The effect of adjuvant radiotherapy on M0 adenoid cystic carcinoma of the breast: a retrospective cohort study based on SEER data

Introduction

According to the latest data released by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, breast cancer remains the most frequently diagnosed cancer among women in the United States (1). Breast cancer is typically classified into distinct molecular subtypes based on the expression levels of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Triple-negative breast cancer (TNBC) lacks the expression of ER, PR, and HER2. TNBC accounts for 15–20% of invasive breast cancer cases, and is usually recognized as aggressive; patients with TNBC have a higher possibility of experiencing distant metastasis and early recurrence (2,3).

Adenoid cystic carcinoma of the breast (ADCC) is a rare histologic subtype of breast cancer, accounting for 0.1% of all breast tumors (4). Although the molecular subtype of ADCC is primarily classified as TNBC, it consistently exhibits indolent clinical behavior with a low propensity for axillary lymph node involvement and distant metastasis, and differs significantly from other pathologic types (5-7).

Due to the rarity of ADCC, earlier retrospective studies involving limited case series concluded that surgical intervention, including partial or total mastectomy, was associated with favorable survival outcomes (5). More recently, Huang et al. (5) expanded on this research through an analysis of SEER data, and reported that breast-conserving surgery may yield superior survival rates compared to mastectomy in patients with stage I or II ADCC. While adjuvant chemotherapy (CT) might not be essential (8-10), the role of radiotherapy (RT) remains controversial. Some studies have reported that postoperative RT significantly improves overall survival (OS), particularly after breast-conserving therapy (BCT) (9,11). Conversely, other studies have not recommended routine adjuvant RT due to the lack of any significant survival benefit and its associations with considerable treatment-related toxicities (8,12).

Presently, individual therapy is a commonly recommended approach for the treatment of tumors. However, due to the rarity and favorable prognosis of ADCC, there are no universally agreed-upon guidelines for its treatment, and no consensus has been reached as to the optimal surgical approach and necessity of adjuvant therapy for non-metastatic M0 ADCC (4,9,11,13-15).

Therefore, the current study aimed to assess the effect of surgical procedures with RT or without RT on OS and breast cancer-specific survival (BCSS) in M0 ADCC patients. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-231/rc).

Methods

Data source

All the data were extracted from the SEER database through SEER*Stat (version 8.4.33). The SEER database is a nationally representative, population-based cancer registry that covers approximately 28% of the United States population and provides authoritative information on cancer incidence, treatment, and survival.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. As all the data in this population-based analysis were retrieved from the publicly available SEER database, ensuring patient anonymity, institutional ethics committee approval and written consent were not required.

Study population

This retrospective cohort study initially identified 759 patients diagnosed with a histology-confirmed diagnosis of ADCC (International Classification of Diseases for Oncology-3 morphology code: 8200/3) in the SEER database from 2000 to 2021. The sample was selected based on the availability of complete data on vital status and survival time. As illustrated in Figure 1, patients were included in the study if they met the following inclusion criteria: (I) had comprehensive clinicopathological data available; (II) had been diagnosed at the M0 stage; (III) had tumor size data available; and (IV) had surgical approach data available. Patients were excluded from the study if they met any of the following exclusion criteria: had not undergone surgical treatment, had an unknown surgical status, had been diagnosed at the distant metastasis (M1) or unknown metastasis status (Mx) stage, and/or had an unknown tumor size. After applying these criteria, a final analytical cohort of 716 patients was established for the study.

Figure 1 Flow diagram of study cohort selection. ADCC, adenoid cystic carcinoma of the breast; ICD-O-3, International Classification of Diseases for Oncology, third edition; M, metastasis; SEER, Surveillance, Epidemiology, and End Results.

Clinical and pathological characteristics

Data on the clinical and pathological characteristics of the included patients were systematically extracted from the SEER database. These variables included gender, age, race, year of diagnosis, histological grade, tumor stage, nodal status, TNM classification (primary tumor, regional lymph node, distant metastasis), type of surgery, adjuvant therapy, and the ER, PR, and HER2 expression levels. Breast surgery was categorized as BCT or mastectomy. Records regarding adjuvant treatments, including CT and RT, were also documented. In this study, the non-RT group included all patients who did not receive RT treatment, including those who were eligible for RT but declined the treatment.

