There are various reports on the prediction of distant metastasis. However, the recurrence site differs depending on the subtype, and tumor size and lymph node metastasis are common risk factors [5, 24–26]. In addition, young age [5], histopathological grade, and lymphovascular invasion have also been reported as risk factors [5, 25], although there are reports suggesting otherwise, as well. In this study, operative procedure was shown to be a predictive factor for distant metastasis, and the cause was found to be correlated with the operative procedure as well as some clinicopathological features, such as age, tumor diameter, and Ki67, also referred to as risk factors.
For the prediction of distant metastasis, some research groups have examined the molecular pathological features of cancer cells; for example, co-expression of α6β4 integrin and neuroepithelioma transforming gene 1 (Net1) [27], expression of YKL-39 (a kind of chitinase-like protein) [28], and overexpression of phosphorylated PLC-gamma-1 (one of the phosphoinositides) were reported in this regard [29]. These expression levels have been shown to promote invasion and metastasis of cancer cells both in vivo and in vitro; hence, these studies retrospectively examined the use of clinical samples as a predictor of distant metastases. There have also been reports that examined the molecular characteristics of cancer cells considering the circulating tumor cells (CTCs) that are deeply involved in distant metastasis [30, 31]. One such report suggested CTCs to possibly be an indicator of the therapeutic effect of chemotherapy or endocrine therapy [32], whereas some other studies reported them as a predictor of distant metastatic recurrence of breast cancer based on clinical deta [33, 34]. Some publications have even reported the prediction of distant metastasis using genetic assays [35].
Mutations in p53, a gene involved in deoxyribonucleic acid (DNA) repair, are involved in recurrence; Narod has reported p53 accumulation to be a strong predictor of recurrence [36]. Filipits et al. predicted distant metastasis using RNA-based multigene score [37]. A genomic evaluation study shows a higher mutation burden to accompany recurrence than primary tumor [38]. These results together suggest gene mutations to potentially cause local or host immune tolerance at the distant metastatic site [4].
Formation of distant metastases in cancer generally follows the concept of “seed and soil.” While we have discussed the “seed” until now [39], TME corresponds to the “soil” as per this concept [8, 9]. TILs are also included in the cells that constitute the TME. In breast cancer, TILs have been reported to vary by subtype. In particular, HER2BC and TNBC have been reported to show significantly higher TIL density than HR+HER2−BC, and TILs have been proven to predict the therapeutic effect of chemotherapy [13, 40–42]. Conversely, there are very few reports examining the correlation between TILs and clinicopathological factors or therapeutic effects in HR+HER2−BC.
In this study, we excluded patients who had undergone neoadjuvant/adjuvant chemotherapy based on three reasons. First, chemotherapy affects the immune microenvironment, including TILs, in preoperative chemotherapy study, and related changes may affect prognosis [43]. TILs are also predictors of the therapeutic effect of adjuvant chemotherapy; therefore, adjuvant chemotherapy may also affect the tumor immune microenvironment. Secondly, axillary lymph node metastasis before adjuvant chemotherapy was diagnosed based on image only, due to which the diagnosis was not accurate. Lastly, different chemotherapy regimens are known to have different effects and neoadjuvant chemotherapy causes more local recurrence than adjuvant therapy [44].
There are some reports on the relationship between recurrence sites and TILs. Park et al. reported patients with TILs higher than 10% in early-stage TNBC to show significantly more locoregional recurrence than those with lower TILs [45]. In cervical squamous cell carcinoma, low TILs are also likely to cause distant metastasis [46]. Moreover, distant metastasis is reported to be predicted from pathological features, including lymphocytes of lymph nodes in breast cancer with lymph node metastasis, although not from the density of lymphocytes around the cancer [47]. Bidwell et al. have shown innate immune escape to promote bone metastasis, based on clinical data and experiments in mice [48]. Some studies using breast cancer cell lines in vivo had also report immunosuppression in the tumor immune environment to increase the risk of lung metastasis [49, 50]. In this study, TILs were suggested to possibly be a distant metastatic predictor, although not an independent factor. We have reported that TILs may also be involved in lymph node metastasis in HR+HER2−BC [51]. In this study, TILs were considered to be strongly correlated with lymph node metastasis, being involved in distant metastasis prediction as well as prognosis after recurrence.
The greatest limitation of this study was that very few cases of recurrence were examined. Another limitation was that the types of adjuvant endocrine therapy were different. However, TILs can be evaluated in needle biopsy specimens for the diagnosis of breast cancer and are highly useful. Filipits et al. predicted distant metastases using the above-mentioned predictors in combination [37] and TILs may be considered to be an additional condition. When distant metastasis generates symptoms, the patient’s QOL is impaired.