Is surgical axillary staging necessary in women with T1 breast cancer who are treated with breast-conserving therapy?

With improvements in breast cancer screening, increasing numbers of patients are being diagnosed at an early stage with reduced axillary lymph node involvement [1]. As such, surgical treatment of primary breast cancer has de-escalated over the last decades, with breast-conserving surgery (BCS) and sentinel lymph node biopsy (SLNB) being increasingly performed over mastectomy and axillary lymph node dissection (ALND) [2]. Currently, ALND is performed only if the result of SLNB is positive [3]. The International Breast Cancer Study Group (IBSCG) 23-01 trial demonstrated no local control or survival advantages associated with ALND, even in women with micrometastatic SLNs [4]. Furthermore, both the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial and the European Organization for Research and Treatment of Cancer (EORTC) AMAROS trial indicated that ALND could be safely omitted in most patients with 1–2 metastatic SLNs [5, 6].

Although SLNB is highly reproducible, accurate, and associated with reduced morbidity, it is not a risk-free procedure [7]. A 4%–14% rate of complications, such as allergic reactions, hematoma, lymphedema, paresthesia, chronic pain, and immobility, still occurs after SLNB [8–11]. Additionally, the false negative rate of axillary lymph node status predicted by SLNB is 5%–10%, despite the axillary recurrence rate being only 0.3% [3, 12–14]. Taken together, the value of surgical axillary staging for early-stage breast cancer treated with breast-conserving therapy (BCT) remains controversial in the current era of personalized medicine.

The shift in the size of breast tumors is believed to be associated with the increasing use of screening mammography [15]. Until 1999, the average tumor size at initial presentation (stage I–III) has decreased by 10% every 5 years for two decades [16]. However, the rates of T1 tumors (≤ 2 cm) remained relatively unchanged for the past 15 years, and the average tumor size was approximately 1.8 cm [17]. Therefore, using the Surveillance, Epidemiology, and End Results (SEER) database, we aimed to investigate the safety of waiving surgical axillary staging in patients with T1 breast cancer who are treated with BCT.

The risk of lymph node metastasis in patients with ductal carcinoma in situ (DCIS) is estimated to be only 1%–6%, for whom surgical axillary staging is not required according to the National Comprehensive Cancer Network (NCCN) guidelines [23, 24]. In the present study, the rates of lymph node metastasis in patients with T1mic, T1a, T1b, and T1c tumors were 2.8%, 4.5%, 9.3% and 21.0%, respectively. Therefore, it seems reasonable to omit surgical axillary staging for patients with T1mic or T1a tumors. Furthermore, our survival analysis showed no difference in BCSS between staging and non-staging groups in patients with T1mic, T1a, and T1b tumors, whereas surgical axillary staging only prolonged BCSS of patients with T1c breast cancer.

Young breast cancer patients often present with a more advanced stage and aggressive subtypes at diagnosis, resulting in a poorer prognosis [2]. However, there is a paucity of data regarding the safety of treating young women with less aggressive axillary surgery. A randomized trial (INT09/98) was conducted to determine the impact of avoiding axillary surgery in patients with T1N0 breast cancer [25]. In that trial, 517 patients aged 30–65 years with T1N0 breast cancer were recruited between 1998 and 2003 and were randomized to undergo quadrantectomy either with or without ALND. After a median follow-up of 10 years, no difference was observed in overall survival (OS) and disease-free survival (DFS) between the two treatment arms [25]. In the current study, BCSS did not differ between the two treatment arms in patients aged 50–65 years, which is partially consistent with the results of the INT09/98 trial. However, we identified that surgical axillary staging significantly prolonged BCSS in patients younger than 50 years, suggesting that we should still adhere to the current standard treatment for premenopausal patients.