Follow-up procedure

The SEER program provided follow-up data for OS and BCSS. This program routinely tracks vital status and cause of death through linkages with state vital statistics offices and the National Death Index. Survival time was calculated in months from the date of diagnosis until the date of death or the last follow-up.

Statistical analysis

OS and BCSS were estimated using the Kaplan-Meier method. Tumor size was analyzed using a binary cutoff value of 10 mm. This threshold was selected based on its established prognostic value in breast cancer literature and to ensure sufficient statistical power within subgroups for analysis, a common approach in studies of rare malignancies. Group comparisons were performed using the log-rank test. The association between the clinical variables and survival outcomes were evaluated using Cox proportional hazards models. Both univariate and multivariate analyses were conducted to assess the influence of various factors on survival. A significance level of P<0.05 was set for all two-sided tests. All analyses were conducted using SPSS software (version 25.0; IBM, Armonk, NY, USA).

Results

Patient characteristics

Overall, 716 patients with ADCC were included in the analysis. The general characteristics of the included patients are listed in Table 1. The ADCC patients had a median age of 60 years at diagnosis. Of the patients with ADCC, 350 patients (48.9%) received RT (the RT group) and 366 patients (51.1%) did not receive RT (the non-RT group). There were no significant differences between the RT group and non-RT group in terms of age, sex, marriage, race, laterality, T stage, nodal status, and CT (all P>0.05). However, there were statistically significant differences between the two groups in terms of surgery, ER status, PR status, and HER2 status (all P<0.05).

Among the patients with ADCC, the majority were white (n=591, 82.5%), married (n=410, 57.3%), and had not undergone CT (n=624, 87.2%). The laterality of the lesions was roughly evenly distributed between the left and right sides (48.5% vs. 51.5%). The patients with ADCC were mainly in the T1 stage (n=424, 59.5%) and T2 stage (n=258, 36.2%), and 95.8% of these patients showed no lymph node involvement. Additionally, most patients with ADCC who received RT also underwent BCT (n=324, 92.6%), while most patients who did not receive RT underwent mastectomy (n=213, 58.2%). In addition, the negative rates for ER and PR were 72.3% and 79.7%, respectively. Of the 323 cases with known HER2 status, 98.1% were HER2 negative and only 1.9% were HER2 positive.

The effect of treatment on survival in patients with ADCC

No significant difference in OS was observed in the ADCC patients who underwent BCT versus mastectomy (P=0.28); however, a significant difference in BCSS was observed (P=0.002) (Figure 2A,2B). Conversely, the Kaplan-Meier survival analysis of the RT and non-RT groups showed that the OS rate was lower in the non-RT group than the RT group (P=0.002), while the BCSS rates of the two group were similar (P=0.10) (Figure 2C,2D). In relation to CT, while no significant difference was observed in terms of the OS rates (P=0.61), the CT group had a significantly worse BCSS rate than the non-CT group (P<0.001) (Figure 2E,2F).

Figure 2 OS and BCSS of patients with ADCC, stratified by treatment type: (A,B) surgery; (C,D) radiation; (E,F) chemotherapy. ADCC, adenoid cystic carcinoma of the breast; BCSS, breast cancer-specific survival; OS, overall survival.

Subgroup analysis of OS and BCSS in patients with ADCC

We also analyzed the survival of the ADCC patients who received RT and those who did not receive RT after different surgical procedures (Figure 3A-3D). Significant difference was found in the OS of the patients who underwent BCT and received RT and those who underwent BCT and did not receive RCT (P=0.001); however, we found that the long-term survival of the RT group was significantly better than that of the non-RT group. In relation to the patients who underwent mastectomy, no significant differences were found between the RT group and non-RT group in terms of OS and BCSS (P=0.75 and P=0.95, respectively). We also conducted a subgroup analysis of the patients with ADCC who underwent BCT, did or did not receive RT, and had a tumor size ≤10 mm or a tumor size >10 mm (Figure 3E-3H). Notably, there were no significant differences in the OS rate and BCSS rate of the patients with a tumor size ≤10 mm (P=0.22, P=0.43); however, a significant difference was observed in the OS rate of the patients with a tumor size >10 mm (P=0.002).

