Symptomatic Metastases have Poorer Prognosis in Breast Cancer Patients Under Intensive Surveillance

Purpose The purpose of this study was to investigate risk factors for post-metastasis overall survival (PMOS), and to analyze the effect of early detection of distant metastases before symptoms occur on survival in breast cancer patients under intensive surveillance. Methods A total of 7,840 patients underwent surgery for breast cancer from January 2010 to December 2014 at Samsung Medical Center; of these, we retrospectively studied 316 metastatic breast cancer patients. The patients were divided into two groups based on method of metastases detection, routine surveillance without symptoms (asymptomatic group) or follow-up for new-onset symptoms (symptomatic group). Results Multivariate analysis of PMOS showed that the patients with multiple metastases had a 1.872 fold risk of PMOS (p = 0.011) compared to the patients with bone metastasis only. The hazard ratio for the symptomatic group was higher than that for the asymptomatic group (p < 0.001). When patients were stratied by tumor subtype, patients who were HR-positive and asymptomatic on diagnosis of distant metastasis had a better prognosis than those who were HR-positive and symptomatic on diagnosis. However, patients who were HER2-positive showed no signicant survival difference between two groups. Conclusion Breast cancer patients who were diagnosed with distant metastasis after symptoms occurred had a poorer prognosis than patients who were diagnosed before symptoms had developed. It is important to follow up patients regularly for symptoms related to distant metastases. Our ndings validate the need for intensive surveillance, suggesting reconsideration of the guidelines for metastases screening in breast cancer patients. conserving surgery, SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, IDC invasive ductal carcinoma, HR hormone receptor,


Introduction
The global burden of breast cancer in women is substantial and on the rise in several countries [1,2]. Although the incidence of breast cancer has steadily increased, the overall survival rate for breast cancer has improved in recent years due to early detection and advances in primary treatment; therefore, the number of breast cancer survivors has been gradually increasing [3]. As the number of breast cancer survivors increases, interest in patient surveillance for distant metastases has increased.
The bene t of intensive surveillance for postoperative metastasis in breast cancer patients before symptoms occur has long been debated because there is no evidence that early detection of distant metastases could improve overall survival of patients. The National Comprehensive Cancer Network (NCCN) guidelines do not recommend routine testing for recurrence or distant metastasis in asymptomatic patients during follow-up for breast cancer and rather recommend that patients should be tested only if they develop symptoms [4]. However, as both diagnostic imaging and treatment of metastatic breast cancer improve, some clinicians have come to believe that intensive surveillance for postoperative metastasis is necessary in breast cancer patients before symptoms occur, and the prognosis of metastatic breast cancer patients can be better when distant metastasis is detected in an early state as a small tumor.
The purpose of this study was to investigate risk factors for post-metastasis overall survival (PMOS) in breast cancer patients under intensive surveillance, and to ascertain whether early detection of distant metastases before symptom onset confers a prognostic bene t in these patients.

Patients
A total of 7,840 patients underwent surgery for breast cancer from January 2010 to December 2014 at Samsung Medical Center. Of these, nine patients with stage IV at diagnosis were excluded; The patients had palliative breast surgery because of wound care or progressive/stable disease on breast lesion despite the improvement of metastatic organ. In addition, patients with locoregional recurrence, lack of follow up or electric medical records after metastasis, or without distant metastasis were excluded.
Finally, we conducted a retrospective review of 316 breast cancer patients. These patients were divided into two groups based on presence or absence of symptoms at the time of metastasis detection; the asymptomatic group had 204 patients (64.6%) while the symptomatic group had 112 patients (35.4%) ( Fig. 1).
Inclusion criteria were periodically monitored for metastases through imaging and laboratory tests.
Physical examination, tumor markers, breast ultrasonography, mammography, breast magnetic resonance imaging, chest computerized tomography, abdomino-pelvic computerized tomography and bone scan were conducted at 1-year intervals depending on disease stage. Imaging and laboratory tests were conducted in accordance with South Korean health insurance policies. A total of 316 metastatic breast cancer patients was divided into two groups: the asymptomatic group included patients who were diagnosed with distant metastasis without symptoms during regular follow-up, while the symptomatic group included patients who were diagnosed with distant metastasis with symptoms either during or before the regular follow-up period. Patients diagnosed with distant metastasis received palliative treatment according to our institution's guidelines. Patients were de ned as having a family history of breast cancer when a rst-or second-degree relative had a history of breast cancer. This study was approved by the Institutional Review Board of Samsung Medical Center (IRB le no. 2020-06-012).

