In our study, breast cancer patients diagnosed with distant metastasis after symptom onset had a poorer prognosis than patients without symptom at diagnosis. When stratified by tumor subtype, asymptomatic patients with HR-positive breast cancer had a better prognosis than symptomatic patients; however, there was no significant survival difference between symptomatic and asymptomatic patients with HER2-positive 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 beneficial 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 [7–10]. Previous studies regarding follow-up for distant metastases in asymptomatic breast cancer patients are insufficient, 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 significantly 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 significantly shorter in breast cancer patients with multiorgan metastases or non-bone-specific 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 significant survival benefit can be achieved in select patients [13, 15–20]. In breast cancer patients who have either bone metastasis only or one metastatic organ, early detection before metastatic progression can confer a survival benefit; 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 findings validate the need for intensive surveillance in this patient population, suggesting reconsideration of the guidelines for metastases screening in breast cancer patients.