In this retrospective study, we described the clinicopathological characteristics and analyzed the prognosis of patients with synchronous lung metastases at initial MBC diagnosis in China. We identified 809 patients with BCLM upon newly diagnosis of MBC, accounting for 35.7% of all MBC patients. Compared with other groups, patients with triple-negative subtype had the highest percentage of lung metastases, consistent with previous findings [12–14]. The incidence of lung metastasis in triple-negative breast cancer (TNBC) could reach up to 40% [15], similar with 42.3% in our data. Additionally, the prognosis of BCLM patients differed remarkably in tumor subtypes, varying between 26.8 months of triple-negative subtype and 49.0 months of HR+/HER2- subtype.
Our study confirmed the results that TNBC was more aggressive and preferred to develop lung metastases. The molecular mechanisms underlying TNBC metastasis to lung might offer therapeutic targets for clinical prevention and management. Minn et al. [16] identified fascin as a mediator promoting basal-like breast cancer metastasis to lung, due to its close association with cell motility. Iriondo et al. [17] observed that inhibition of transforming growth factor-β1-activated kinase-1 (TAK1) could suppress lung metastasis in TNBC, which might provide a novel target for impairing TNBC lung metastasis. A single mutation on microrchidia family CW-type zinc finger 2 (MORC2) promoted TNBC lung metastasis by regulating heterogeneous nuclear ribonucleoprotein M (hnRNPM)- mediated CD44 splicing, which indicated that the knockdown of hnRNPM might reduce lung metastatic potential of TNBC cells with mutant MORC2 [18]. Another research revealed that the overexpression of transcription and export complex 2 subunit (ENY2) could promote TNBC progression and lung metastasis both in vitro and in vivo [19]. Further mechanisms clarifying TNBC lung metastasis are certainly worth exploring, which may provide potential targets for new drugs.
Our data also indicated that patients with older age and worse performance status were more likely to present with lung metastases at initial MBC diagnosis. The increasing risk of lung metastases associated with aging was consistently found in population-based studies [6, 20]. On the contrary, previous studies observed that younger patients had a higher risk of liver metastases [5, 21]. Interestingly, our study also revealed that patients with liver or bone metastases had lower odds of lung metastases at diagnosis. The predictive features associated with different metastatic sites may help clinicians distinguish patients with distinct organ-specific metastases during the clinical practice.
The BCLM patients in our data achieved a median OS of 41.7 months since MBC diagnosis, among which triple-negative subtype experienced the worst outcome of 26.8 months and HR+/HER2- subtype the best of 49.0 months. The prognosis of MBC patients varied remarkably by the metastatic organs, with the best for bone, followed by lung, liver and the worst for brain metastases [7, 22]. Previous findings recorded a survival ranging from 21.0 to 58.5 months in MBC patients with lung metastases [1, 6, 23]. A pulmonary metastasectomy study reported a median survival of 23.6 months in TNBC patients with an isolated and limited number of lung metastases, significantly poorer than HR + or HER2 + patients [24]. A population-based research showed that TNBC patients with metastases confined to lung had a median OS of only 14.0 months [25]. TNBC is still lethal and remains intractable to existing treatments, extremely desirable for novel therapies to improve the prognosis.
We also identified prognostic factors for survival of BCLM patients and found that worse performance status, later N-stage, HR-/HER2 + subtype, triple-negative subtype and the simultaneous presence of liver or bone metastases were significantly correlated with poor outcome. Multiple sites of first metastases had significantly unfavorable prognosis than single site first metastases [26, 27]. In our data, the extrapulmonary metastases of bone and liver had 1.33 and 2.57 times of mortality risk than lung-only metastases at MBC diagnosis, respectively. Brain metastases also worsen the outcome of BCLM patients but the difference did not reach significance, probably due to the late onset of brain metastases during the clinical course, with an incidence of only 6.90–7.56% in newly MBC diagnosis patients [27–29].
There were some limitations in our study. Firstly, discordance in tumor phenotype has been reported in multiple studies [30], but we did not have enough information on the receptor status of metastatic tumors, which might cause some bias in the analysis of incidence and survival outcomes when stratified by breast cancer subtype. Additionally, the number of lung lesions was an important risk factor for BCLM patients [31], but it was not documented in detail in our database. Finally, the retrospective nature of this research and relatively small population require future studies to confirm the results.