receptor 2 (HER2) overexpression than pure DCIS, with a prevalence of approximately 40%-50% [8,10]. In invasive breast cancers, HER2 overexpression is a well-known prognostic factor [11], as HER2-positive tumors exhibit a higher risk of recurrence and poorer survival outcomes compared to HER2-negative tumors in the absence of HER2-targeted therapies [12-16]. The APT trial previously demonstrated that adjuvant paclitaxel and trastuzumab resulted in excellent long-term outcomes with 10-year invasive disease-free survival of 91.3% and OS of 94.3% in patients with small, node-negative HER2-positive breast cancers [17,18], leading to wide acceptance of this regimen. However, the APT trial included only a small number of patients with MIBC. Currently, the prognostic implication of HER2-positivity is less clear in MIBC [19], as is the role of adjuvant chemotherapy and HER2-targeted therapies. Large-scale studies on the outcomes of HER2-positive MIBC are lacking.

This study assessed the prognosis, patterns of recurrence, and long-term outcome of HER2-positive MIBC, as well as evaluated the role of adjuvant chemotherapy.

Materials and Methods

1. Patients

Patients who underwent curative resection for HER2-positive MIBC (pT1mi, defined as tumors ≤ 1 mm in size [1]) without evidence of lymph node metastasis (pN0) between January 2000 and January 2020 were retrospectively identified from the Asan Medical Center, a tertiary referral center in South Korea. HER2-positivity was defined by either the overexpression of the HER2 protein, indicated by 3+ on immunohistochemistry, or by amplification of the HER2 gene of 2.0 or higher on fluorescence in situ hybridization [20]. Clinical data were obtained from the electronic medical record system, which included baseline patient characteristics, treatment history, and survival outcomes.

This study used a part of a previously reported dataset of MIBC [21], but it is distinguished by an extended follow-up of an additional 4 years, and included further analyses focusing on HER2-positive subtypes and detailed adjuvant treatment regimens.

2. Treatment and assessments

Adjuvant chemotherapy and radiation therapy were administered after surgery at the discretion of the physicians. Adjuvant endocrine therapy was administered to patients with estrogen receptor (ER) positive tumors. Patients were routinely followed up with breast ultrasound and mammography every 6 months for the first 5 years, and annually thereafter.

3. Statistical analysis

Survival outcomes were estimated using the Kaplan-Meier method and compared by the log-rank test. Invasive breast cancer-free survival (IBCFS) was defined as the time from the surgery to the development of local or distant recurrence (not including second non-breast cancer) or death from any cause, whichever occurred first. Distant recurrence-free survival (DRFS) was defined as the time from the surgery to the development of distant recurrence or death from any cause. OS was defined as the time from the surgery to death from any cause. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) and corresponding confidence intervals (CIs). All p-values were two-sided with a significance level of 95%. All statistical analyses were performed using the R software ver. 4.2.1 (R Foundation for Statistical Computing).

Results

1. Patient characteristics

A total of 799 patients were included in the analyses (Fig. 1). The clinicopathological characteristics of patients are delineated in Table 1. The median age at surgery was 51 years (range, 23 to 79 years), and 51.6% (n=412) of patients were premenopausal. The median size (greatest dimension) of DCIS in the tumor bed was 4.0 cm (range, 0.1 to 17.0 cm), with 272 patients (34.0%) having a DCIS size of ≥ 5.0 cm. High-grade DCIS in the tumor bed was confirmed in 570 patients (71.3%). Of the patients, 58.8% (n=470) had histologic grade 3 tumors, and 29.8% (n=238) had ER-positive tumors. Multifocality, defined as the presence of two or more distinct foci of microinvasion, was confirmed in 138 patients (17.3%).

At diagnosis, biopsy results were available in 784 patients (98.1%). Among those, 412 patients (52.6%) were diagnosed with DCIS, 86 patients (11.0%) were diagnosed with MIBC, 273 patients (34.8%) had unknown extent of invasion (S1 Table).