Figure 3 Subgroup analysis of OS and BCSS in patients with ADCC receiving different radiation treatments. Analyses are stratified by the type of primary surgery: (A,B) breast-conserving therapy; (C,D) mastectomy. The breast-conserving therapy cohort was further subdivided based on a tumor size: (E,F) of ≤10 mm; (G,H) and >10 mm. ADCC, adenoid cystic carcinoma of the breast; BCSS, breast cancer-specific survival; OS, overall survival.

Univariate and multivariate analyses of clinical and pathological characteristics

Table 2 sets out the results of the univariate and multivariate analyses. In the univariate analysis, age, nodal status, and RT were associated with OS, while sex, race, HER2 status, nodal status, CT, and surgery were associated with BCSS. The multivariate analysis identified RT and age as independent risk factors for OS, and race and CT as independent risk factors for BCSS in the patients.

Discussion

Adenoid cystic carcinoma is a gland-based malignancy that occurs most commonly in the salivary glands but can also occur in the lacrimal glands, the external auditory canal, the upper respiratory and lung, and the female reproductive tract, and in rare instances, in the breast (16). ADCC was first described by Billroth in 1856 as cylindrical carcinoma of the breast and later by Geschickter in 1945 (14). Histologically, ADCC resembles its salivary gland counterpart, and its diagnostic criteria emphasize a biphasic cellular pattern as the most critical single feature (6).

ADCC occurs mainly in older women (17), usually around the areola or in the center of the breast, and manifests clinically as a slow-growing, well-defined, and mobile solid mass (18). Breast pain is also a classic symptom of ADCC, although it is rare (19). The average diameter of ADCC has been reported to be 3 cm, but in some cases, the diameter of large ADCC has been reported to reach 30 cm (16,20).

TNBC is the molecular subtype of breast cancer with the worst prognosis. In the absence of well-defined molecular targets, the treatment of TNBC primarily relies on CT (21). Although patients with TNBC exhibit a high clinical response to neoadjuvant CT, they still experience higher rates of distant recurrence and poorer prognosis than those with other breast cancer subtypes (22).

Notably, while the molecular subtype of most cases of ADCC is TNBC, the clinical manifestations of ADCC are indolent, and the tendency of axillary lymph node involvement and distant metastasis is low, and patient prognosis is excellent (7). Thus, the molecular subtype may not be the primary factor associated with prognosis. Research has shown that patient characteristics, including the cancer stage classification, tumor size, positive lymph nodes, and primary treatment type, are highly correlated with a worse prognosis (23). Further, studies have shown that a positive prognosis might be related to the ADCC characteristics expressed by the MYB-NFIB fusion gene and the down-regulation of genes associated with migration, proliferation, and immune response (24-27).

Initially, most studies supported mastectomy as the primary and optimal treatment for ADCC due to limited retrospective research and previous literature. In fact, patients with ADCC who undergo mastectomy have a favorable prognosis, with a high long-term survival rate (18). However, it is essential to determine whether lymph node metastasis or distant metastasis is present before treatment. Axillary lymph node dissection is recommended for those with axillary lymph node metastasis (28).

Khanfir et al. recommended BCT followed by postoperative RT for the treatment of patients with ADCC (10), marking a significant turning point in the treatment of ADCC. Several studies have found that BCT is a reasonable alternative for patients with ADCC, and that axillary surgery might be safely omitted if there is no clinical evidence of axillary lymph node metastasis (5,9,29). Similarly, in our study, compared to those who underwent mastectomy, the ADCC patients who underwent BCT showed a significant advantage in terms of OS. Additionally, based on data from the SEER database and the National Cancer Center of China, Li et al. reported that adjuvant CT may not be necessary for patients with ADCC (8). The analysis results of this study also support this finding.

Research has shown that the use of RT as a component of BCT or after mastectomy reduces the risk of local-regional recurrence and improves the long-term BCSS and OS of patients (30-32). Additionally, previous studies have suggested that adjuvant RT after BCT in ADCC patients can decrease local recurrence rates and improve long-term survival rates (4,9,33). However, a recent study suggested that ADCC patients in the low-risk subgroup (i.e., those aged <60 years with T1–2 tumors and grade I/II disease) may be exempted from postoperative RT (11,12).

