In 2012, a 45-year-old woman complained of right nipple discharge (white, occasionally streaked with blood). Imaging tests revealed a tumor (2.0 × 1.5 × 0.5 cm) located in the outer upper quadrant of the right breast. An excisional biopsy was performed at the First Hospital of China Medical University on 5 April 2012. The findings revealed intraductal papilloma, moderate-to-severe atypical hyperplasia, and malignant transformation of the local ductal epithelium. Immunohistochemistry (IHC) detected estrogen receptor (ER) (35%+), progesterone receptor (PR) (75%+), human epidermal growth factor receptor 2 (HER2) (intraduct: 3+), and Ki-67 (25%+) ( Figures 1A–D ). On 18 April 2012, BCS and sentinel lymph node biopsy were performed at the same hospital. An elliptical incision was created in the upper outer quadrant of the right breast, and quadrantectomy with posterior areolar gland resection was performed. Five safety margins were obtained and submitted for intraoperative frozen tissue pathology. No cancers were detected. An arc incision was made in the right axillary region, and two lymph nodes were sent for pathology. The postoperative pathological diagnosis revealed no lymph node involvement. The breast cancer was graded as pTisN0M0.

The patient received six cycles of advanced first-line TE regimen chemotherapy (T: docetaxel, 75 mg/m²; E: epirubicin, 60 mg/m²; intravenous injection, every 21 days as a cycle) from 23 June 2017, to 13 October 2017. Evaluation of the condition in the second, fourth, and sixth cycles revealed a stable disease. In October 2017, the patient was involved in a clinical trial involving adjuvant endocrine therapy. On 1 November 2017, the patient was administered anastrozole (1 mg/day, orally) and goserelin (3.6 mg/28 days, subcutaneously). The final evaluation on 30 August 2019, was a partial response based on the CT of the liver and lung, where no lesions were observed in the liver, and the lesions in the lung had significantly shrunk. However, a suspected larger intrahepatic focus was observed on abdominal CT on 21 November 2019, and on MRI on 25 November 2019, compared with the last evaluation ( Figures 2C–F ). CT of the lung did not show any progression of the pulmonary metastatic foci.

At the cellular level, DCIS cells resemble invasive cancer cells (12). Research also demonstrated that by nature DCIS was truly a kind of cancer and possessed the ability to cause metastasis without invasion through the basement membrane (13). In several studies, approximately half of the patients who died from DCIS of the breast did not develop invasive breast cancer (13, 14). Besides, it has been stated that some patients diagnosed with pure DCIS without microinvasion still have positive lymph nodes (15–17). Other compelling evidence is that circulating tumor cells exist in the peripheral blood or bone marrow of patients diagnosed with pure DCIS (18, 19). These studies revealed the possibility of DCIS cells entering the circulating or lymphatic system before passing the basement membrane (20). Pathological research conducted by Gadre et al. indicated a possible mechanism (21). The researchers observed the presence of mucin in 36 of 41 ducts involved in DCIS (87.8%) and of mucin and vessels in 26 of 41 (63.4%). Variable amounts of CD68+ and VEGF+ macrophages identified in mucinous DCIS support the hypothesis that macrophages participate in the recruitment of facultative endothelial cells. In the four cases of mucinous DCIS without microinvasion, neovascularization was 100% present. This research also highlighted that DCIS is highly heterogeneous, and some subtypes have the potential to cause direct metastasis. Further research is required to facilitate detailed classification of DCIS according to histological appearance and molecular expression and to explore other underlying mechanisms.

Serum tumor markers are substances secreted by tumor cells or by the human body in response to the tumor and are elevated in the presence of malignant tumors (22). Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)153 are the most widely used serum tumor markers for breast cancer (23–25). CEA and CA153 have been recommended by the European Group on Tumor Markers to predict the prognosis and monitor the recurrence and therapeutic effects (26). CEA is extensively expressed in half of the breast cancers (27). CA153 has been proven to independently predict breast cancer recurrence and indicates the prognosis of advanced breast cancer (28). However, the combination of CEA and CA153 measurement does not possess satisfactory sensitivity in detecting metastasis of breast cancer (29), and the additional measurement of CA125, C-reactive protein (CRP), and other related biomarkers can improve the sensitivity of monitoring tumor progression (30). According to the study by Wang et al., CEA, CA153, and CA125 were detected to be higher in breast cancer patients with metastasis (31), and they were also related to tumor size, node status, and TNM stage (32, 33). CRP, as an inflammatory marker, was reported to be associated with poor prognosis in breast cancer (34–36) and increased significantly in the serum of patients with breast cancer metastasis (37). High serum levels of another inflammatory marker, β2-microglobulin (β2-MG), are also related to poor outcomes in metastatic breast cancer (36). Studies reported a protective relationship between serum alpha-fetoprotein levels and breast cancer (38, 39). However, according to a study by Zhao et al., alpha-fetoprotein exhibited no diagnostic significance in breast cancer nor did CA199 and CA724 (40).

In the present case, there were no abnormalities in the serum tumor marker levels, except CEA before metastasis was detected in May 2017. Subsequently, abnormal values of several other biomarkers were observed ( Table 1 ). However, a slight increase in a single marker is not of great clinical significance. Other serum markers did not effectively predict metastasis, which is a reminder to clinicians not to be overly reliant on the diagnostic function of serum markers. During chemotherapy, the serum levels of CEA and CA153 gradually decreased, indicating the positive effect of chemotherapy.

The risk factors for developing DM in DCIS include younger age (≤40 years), lymph node metastasis, microinvasion, necrosis, little or no expression of hormone receptors, poor differentiation, previous or simultaneous invasive locoregional recurrence, positive HER2 expression, and high Ki-67 staining (>10%) (1, 5, 41, 42). In this case, there is no relevant risk factor except HER2 expression (3+) and high Ki-67 staining (25%). However, due to the rare rate of DM after DCIS, neither these risk factors nor the present treatment methods were statistically significant. Most distant metastases are detected after local recurrence (1). Therefore, further research is required in this regard.

This case demonstrates the poor potential outcome in pure DCIS, which has been underestimated for a long time. Further research should be conducted to determine the mechanisms, risk factors, and effective treatments for metastasis. Regular reexamination and monitoring are indispensable for patients after DCIS.