2. Treatments

All patients underwent curative resection, of which 38.4% (n=307) underwent breast-conserving surgery and 61.6% (n=492) underwent mastectomy. A total of 297 patients (37.2%) received adjuvant radiotherapy.

Adjuvant chemotherapy was administered to 140 patients (17.5%), all of whom had ER-negative diseases. Among them, 135 patients (96.4%) were treated with doxifluridine, three (2.1%) were treated with four cycles of AC (doxorubicin and cyclophosphamide), and two (1.4%) were treated with six cycles of CMF (cyclophosphamide, methotrexate, and fluorouracil). Trastuzumab was administered to one patient (0.1%) following adjuvant AC.

Among 238 ER-positive patients, 98.7% (n=235) received adjuvant endocrine therapy. Of these, 186 (79.1%) received tamoxifen, 41 (17.4%) received aromatase inhibitors, and eight (3.4%) received sequential therapy with tamoxifen followed by an aromatase inhibitor. Among 146 premenopausal patients, four received ovarian function suppression.

3. Survival outcomes

The median follow-up duration was 119.0 months (95% CI, 114.0 to 127.0). A total of 78 IBCFS events (9.8%) and 27 DRFS events (3.4%) were recorded during follow-up. The 5- and the 8-year IBCFS rates were 94.4% (95% CI, 92.8 to 96.0), and 91.2% (95% CI, 89.1 to 93.3), respectively (Fig. 2A). The 5-year DRFS rate was 98.3% (95% CI, 97.5 to 99.2) and the 8-year DRFS rate was 97.5% (95% CI, 96.4 to 98.7) (Fig. 2B). The 5-year OS rate was 99.5% (95% CI, 99.0 to 100) and the 8-year OS rate was 98.8% (95% CI, 98.0 to 99.6) (Fig. 2C). During follow-up, 16 deaths were recorded, of which three (18.8%) were attributable to breast cancer, five (31.2%) were due to other causes, and the cause of death of eight patients (50.0%) could not be confirmed.

4. Effect of adjuvant chemotherapy on survival outcomes

Patients who received adjuvant chemotherapy were younger (median age, 48 vs. 51 years), and had a higher proportion of premenopausal patients (61.4% vs. 49.5%). The proportion of patients who underwent mastectomy was higher among those who received adjuvant chemotherapy (75.7% vs. 58.6%). All patients who received adjuvant chemotherapy were negative for ER, whereas 36.3% of patients who did not receive adjuvant chemotherapy were positive for ER (S2 Table).

Overall, no significant difference was observed in IBCFS, DRFS, and OS between patients who received adjuvant chemotherapy and those who did not. The 8-year IBCFS rates were 91.0% (95% CI, 88.6 to 93.4) vs. 91.4% (95% CI, 86.9 to 96.2) in those who did not versus those who received adjuvant chemotherapy (p=0.860) (Fig. 3A). The 8-year DRFS rates were 97.4% (95% CI, 96.1 to 98.7) vs. 97.9 (95% CI, 95.5 to 100.0), respectively (Fig. 3B) and the 8-year OS rates were 98.9% (95% CI, 98.0 to 99.8) vs. 98.6 (96.6 to 100.0), respectively (Fig. 3C).

The most common first IBCFS events were invasive ipsilateral breast tumor recurrence in both groups, with a numerically higher prevalence observed in the adjuvant chemotherapy group (3.8% in those without chemotherapy vs. 8.6% in those with chemotherapy) (Table 2). The lack of differences in IBCFS following the administration of adjuvant chemotherapy was consistent across different subgroups including different menopausal status, surgical methods, size and grade of DCIS in tumor bed, tumor grade, and ER status (Fig. 4).

5. Prognostic factors for survival

We performed Cox regression analyses for IBCFS, DRFS, and OS (Table 3, S3 Table). Multifocality was associated with poor IBCFS in univariate analysis (HR, 1.87; 95% CI, 1.12 to 3.11; p=0.016), but not in multivariate analysis (HR, 1.45; 95% CI, 0.83 to 2.52; p=0.200). Moreover, multifocality was not significantly associated with DRFS or OS. Other clinical factors, including young age at surgery, surgical modality, DCIS size or the presence of high-grade DCIS in tumor bed, high tumor grade (histologic grade 3), hormone receptor status, and administration of adjuvant chemotherapy, were not associated with IBCFS, DRFS, or OS.

