Metastatic breast cancer represents a biologically heterogeneous population with diverse metastatic patterns exhibiting highly unpredictable clinical behaviors [25–27]. Prognosis varies significantly among patient subtypes [28, 29]. Despite advancements in adjuvant therapy, some early breast cancer patients experience distant metastasis and are generally incurable, leading to poor prognosis [3, 4]. Most such cases are the HR+/HER2- breast cancer subtype [5, 6]. Therefore, it is important to assess clinicopathological factors associated with the prognosis of the major subtype, which helps us identify appropriate therapeutic strategies.
Several concepts regarding the prognosis of HR+/HER2- metastatic patients have been considered important in evaluating survival after recurrence [11], and the current study was performed based on post-recurrent characteristics, especially the metastatic site. Previous studies have shown that first metastatic sites (single, multiple, liver, or other visceral metastases) are significantly related to survival after recurrence in HR+/HER2- patients [10–13], but there has been clinical diversity in the metastatic distribution patterns of both single metastasis and multiple metastases [25–27]. Therefore, we studied the prognosis of HR+/HER2- patients with single and multiple metastases separately.
Multiple metastases are considered a poor prognostic factor [10–18]. The prognosis of patients with multiple metastases may vary with the metastatic organ sites due to the heterogeneity [25–27], but there has been no report investigating prognosis by each relevant metastatic site involved in multiple metastases. In the current study, multiple metastases not involving liver or brain metastasis had no significant relationship with prognosis after recurrence, whereas multiple metastases including liver or brain metastasis was a strong independent prognostic factor for worse outcomes in HR+/HER2- patients. This finding supports the assumption that multiple metastases involving liver or brain metastasis is indicative of extensive spreading or dissemination of cancer cells, or lethal organ dysfunction, leading to poor survival outcomes [11, 15, 24]. In real-world practice, patients with multiple metastases are more likely to receive cytotoxic therapy because their vital organs are potentially damaged or in “visceral crisis” [19–21]. However, not all multiple metastases may lead to poor outcomes due to their own heterogeneity [19]; therefore, we should determine the most reliable and decisive prognostic factors for HR+/HER2- patients with multiple metastases.
Single metastasis has been regarded as a better prognostic factor than multiple metastases in many previous studies [10–18], because patients with single metastasis have better prognosis due to the probability of less tumor burden than with multiple metastases. However, most patients with single metastasis will eventually develop multiple metastases, finally leading to poor outcomes. We thought we should identify more useful and valuable prognostic factors in HR+/HER2- patients with single metastasis. Thus, in this study, we analyzed the prognosis of patients with single metastasis by classifying single metastasis into diffuse lesions and non-diffuse lesions. To the best of our knowledge, this is the first study to investigate the prognosis of patients with single metastasis based on the metastatic distribution patterns between diffuse and non-diffuse lesions, and to evaluate the time to dissemination of single metastasis to multiple metastases. We found that no metastatic organ site with single metastasis was significantly associated with prognostic outcomes, though diffuse lesions in single metastasis were independently related to worse prognosis and easier systemic dissemination to multiple metastases. Diffuse lesions in single metastasis may likely behave as multiple metastases due to the dissemination potential. According to traditional guidelines [7–9], non-cytotoxic therapy is indicated as first-line treatment for HR+/HER2- patients with single metastasis. Thus, our study suggests reconsidering the therapeutic guidelines, and additional treatment strategies should be demanded for patients with diffuse lesions in single metastasis due to the potential for poor prognosis. Our proposal may meet the unmet need for more efficacious treatments for HR+/HER2- patients with diffuse lesions in single metastasis. The initial use of more advantageous treatments, including novel targeted agents [30], could provide more beneficial effects and support better prognoses for these patients.
Our study had some limitations. First, our study was performed as a retrospective chart review without validation, and sampling biases may not have been avoidable. Second, the sample size of our study was small, and our results should be interpreted with caution. However, the selection of patients with HR+/HER2- recurrent breast cancer and exclusion of HER2+, triple-negative, and de novo breast cancer patients may have allowed the recruitment of a patient population with relative homogeneity. Future studies with a larger cohort of patients may yield more conclusive evidence of the prognostic findings in this study. Despite these limitations, the current study provides important insights about the real-world clinical outcomes for patients with recurrent metastatic HR+/HER2- breast cancer.