Statistical analysis
Statistical analyses were performed using SPSS Statistics version 25 (IBM Corp., Armonk, NY, USA). Continuous variables were compared with Student's t-test, and categorical variables were compared with Chi-square test and Fisher's exact test. Continuous variables were reported as median and interquartile range (IQR). Categorical variables were reported as the number and percentage. PMOS was analyzed using univariable and multivariable Cox regression analyses, and the Kaplan-Meier method with log-rank test was used to compare survival curves of the asymptomatic and symptomatic groups. Ninety-ve Page 4/18 percent (95%) con dence intervals and odds ratios were calculated, and statistical signi cance was de ned as p < 0.05 for all tests.

Patients characteristics
The baseline characteristics of the patients were similar between the two groups with respect to age, surgery type, histopathology, and pathologic stage. There were signi cantly more patients with hormone receptor (HR)-positive breast cancer in the asymptomatic group than in the symptomatic group (69.7% vs. 53.6%, p = 0.013). There was no signi cant difference in number of patients positive for human epidermal growth factor receptor 2 (HER2) between the two groups. There were signi cantly more patients who underwent neoadjuvant chemotherapy (42.9% vs. 28.4%, p = 0.009) or adjuvant radiotherapy (90.2% vs. 76.0%, p = 0.002) in the symptomatic group than in the asymptomatic group; however, there was no signi cant difference in number of patients who underwent adjuvant chemotherapy between the two groups ( Table 1).   (Table 3). When strati ed by subtype, the HR-positive breast cancer subtype showed a signi cantly better prognosis in the asymptomatic group than in the symptomatic group, whereas there was no difference in PMOS between the two groups for the HER2-positive subtype (Figs. 2,3).