Discussion

Clinical data on the long-term outcomes of MIBC, especially on HER2-positive subtypes, is scarce due to the low incidence of MIBC among invasive breast cancers. To the authors’ knowledge, this retrospective study included the largest number of patients with HER2-positive MIBC and provided detailed long-term follow-up data, close to 10 years. We observed that the OS of patients with MIBC was excellent, with an 8-year OS rate of 99%; however, clinically meaningful IBCFS events with an 8-year IBCFS event rate of 8% were noted. Adjuvant cytotoxic chemotherapy, mostly 5-fluorouracil-based, did not improve survival.

The survival outcomes were generally consistent with those reported previously in patients with MIBC [6-8], i.e., a 5-year OS rate of 97%-100% and a 5-year disease-free survival rate of 93%-95%. Although patients with MIBC demonstrate an overall favorable prognosis, we identified clinically meaningful rates of IBCFS events despite the exclusion of patients with nodal metastasis, a known poor prognostic factor in MIBC [8]. Therefore, further exploration of additional treatment strategies, including identifying high-risk subsets and tailoring adjuvant systemic therapy, should be warranted in this early-stage cancer.

Among the patient characteristics evaluated, multifocality was identified as the only poor prognostic marker in the univariate analysis, but this association was not retained in the multivariate analysis. Although multifocality has been proposed as a prognostic marker in previous studies [22,23], it has not been consistently established as a prognostic factor in meta-analyses [8]. Patient age and hormone receptor status, which had been inconsistently suggested as potential prognostic markers [24], were insignificant for IBCFS in our study [8].

Consistent with the outcomes of our study, previous studies investigating the role of adjuvant chemotherapy in MIBC have failed to demonstrate a survival benefit [24,25]. Moreover, adjuvant chemotherapy did not confer a survival benefit even after adjusting for clinical characteristics, including patient age, surgical method, size and grade of DCIS in tumor bed, multifocality, tumor grade, and ER status. In addition, subgroup analysis failed to identify any patient subgroups that could benefit from adjuvant chemotherapy. A major limitation is that the majority (96.4%) of patients who received adjuvant chemotherapy were treated with doxifluridine, an oral 5-fluorouracil derivative with limited efficacy and which is no longer recommended [26]. Thus, further research with modern regimens is warranted.

An important comparison can be drawn with the APT trial, where a small percentage (2.2%) of patients had MIBC, and most were small IDC cases [17,18]. Although the prognosis for MIBC has been widely reported to be worse than that of pure DCIS, it is more favorable compared to that of small invasive carcinoma [9]. Direct comparisons are not possible; however, the 8-year IBCFS rates of 91.2% observed in our study were numerically lower than the outcomes reported in the APT trial. The APT trial reported a 10-year recurrence-free survival rate of 96.3% with adjuvant paclitaxel and trastuzumab in patients with HER2-positive IDC [18]. In contrast, the NSABP B-43 compared adjuvant trastuzumab versus placebo after lumpectomy for patients with HER2-positive DCIS and did not report a significant reduction in the IBTR rates, though it showed a trend toward numerical improvement in non-invasive IBTR rates [27]. Given the distinct clinical features of MIBC compared to DCIS, including more aggressive pathological features and lower survival rates [9,10,24,28], as well as the excellent survival outcomes in the APT trial, further investigation is warranted on the incorporation of HER2-targeted therapies into the treatment paradigm for MIBC and the necessity for combining adjuvant cytotoxic chemotherapy.

