Triple negativity and young age as prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm or less

Owing to the increased use of screening mammography, the proportion of early stage breast cancer is increasing internationally [1‐3]. In Korea, an increase in the percentage of stage 0 and I types of breast cancer has also been reported. The proportion of stage 0 breast cancer was 7.5% in 2002 and increased to 11.3% in 2003. For stage I breast cancer, the proportion of patients increased from 29.5% to 36.5% over the same period [4, 5].

Generally, it has been reported that the prognosis of small-sized, node-negative breast cancer is excellent with complete surgical resection of the primary tumor, even without systemic adjuvant therapy [6]. For patients with microinvasive breast cancer, which is defined as tumor foci of 0.1 cm or less, a very small percentage of women relapse or die of breast cancer [7]. According to an analysis of the Surveillance Epidemiology and End Results (SEER) data from 1998 to 2001, the ten-year overall breast cancer specific mortality of patients with T1a, bN0M0 disease was 4% [8].

Nevertheless, certain subgroups of patients who were initially diagnosed with small, node-negative breast cancer tumors have a risk of recurrence. Some authors have reported that young patients under 35 years old had poor prognosis [9]. The biological factors of a high grade of tumor [8, 10, 11] and high Ki-67 [12] were associated with a high relapse or high mortality rate.

There have been few clinical studies with large numbers of patients over a long duration of observation sufficient for the evaluation of the prognosis of node-negative breast cancer of 1cm or less in size. In addition, few studies have evaluated the long-term prognosis according to the hormone receptor and human epidermal growth factor receptor 2 (HER2) statuses because many patients were not examined for estrogen receptor (ER), progesterone receptor (PR), or HER2 status before these tests became widely available. Therefore, some controversy remains regarding treatment decisions for these patients.

The features of breast cancer vary among Asian countries, but there is a common tendency of younger age-onset and a large proportion of premenopausal women [5, 13]. Some studies have reported higher rates of hormone receptor negative or high-grade breast tumor in Asian populations [14]. However, the ethnic differences associated with recurrence or mortality remain unclear, especially in node-negative early breast cancer of 1cm or less.

The aim of this study was to evaluate the overall prognosis of lymph node negative invasive ductal carcinoma of the breast of ≤ 1 cm in size, including microinvasive carcinoma (T1mic) in a Korean population. Moreover, through identification of subgroups of patients with a high risk of recurrence and their characteristics, we set out to determine which subgroup of patients would be candidates for systemic adjuvant therapies.

The results of this study confirmed an excellent short-term prognosis of lymph-node-negative invasive ductal carcinoma of the breast of 1 cm or less in a Korean population. Among 375 patients, only one patient died of breast cancer and only twelve cases of recurrence were reported. The overall five-year cumulative RFS rate was 97%. Univariate and multivariate analyses revealed that triple negative status and age younger than 35 years were significantly associated with shorter RFS.

There are a number of studies that focus on the prognosis and predictors of recurrence of node-negative early breast cancer. Though many reviews were retrospective and had small populations, high tumor grade was the most consistent factor associated with poor outcome in these studies [6, 17‐19]. Chia et al. surveyed 430, a relatively large number of patients with T1a,b breast cancer. They noted that patients with grade 3 tumor had shorter 10-year RFS compared to grade 1, 2 patients (with 74% vs. 82%, p = 0.007) [10]. Age, tumor size, lymphovascular invasion and estrogen receptor negativity were also commonly found to be poor prognostic factors [20‐23]. In another report, Ki-67 and p53 were considered as significant prognostic factors of survival [24]. More recently, reports have shown that HER2-positive disease is a risk factor of recurrence in node-negative tumors 1cm or smaller [25]. However, most studies on the prognosis of node-negative early breast cancer were performed in Western countries. In contrast, few studies exist regarding the biology and prognosis of Asian breast cancer patients.