Discussion
In our study, breast cancer patients diagnosed with distant metastasis after symptom onset had a poorer prognosis than patients without symptom at diagnosis. When strati ed by tumor subtype, asymptomatic patients with HR-positive breast cancer had a better prognosis than symptomatic patients; however, there was no signi cant survival difference between symptomatic and asymptomatic patients with HER2positive breast cancer. Our data demonstrate that it is important to follow up patients regularly for symptoms related to distant metastases before symptom onset in breast cancer patients, and this can be bene cial for prognosis.
According to the NCCN guidelines, it is recommended to perform annual mammography and a full history and physical examination one to four times per year for 5 years as routine follow-up for breast cancer patients who underwent primary treatment. Unless there are clinical signs and symptoms suggestive of recurrent disease, laboratory and imaging studies are not recommended for routine screening for distant metastasis [4]. Although the incidence of breast cancer has been steadily increasing in recent years, the overall survival rate of breast cancer patients has improved due to early diagnosis and advancements in treatment. As such, the number of breast cancer survivors has been increasing [5]. With advancements in diagnosis and treatment of breast cancer, it has become more important to detect recurrence or distant metastasis early through appropriate follow-up in breast cancer patients who received initial treatment, as well as breast cancer survivors in remission, to improve overall survival and quality of life. Several previous studies have reported that detection of ipsilateral breast recurrence or contralateral breast cancer in the asymptomatic phase leads to improved survival relative to that associated with detection in the symptomatic phase [5,6]. However, other studies have shown that survival is not improved by intensive surveillance programs in asymptomatic breast cancer patients [7][8][9][10]. Previous studies regarding follow-up for distant metastases in asymptomatic breast cancer patients are insu cient, and there is no evidence for the necessity of a follow-up program for breast cancer survivors.
Several prognostic factors, such as biological breast cancer subtypes, tumor size, nodal involvement, and histologic grade, have been linked to an elevated risk of distant metastasis in breast cancer after primary treatment [11,12]. In this study, there was no difference in PMOS according to cancer stage. However, in HR-positive patients, the asymptomatic subgroup had a signi cantly longer PMOS. According to a study analyzing data from the Surveillance, Epidemiology, and End Results (SEER) population-based database [12], patients with HR-positive and HER2-negative cancer were most likely to develop metastasis, while patients with HR-negative and HER2-positive cancer were less likely to develop metastasis regardless of metastatic pattern. In addition, the sites of distant metastasis differed by breast cancer subtype. Other studies reported differences in time to metastatic disease and overall survival after diagnosis of metastasis according to tumor subtype [13,14]. In our study, we compared the PMOS of asymptomatic patients to that of symptomatic patients; however, further study is needed on the method for optimal post-op surveillance by breast cancer subtype by analyzing metastatic patterns, including metastatic frequency, site, and time to metastasis, of each breast cancer subtype.
Our study showed that PMOS was signi cantly shorter in breast cancer patients with multiorgan metastases or non-bone-speci c metastasis at time of diagnosis of distant metastasis. Bone is the most common site of metastasis in breast cancer patients [12]. Several studies have reported that patients with bone metastasis have a better prognosis than patients with other single-or multi-organ metastases, and a signi cant survival bene t can be achieved in select patients [13,[15][16][17][18][19][20]. In breast cancer patients who have either bone metastasis only or one metastatic organ, early detection before metastatic progression can confer a survival bene t; therefore, routine follow-up in asymptomatic breast cancer patients who underwent primary treatment is reasonable. Treatment for metastasis should be conducted in the early phase when the tumor burden is small, and it is necessary to follow up more actively in patients with high risk of metastasis.
As above, it can be seen that not only the breast cancer stage, but also subtype and sites of metastasis affect prognosis of metastatic breast cancer patients [13,21,22]. As treatment of metastatic breast cancer has improved depending on the tumor subtypes, early detection and treatment may be important when the tumor burden is small without symptoms. With respect to the HER2-positive subtype, availability of new target therapies and other treatment options for HER2-positive patients with distant metastasis result in good prognosis, and screening for distant metastases might be reasonable after diagnosis of for HER2-positive patients [13,23]. In addition, as a study on additional imaging modalities that detect recurrences or distant metastases, the imaging modalities, such as US, MRI, and PET-CT, as post-treatment surveillance are potentially useful and show high sensitivity and accuracy for detecting recurrences or distant metastases [24]. With advanced diagnostic imaging and treatments, early diagnosis and treatment can improve prognosis when the tumor burden is small in breast cancer patients with distant metastasis.
This study had a few limitations. This study was a retrospective review performed at a single institution; therefore, there is a possibility of selection bias. In addition, patients in the asymptomatic group might have caused lead time bias due to early detection of distant metastases. Finally, all breast cancer patients are given equal healthcare in accordance with the national insurance policies in Korea, resulting in regular annual surveillance, and in this study, symptomatic metastases had poorer prognosis than asymptomatic metastases during intensive surveillance. The ideal study design would be to divide patients without regular surveillance according to presence of symptoms to discover if the prognosis of asymptomatic metastases is good. However, since all patients were routinely monitored in this study, the inclusion criteria were divided and analyzed according to presence of symptoms during the regular surveillance period. Research related to surveillance for distant metastasis in breast cancer patients is progressing [25], however, further studies will be necessary to evaluate whether asymptomatic metastasis is a good prognostic factor, and to investigate the term or modality of intensive surveillance. Despite these limitations, this study is meaningful because our results demonstrate poor prognosis of distant metastasis after symptoms occur in breast cancer patients under intensive surveillance.
In conclusion, breast cancer patients diagnosed with distant metastasis after symptoms occurred had a poorer prognosis than patients without symptoms at diagnosis. Detection of symptomatic distant metastases was associated with aggravated PMOS in breast cancer patients. Therefore, it is important to follow up patients regularly for symptoms related to distant metastases. Our ndings validate the need for intensive surveillance in this patient population, suggesting reconsideration of the guidelines for metastases screening in breast cancer patients. No funding was obtained for this study.

Con icts of interest
The authors declare that they have no competing interests.

Availability of data and material
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Code availability Not applicable.
Authors' contributions SMJ, and SKL contributed to the conception and design of the study. SMJ, JMR, BJC, JHY, JEL, SWK, and SJN collected and analyzed the data. SMJ, SKL wrote and reviewed the manuscript. All authors reviewed and approved the nal version of the manuscript.

Ethics approval
The data, including demographic factors, pathologic ndings, and perioperative treatment were collected from the electronic medical records after Institutional Review Board Approval in Samsung Medical Center (IRB le no. 2020-06-012).

Consent to participate
Signed informed consent from the patients was not required.

Consent for publication
Not applicable.