Our study has several limitations, including its single-centered, retrospective design. All patients were of Asian ethnicity, and the majority of adjuvant chemotherapy regimens were older with subpar efficacy. Despite these limitations, the study’s strengths include the homogeneous study population, focusing on HER2-positive MIBC, which accounts for a significant proportion of MIBC. Furthermore, the large sample size and long-term follow-up enhance the study’s robustness. We believe that the study offers valuable data into the natural history of HER2-positive MIBC.

In conclusion, clinically meaningful rates of IBCFS events were observed in patients with HER2-positive MIBC without nodal metastasis with long-term follow-up, despite the early stage of the disease. Adjuvant chemotherapy did not improve survival; however, this finding is limited by the use of a less effective, previously applied regimen. Further investigation is required to develop effective adjuvant strategies, particularly to explore the potential role of adjuvant trastuzumab in improving the outcomes for HER2-positive MIBC.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2024-1120_S1_Table.pdf

crt-2024-1120_S2_Table.pdf

crt-2024-1120_S3_Table.pdf

NOTES

Ethical Statement

The study protocol was approved by the Institutional Review Board of Asan Medical Center (#2024-0675). This study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. Informed consent from the patients was waived.

Author Contributions

Conceived and designed the analysis: Shin Y, Jeong H, Jeong JH.

Collected the data: Shin Y, Lee SY, Jeong H, Ahn JH, Jung KH, Kim SB, Kim HJ, Lee JW, Son BH, Ko B, Kim JS, Chung IY, Lee HJ, Gong G, Lee SB, Jeong JH.

Contributed data or analysis tools: Shin Y, Lee SY, Jeong H, Jeong JH.

Performed the analysis: Shin Y, Jeong H, Jeong JH.

Wrote the paper: Shin Y, Jeong H, Jeong JH.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Fig. 1.

Consort diagram showing the patient inclusion and exclusion criteria. HER2, human epidermal growth factor receptor 2; MIBC, microinvasive breast cancer.

Fig. 2.

Invasive breast cancer-free survival (IBCFS) (A), distant recurrence-free survival (DRFS) (B), and overall survival (OS) (C) in overall patients. CI, confidence interval.

Fig. 3.

Invasive breast cancer-free survival (IBCFS) (A), distant recurrence-free survival (DRFS) (B), and overall survival (OS) (C) according to whether adjuvant chemotherapy was administered or not. CI, confidence interval.

Fig. 4.

Forest plot of HRs of IBCFS between groups by stratification variables. CI, confidence interval; CTx, chemotherapy; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HR, hazard ratio; IBCFS, invasive breast cancer-free survival; RT, radiotherapy.

Table 1.

Patient baseline characteristics

Characteristic	No. of patients (%) (n=799)
Age at surgery (yr)
< 50	363 (45.4)
≥ 50	436 (54.6)
Age (yr), median (range)	51 (23-79)
Menopausal status
Premenopausal	412 (51.6)
Postmenopausal	387 (48.4)
Type of surgery
Breast-conserving surgery	307 (38.4)
Mastectomy	492 (61.6)
DCIS size in the tumor bed (cm)
< 2.0	154 (19.3)
≥ 2.0, < 5.0	342 (42.8)
≥ 5.0	272 (34.0)
Unknown	31 (3.9)
DCIS size in the tumor bed (cm), median (range)	4.0 (0.1-17.0)
DCIS grade in the tumor bed
Low	3 (0.4)
Intermediate	205 (25.7)
High	570 (71.3)
Unknown	21 (2.6)
Uni-/multi-focal
Unifocal	661 (82.7)
Multifocal	138 (17.3)
Nuclear grade
G1	4 (0.5)
G2	256 (32.0)
G3	516 (64.6)
Unknown	23 (2.9)
Histologic grade
G1	8 (1.0)
G2	273 (34.2)
G3	470 (58.8)
Unknown	48 (6.0)
Ki-67 index (%)
< 20	175 (21.9)
≥ 20	418 (52.3)
Unknown	206 (25.8)
Estrogen receptor
Positive	238 (29.8)
Negative	561 (70.2)
Progesterone receptor
Positive	136 (17.0)
Negative	663 (83.0)
HER2
Positive	799 (100)
Adjuvant endocrine therapy
Yes	239/243 (98.4)
No	4/243 (1.6)
Adjuvant radiotherapy
Yes	297 (37.2)
Adjuvant chemotherapy
Yes	140 (17.5)
Adjuvant trastuzumab therapy
Yes	1 (0.1)

DCIS, ductal carcinoma in situ; G1, grade 1; G2, grade 2; G3, grade 3; HER2, human epidermal growth factor receptor 2.