In our study, in both the univariate and multivariate analyses, the nodal stage was the independent prognostic factor affecting OS (all P<0.05), while in the univariate analysis, age at diagnosis was the independent prognostic factor affecting BCSS (P<0.05).

The benefit-harm assessment of RT is important. One of the most serious adverse effects of RT is an increased risk of cardiovascular disease (34,35). Patients with a higher tumor burden might derive greater benefits from RT, as it can reduce local-regional recurrence. Conversely, the potential risk of adverse effects from RT might exceed the benefits of RT in patients with a low tumor burden (36).

This study conducted a comprehensive analysis of tumor size and categorized patients with ADCC receiving BCT into two groups: those with tumors measuring 10 mm or less (T ≤10 mm) and those with tumors exceeding 10 mm (T >10 mm). The threshold of 10 mm aligns with the combined T1a and T1b categories in the American Joint Committee on Cancer 8th edition staging system. This dichotomous classification was implemented to clearly delineate the significant prognostic implications of the 10-mm cutoff while ensuring adequate sample sizes within each subgroup. This approach minimizes potential bias arising from small sample sizes, and enhances the scientific validity and reliability of the findings.

The survival prognosis analysis of the RT and non-RT groups showed that for the group of ADCC patients who received BCT and had a tumor size ≤10 mm, radiation had no significant effect on OS and BCSS; however, a significant difference in OS was found in the tumour size >10 mm group. This outcome is consistent with another analysis based on SEER data conducted by Sun et al. (9). Given the well-documented indolent behavior of ADCC and the established association between a smaller tumor size and reduced disease risk, these results suggest that the favorable baseline prognosis for M0 ADCC patients with a tumor size ≤10 mm provides little scope for a discernible OS benefit from adjuvant RT. Consequently, we propose that M0 ADCC patients with a tumor size ≤10 mm who have received BCT may not derive any benefit from RT.

Given the extremely low incidence of ADCC, designing and conducting prospective trials to evaluate the effect of adjuvant RT would not be feasible. Consequently, we conducted this study using a large, population-based cohort from the SEER database. We recognize the inherent limitations associated with this study. As is the case with analyses of large registries, our findings are susceptible to selection bias, information bias, and potential inaccuracies in data coding and documentation.

The retrospective design of this analysis, which relied on the SEER registry, introduces inherent limitations. The database lacks detailed information on several variables critical for comprehensive oncological analysis, including patient performance status, detailed RT parameters (e.g., total dose, fractionation, technique, and treatment volumes), specifics of systemic therapy, rates of local and regional recurrence, and long-term treatment-related toxicities (e.g., cardiovascular events). Additionally, the absence of data concerning comorbidities, socioeconomic status, and the quality of follow-up care may impede a nuanced interpretation of the observed survival benefit and the risk-benefit ratio associated with RT. Despite adjustment for key clinicopathological factors in our multivariate Cox proportional hazards models, the omission of certain clinical variables renders our analysis vulnerable to residual confounding. Additionally, the SEER database is representative of the United States population; thus, the generalizability of our findings to other healthcare systems, ethnic groups, and treatment practices may be limited. Moreover, although clinically relevant, using OS as the primary endpoint does not directly capture local control, which is a primary goal of RT in ADCC. Finally, the small sample size of the patients in the tumor size ≤10 mm subgroup likely resulted in underpowered analyses, limiting the ability to detect a potential survival benefit or risk associated with RT.

Our analysis indicated that patients with tumors ≤10 mm may not derive a significant benefit from RT. These results underscore the necessity for individualized treatment strategies that prudently balance the potential advantages of local control against the risks of long-term toxicities, which are frequently inadequately quantified, particularly in patients with extended life expectancies. Additionally, these findings highlight the importance of validation through multi-institutional collaborations and, ideally, prospective international registries.

Conclusions

The tumor size and surgical approach should be integral components of clinical evaluations when considering the use of RT. Adjuvant RT did not improve the OS and BCSS of the M0 ADCC patients with a tumor size ≤10 mm who had undergone BCT. Therefore, adjuvant RT might not be necessary for M0 ADCC patients with a tumor size ≤10 mm who have undergone BCT.

Acknowledgments

We thank all authors who devoted their time to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-231/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-231/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-231/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Due to all data in this population-based analysis being searched from the public SEER database with patient anonymity, institutional ethics committee approval and written consent were not required.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)