Breast cancer patients older than 65 years tend to have a favorable prognosis and may not benefit from surgical treatment of the axillary lymph nodes [26, 27]. A study began in 1996 recruited 65–80-year-old patients with cT1N0 breast cancer who were randomized to undergo conservative surgery with or without ALND. After 15 years of follow-up, breast cancer-specific mortality and OS did not differ between the ALND and no ALND arms, and the rates of distant metastases were also indistinguishable [28]. However, Sun et al. [26] found that forgoing surgical axillary treatments in women older than 65 years was associated with short OS and BCSS. The controversy among these trials might be attributed to the relatively small sample sizes. Our results showed that it was safe to omit surgical axillary staging in women between 50 and 79 years old. However, we also found that surgical axillary staging significantly prolonged BCSS of patients of at least 80 years old. We speculate that patients of at least 80 years old were less likely to receive standard systemic therapy than younger patients.

Marrazzo et al. [29] indicated that patients with triple-negative breast cancer could be good candidates for BCT without surgical axillary staging. However, in the present study, ER/PR status was not significantly associated with the impact of surgical axillary staging on BCSS. Although adjuvant chemotherapy has been shown to reduce 10-year breast cancer mortality for all subtypes by one-third compared with no chemotherapy [30], patients who were at low risk for recurrence had a small absolute benefit which might be outweighed by long-term toxicities [31]. Consistently, our results showed that chemotherapy did not prolong BCSS of patients with T1 breast cancer either.

Since the importance of surgical axillary staging is still debatable, new ongoing trials, including the Sentinel Node versus Observation after Axillary Ultrasound (SOUND) trial [32] and the Intergroup Sentinel Mamma (INSEMA) trial [33], have been designed to compare SLNB versus observation in cT1-2N0 patients treated with BCT. The SOUND trial, a non-inferiority trial, aimed to recruit 1560 women (780 in each arm), with the primary endpoint being DFS and OS. The INSEMA study planned to randomize patients to either no axillary surgical intervention or SLNB in a 1:4 allocation (1348 patients in no intervention arm). In the present study, each treatment arm in the matched cohort included 5561 patients, and all covariates were comparable after propensity score matching, which was identified as a simulation of randomized clinical trials [20].

Owing to its retrospective nature, the present study had several limitations. Because the SEER database does not have a reliable parameter to distinguish between ALND and SLNB, we assumed that lymph node examination number ≥ 1 represented a formal surgical axillary staging. In general, radiotherapy after BCS is supposed to cover the whole breast with or without regional nodes, which may influence axillary recurrence rates in patients with low-volume axillary disease [6]. In the present study, all patients underwent BCT. However, information regarding the extent and dose of irradiation was not available. Additionally, endocrine therapy was not recorded, but we believe that this might have not largely impacted the results of this study because the majority of patients with early-stage breast cancer who completed appropriate locoregional treatment were likely to undergo standard systemic therapy [34].

In terms of strong preconceptions on the potential therapeutic benefit of axillary surgery, many patients and physicians are unwilling to take the risk for choosing less aggressive surgical management of the axilla, thereby making randomization problematic. Therefore, a large retrospective study might be an ideal design alternative to solve this dilemma [35]. Due to the great disparity in the proportion of patients with or without surgical axillary staging, it is difficult to avoid selection bias. The multivariate model using Cox regression analysis alone may not fully adjust many confounding factors. Therefore, we performed greedy matching techniques to balance all measured covariates in the dataset, which is a pseudo-randomized study design. Further, we used propensity score matching, which is a widely accepted approach for the control of selection bias in observational studies [36].

Due to more effective screening strategies and adjuvant therapies, the potential risks of axillary surgery may now outweigh its potential benefits, especially in early-stage breast cancer patients treated with BCT. Before the results of ongoing clinical trials are announced, findings of the present mono-institutional retrospective study hint a rationale for waiving surgical axillary staging in subgroups of T1 breast cancers, which are characterized as having tumor size < 1 cm, being 50–79 years old, having grade I disease, and favorable histological types. The possibility to de-escalate axillary treatments needs to be further investigated according to the molecular features of the primary tumor, to be more cost-effective and to reduce risks of potentially avoidable morbidity.