Table 2.

IBCFS events by the site of first occurrence

Site	Adjuvant chemotherapy (n=140)	No chemotherapy (n=659)	Total(n=799)
Ipsilateral breast tumor recurrence (invasive)	12 (8.6)	25 (3.8)	37 (4.6)
Other local-regional recurrence	0	4 (0.6)	4 (0.5)
Distant recurrence	2 (1.4)	9 (1.4)	11 (1.4)
Contralateral breast cancer	2 (1.4)	15 (2.3)	17 (2.1)
Non-breast cancer deaths or unknown cause	4 (2.9)	5 (0.7)	9 (1.1)
Total events	20 (14.3)	58 (8.8)	78 (9.8)
Event-free	120 (85.7)	601 (91.2)	721 (90.2)

Values are presented as number (%). IBCFS, invasive breast cancer-free survival.

Table 3.

Univariate and multivariate analysis of risk factors associated with IBCFS

Variable	Univariate analysis			Multivariate analysis
Variable	HR	95% CI	p-value	HR	95% CI	p-value
Age ≥ 50 years	0.72	0.46-1.13	0.150	0.75	0.46-1.22	0.200
Breast-conserving surgery	1.28	0.81-2.01	0.300	1.25	0.71-2.19	0.400
DCIS size ≥ 5 cm	1.13	0.70-1.81	0.600	1.14	0.65-2.01	0.700
High-grade DCIS	0.80	0.49-1.31	0.400	0.53	0.25-1.17	0.120
Multifocality	1.87	1.12-3.11	0.016	1.45	0.83-2.52	0.200
Histologic grade 3	0.95	0.60-1.51	0.800	1.61	0.76-3.42	0.200
Estrogen receptor positivity	0.71	0.42-1.22	0.200	0.63	0.34-1.18	0.200
Adjuvant chemotherapy	1.05	0.62-1.78	0.900	1.26	0.67-2.33	0.500

CI, confidence interval; DCIS, ductal carcinoma in situ; HR, hazard ratio; IBCFS, invasive breast cancer-free survival.

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Ten-Year Follow-up Clinical Outcomes and the Role of Adjuvant Chemotherapy in HER2-Positive Patients with Microinvasive Breast Cancer

Cancer Res Treat. 2026;58(1):151-158. Published online March 5, 2025

DOI: https://doi.org/10.4143/crt.2024.1120

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
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Ten-Year Follow-up Clinical Outcomes and the Role of Adjuvant Chemotherapy in HER2-Positive Patients with Microinvasive Breast Cancer

Fig. 1. Consort diagram showing the patient inclusion and exclusion criteria. HER2, human epidermal growth factor receptor 2; MIBC, microinvasive breast cancer.

Fig. 2. Invasive breast cancer-free survival (IBCFS) (A), distant recurrence-free survival (DRFS) (B), and overall survival (OS) (C) in overall patients. CI, confidence interval.

Fig. 3. Invasive breast cancer-free survival (IBCFS) (A), distant recurrence-free survival (DRFS) (B), and overall survival (OS) (C) according to whether adjuvant chemotherapy was administered or not. CI, confidence interval.

