Occult breast cancer (OBC) is a rare type of breast cancer which presents with axillary lymph node (LN) metastasis without identified primary breast lesion [1,2]. Current National Comprehensive Cancer Network (NCCN) guidelines recommend that axillary LN as well as ipsilateral breast should be treated with modified radical mastectomy or axillary LN dissection (ALND) plus whole breast radiotherapy (RT) even with no detectable breast tumor [3]. However, without prospective randomized trials due to its rarity, evidence on the managements of OBC comes from several retrospective studies including small number of patients [4-7].

Although systemic chemotherapy and endocrine therapy are believed to be performed according to the recommendations for their relatively comparative stage, locoregional managements for OBC such as breast conserving surgery (BCS), mastectomy, ALND, or its combinations have been variously implemented [8,9]. Previous studies suggested that BCS or ALND plus RT resulted in similar recurrence and survival rates compared to mastectomy plus ALND [5-7]. The first population-based data also demonstrated that both mastectomy plus ALND with/without postmastectomy RT and BCS with ALND and RT showed better survival than ALND alone but no difference between the formers was found [2]. However, from the standpoint of the radiation oncologist, no studies have evaluated the effect of RT after mastectomy or ALND with/without breast surgery. In addition, high-risk patients who need more aggressive locoregional treatments are not well-defined in the literature. Therefore, we investigated clinicopathologic factors of OBC with the impact of postoperative RT to determine its prognostic significance using large population-based data.

The main purpose of this population-based retrospective study was to evaluate the clinicopathologic factors affecting OS as well as the impact of RT under different surgical conditions for OBC. Although ALND followed by breast RT is accepted as one of the preferred strategy after many comparisons with mastectomy have been made, the impact of RT after ALND or mastectomy compared with each surgical treatment alone has not been exactly evaluated in previous literatures [5-7]. It is hard to conduct a randomized trial because of the rarity, therefore we used retrospective matching analysis using large database. To the best of knowledge, present updated SEER analysis represents the largest cohort to date in which survival outcome for OBC was analyzed. Significant improvements in survival in the RT group compared with the non-RT group were generally observed, also specifically in patients with single marital status, receiving mastectomy, receiving ALND, and number of metastatic LNs more than 7.

Treatment patterns varied over the years. Although mastectomy did not improve OS compared with breast-conserving therapy (BCT), there were quite a large proportion of patients treated with mastectomy. Previous survey for the members of the American Society of Breast Surgeons demonstrated that mastectomy with ALND preferred in 43%, whereas ALND with whole breast RT in 37% [9]. A previous study for OBC using the SEER data (1983-2006) demonstrated that number of patients who received BCT increased from 29.8% before 1998 to 36.2% after 1998, whereas number of patients who received mastectomy decreased from 50.2% to 42% during the same period, which still held a significant portion [2]. Although BCT is replacing mastectomy with the advent of diagnostic imaging, mastectomy still have been performed in many patients due to physician’s preference or clinical factors, but the role of RT in these patients was also not separately discussed in previous studies [11,12]. Our analysis revealed that RT after mastectomy was an effective adjuvant treatment to reduce mortality, as with survival benefit by adding RT in other node positive breast cancers [13-15]. This survival benefit might derive from the comprehensive nodal irradiation, although the detailed RT field is unavailable from the SEER database. Also, the NCCN guidelines do not mention this in detail. Therefore, physicians should discuss with radiation oncologists to determine whether postmastectomy RT is appropriate or not, even if subsequent validation studies will be required

The standard recommendations in terms of RT field and dose are not well defined in this rare disease. By reviewing the contemporary studies using RT, Table 4 shows that most of RT field includes ipsilateral breast in case of BCS, whereas there is not much information about chest wall irradiation after mastectomy. Among them, Barton et al. [16] recommended the incorporation of ipsilateral breast RT due to the higher 5-year local recurrence-free survival (84% vs. 34%, p < 0.001) and relapse-free survival (64% vs. 34%, p=0.05). The extent or frequency of regional nodal irradiation is also varied for each study, so it is difficult to summarize the conclusions. However, more than 70% of patients received some kinds of regional nodal irradiation, mainly including supraclavicular fossa. In terms of RT dose, a total dose of 40 to 60 Gy has been applied variously according to the surgical extents and residual disease. A previous study showed that no difference in the 5-year local recurrence-free survival (80% vs. 90%, p=0.3) was found between patients who received 50 Gy versus more than 60 Gy [16]. The present study could not address these aspects because information about the exact delivery site of RT (whole breast irradiation, localized axillary RT, or regional nodal irradiation) and RT dose was not included in SEER data. Further specific guidelines will be needed.