In the present study, triple negative status and age younger than 35 were the only independent prognostic factors of recurrence. Other studies have reported similar results in which younger patients showed poorer prognosis than older patients. These authors suggested that poor prognosis observed in young patients under the age of 35 was related to adverse characteristics of their disease, such as a high proportion of node-positive disease, a high proportion of negative estrogen hormone receptor, and a high proliferation index. However, age younger than 35 years remained an independent poor prognostic factor in the multivariate analysis. However, an analysis of the prognosis of a specific subgroup with tumor sizes of 1 cm or less was not performed in this study [9]. In our patients, there were no differences in pathologic characteristics of hormone receptor status or HER2 status according to age group (Table 5). Our data suggest that age younger than 35 is an independent risk factor for recurrence, even in patients with node-negative breast cancer 1 cm or less in size. Therefore, young age less than 35 should be regarded as a poor prognostic factor when adjuvant therapy is considered. This is important, especially for Asian patients, because the proportion of young women in Asian countries is higher than in Western countries [5, 26].

The grade of HER2 overexpression which was a poor prognostic factor in other studies [24, 25, 27, 28] did not have an effect on RFS in our study. This discrepancy can be attributed to the fact that HER2 fluorescence in situ hybridization (FISH) was not performed in most of the patients. There is a possibility that HER2 FISH positive disease was classified as HER2 negative based on immunohistochemical staining only. A literature show that quite a few patients with moderate expression (+2) of HER2 in immunohistochemistry had HER2 gene amplification at FISH [29]. Another explanation for the lack of an association between HER2 status and recurrence may be the inclusion of T1mic disease in the analysis. Patients with T1mic disease have a higher proportion of HER2 positive disease but a very low potential of systemic metastasis or recurrence. In our series, endocrine unresponsiveness and positive HER2 immunohistochemical staining (+3) were more common in T1mic tumor than T1a or T1b disease. The reason for high HER2 positive rate in T1mic tumor is not clearly understood, but other literatures also report the similar findings [12, 30].

More than half of all patients received breast-conserving surgery in our study, but 31.5% of these patients, mainly T1mic or T1a, did not receive post-operative radiotherapy because the tumor size was extremely small. The local recurrence rate of this group was 3.2% (2 in 62 patients), which was not high compared to the patients who received adjuvant radiotherapy (2.9%, 4 in 135 patients). This may have resulted from the very low incidence of recurrence itself; hence, a longer duration of follow up and a larger number of patients are necessary before definitive conclusions can be made regarding the role of post-operative radiotherapy in very small breast cancer.

Our study has several limitations. First, recurrence of early breast cancer is known to be discovered not only during the first decade of follow up, but also during the second decade or even later. Therefore, our duration of follow up was not sufficient for an evaluation of breast cancer prognosis regarding the overall survival and long-term recurrence rate, especially in endocrine-responsive disease. However, an analysis of the short-term recurrence rate and risk factors would be valuable for the identification of specific patient groups who require systemic adjuvant chemotherapy after surgery. Second, other important pathological information, such as mitotic activity [31, 32] and vascular invasion [33] were not included in this analysis. Third, many patients received systemic adjuvant therapy according to their hormone receptor status and other clinical factors. Therefore, we cannot conclude whether the pattern of recurrence reflects the natural history of specific subgroups or a response to the adjuvant therapies given. In fact, 92.4% of hormone receptor positive patients received endocrine therapy while 34.5% of hormone receptor negative patients were treated with adjuvant chemotherapy. It is within the realm of possibility that good prognosis of a patients group with positive ER or PR status was caused by the efficacy of the adjuvant hormonal therapy. In addition, ER and PR positivity was defined as 10% or more staining unlike definitions used in recent studies focusing on breast cancer subtypes, which classified tumors as hormone-receptor positive if 1% or more of tumor nuclei were stained [34]. However, we regarded the tumor with 10% or more positive staining as hormone receptor-positive disease, because the pathology report of our patients, especially who were diagnosed in the early 2000s, used the previous classification standard. There may be a possibility that tumors with positive staining of ER and or PR between 1-9% may have been classified as HR negative.

Finally, a definite conclusion pertaining to the subgroup of patients who required systemic adjuvant treatment could not be determined because a multivariate analysis could not be performed for predictors of systemic recurrence due to the low number of events.

We confirmed that patients with a tumor size of 1cm or less of node-negative invasive ductal carcinoma of the breast have excellent short term prognosis. Studies with a larger sample size and a longer follow up duration are needed for confirmation of this result, but patients younger than 35 years of age and triple negative disease were identified to be the highest risk group of recurrence.