Fig. 4. Forest plot of HRs of IBCFS between groups by stratification variables. CI, confidence interval; CTx, chemotherapy; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HR, hazard ratio; IBCFS, invasive breast cancer-free survival; RT, radiotherapy.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Ten-Year Follow-up Clinical Outcomes and the Role of Adjuvant Chemotherapy in HER2-Positive Patients with Microinvasive Breast Cancer

Characteristic	No. of patients (%) (n=799)
Age at surgery (yr)
< 50	363 (45.4)
≥ 50	436 (54.6)
Age (yr), median (range)	51 (23-79)
Menopausal status
Premenopausal	412 (51.6)
Postmenopausal	387 (48.4)
Type of surgery
Breast-conserving surgery	307 (38.4)
Mastectomy	492 (61.6)
DCIS size in the tumor bed (cm)
< 2.0	154 (19.3)
≥ 2.0, < 5.0	342 (42.8)
≥ 5.0	272 (34.0)
Unknown	31 (3.9)
DCIS size in the tumor bed (cm), median (range)	4.0 (0.1-17.0)
DCIS grade in the tumor bed
Low	3 (0.4)
Intermediate	205 (25.7)
High	570 (71.3)
Unknown	21 (2.6)
Uni-/multi-focal
Unifocal	661 (82.7)
Multifocal	138 (17.3)
Nuclear grade
G1	4 (0.5)
G2	256 (32.0)
G3	516 (64.6)
Unknown	23 (2.9)
Histologic grade
G1	8 (1.0)
G2	273 (34.2)
G3	470 (58.8)
Unknown	48 (6.0)
Ki-67 index (%)
< 20	175 (21.9)
≥ 20	418 (52.3)
Unknown	206 (25.8)
Estrogen receptor
Positive	238 (29.8)
Negative	561 (70.2)
Progesterone receptor
Positive	136 (17.0)
Negative	663 (83.0)
HER2
Positive	799 (100)
Adjuvant endocrine therapy
Yes	239/243 (98.4)
No	4/243 (1.6)
Adjuvant radiotherapy
Yes	297 (37.2)
Adjuvant chemotherapy
Yes	140 (17.5)
Adjuvant trastuzumab therapy
Yes	1 (0.1)

Site	Adjuvant chemotherapy (n=140)	No chemotherapy (n=659)	Total(n=799)
Ipsilateral breast tumor recurrence (invasive)	12 (8.6)	25 (3.8)	37 (4.6)
Other local-regional recurrence	0	4 (0.6)	4 (0.5)
Distant recurrence	2 (1.4)	9 (1.4)	11 (1.4)
Contralateral breast cancer	2 (1.4)	15 (2.3)	17 (2.1)
Non-breast cancer deaths or unknown cause	4 (2.9)	5 (0.7)	9 (1.1)
Total events	20 (14.3)	58 (8.8)	78 (9.8)
Event-free	120 (85.7)	601 (91.2)	721 (90.2)

Variable	Univariate analysis			Multivariate analysis
Variable	HR	95% CI	p-value	HR	95% CI	p-value
Age ≥ 50 years	0.72	0.46-1.13	0.150	0.75	0.46-1.22	0.200
Breast-conserving surgery	1.28	0.81-2.01	0.300	1.25	0.71-2.19	0.400
DCIS size ≥ 5 cm	1.13	0.70-1.81	0.600	1.14	0.65-2.01	0.700
High-grade DCIS	0.80	0.49-1.31	0.400	0.53	0.25-1.17	0.120
Multifocality	1.87	1.12-3.11	0.016	1.45	0.83-2.52	0.200
Histologic grade 3	0.95	0.60-1.51	0.800	1.61	0.76-3.42	0.200
Estrogen receptor positivity	0.71	0.42-1.22	0.200	0.63	0.34-1.18	0.200
Adjuvant chemotherapy	1.05	0.62-1.78	0.900	1.26	0.67-2.33	0.500

Table 1. Patient baseline characteristics

DCIS, ductal carcinoma in situ; G1, grade 1; G2, grade 2; G3, grade 3; HER2, human epidermal growth factor receptor 2.

Table 2. IBCFS events by the site of first occurrence

Values are presented as number (%). IBCFS, invasive breast cancer-free survival.

Table 3. Univariate and multivariate analysis of risk factors associated with IBCFS

CI, confidence interval; DCIS, ductal carcinoma in situ; HR, hazard ratio; IBCFS, invasive breast cancer-free survival.