The benefit of adding RT is not limited just after mastectomy. Previous studies have rather recommended incorporation of breast RT with ALND. Historically, locoregional recurrence was too high (around 50%) in patients who did not receive breast treatment after ALND [17-19]. Shannon et al. [17] reported that 69% of patients without breast RT underwent locoregional recurrence; however, this figure decreased to 12.5% in those receiving breast RT (p=0.02). Vlastos et al. [12] also reported that patients who were observed without breast treatment showed 50% OS, whereas those who received breast RT after axillary surgery showed 83% OS. Therefore, “blind” treatment to the ipsilateral breast seemed to be important. Our results showed that application of RT has a positive effect on OS rate in both unmatched and matched cohort. Especially, patients treated with ALND also derived OS benefit from RT in subgroup analysis. A recent meta-analysis including seven previous studies demonstrated that ALND plus RT was superior to ALND alone regarding locoregional recurrence (12.7% vs. 34.3%, p < 0.01) and there was a trend toward improved mortality rates (9.5% vs. 31.4%, p=0.09) [20]. In addition, MD Anderson Cancer Center reported that there were no local or regional failures in 36 OBC patients dealt with contemporary imaging and multimodal BCT [7]. These data supported our findings by indicating that breast RT after axillary treatment only is mandatory and ALND combined with RT also appears as an attractive option to avoid mastectomy and its complications. Therefore, mastectomy could be safely omitted in the setting where a patient is willing to undergo breast RT after ALND.

One of the interesting points of our results was that the extent of breast operation (mastectomy/lumpectomy/not done) did not affect OS significantly. Instead, ALND was an important prognostic factor. Previous studies also reported similar findings. The 5-year OS of BCS, mastectomy, and no operation groups was 72.0%, 74.0%, and 87.5%, respectively, with no significant differences observed between them (p=0.49) in the study by Woo et al. [21]. He et al. [5] also demonstrated that there were no differences in survival rates between mastectomy, BCS, and no breast operation. This may be due to the nature of OBC that an axillary clearance rather than breast operation could further reduce overall tumor burden. However, this does not mean that the breast operation is not important. In our results, a significantly prolonged OS was observed when RT was given to patients treated with mastectomy or ALND, not patients with lumpectomy or ALNS (Fig. 2). It is possible that there was a survival benefit of RT in the situations of more radical surgery. Also, as with the previous literatures mentioned above, the “blind” breast RT after BCS is effective for local control, but this may not be translated into OS differences [5,16]. More precise data are needed to clarify the impact of breast operation or blind breast RT on OS.

Regardless of the surgical approach, one of the most important prognostic factors was the number of positive nodes. Five-year OS was 85.6% with 1-7 positive nodes, whereas only 70.2% with eight or more positive nodes. This tendency was maintained regardless of propensity score matching. Walker et al. [2] reported that more than 10 positive LNs were correlated with an unfavorable OS (HR, 2.04; p=0.005). He et al. [5] also showed that patients with four or more involved LNs had significantly worse outcomes (HR, 4.63; p=0.042 for survival and HR, 3.62; p=0.038 for recurrence). Recent multicenter study from Korea demonstrated that patients who had N1 disease showed a fairly good 10‐year OS of 96.8% compared with 82.6% in N2 and 80.8% in N3 disease (p=0.004) [6]. Therefore, adequate ALND should be performed to identify accurate LN status and also reduce the chance of occult nodal metastases. Additionally, age over 70 years at diagnosis was found to be a poor prognosticator in multivariate analysis. Similar results have been reported in the previous SEER data (RR, 1.06 with age as a continuous variable; p < 0.001) [2]. It seems a little bit contradictory considering the poor prognostic impact of young age in common breast cancer. Because the endpoint of our study was OS but not breast cancer-specific survival, it is not surprising that inferior survival outcomes were observed in the elderly patients. However, unknown factors such as systemic treatment, intrinsic molecular subtype or histologic grade might have induced the above results. In other literatures on OBC, no significant difference was reported according to the age-related parameters.

One of the major limitations of this study is an absence of information on systemic chemotherapy and endocrine therapy due to the limitation of SEER data, thus could not be included in the analysis. The lack of these important factors could make potential bias because of heterogeneous systemic treatments during a relatively long period with improvements in outcome over the recent period, although one previous review for the managements of OBC reported that most patients in United States (93%) had received chemotherapy [8]. Current NCCN guidelines recommend that systemic chemotherapy/endocrine therapy be given according to the stage II or III disease as well as neoadjuvant therapy also be considered for N2-3 disease [3]. In addition, the effects of chemotherapy have not been reported to be particularly different in this orphan disease in relation to common breast cancer. These observations emphasize the need for additional large sample studies to better understand prognostic impacts of systemic chemotherapy/endocrine therapy for this rare disease. There are another several limitations to this study. Retrospective nature is an unavoidable weakness although we tried to obtain unbiased comparison by using propensity score matching. However, propensity score matching itself could not solve the problem of hidden bias caused by unexamined factors, and there were lots of missing values which were dealt with imputation methods. Last but not least, failure patterns could not be analyzed. It is important to point out that locoregional recurrence is not captured in SEER data, being limited to survival outcomes.

Based on our results, RT may offer survival benefit in OBC even after mastectomy or ALND, especially in patients with more metastatic LNs. Combined ALND and RT irrespective of breast operation may appear as the best treatment approach in these patients favoring minimal invasive procedure. Age and number of metastatic LNs were also significant prognosticators. Individualized locoregional treatment strategies based on certain risk factors needs to be further investigated. Prospective studies with a sufficient sample size are needed to validate these findings.