Background

Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations.

Methods

We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019.

Results

Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use.

Conclusion

Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.

中文翻译：

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阿托伐他汀促进转移性三阴性乳腺癌的化疗效果

背景

转移性三阴性乳腺癌 (mTNBC) 主要通过化疗进行治疗。然而，随着肿瘤进入休眠状态，经常会出现耐药性。他汀类药物被认为对癌症有效，但由于它们会延长和促进休眠，同时使用是否会干扰原发性和 mTNBC 的化疗是一个悬而未决的问题。我们在动物模型和临床相关性中检查了这个问题。

方法

我们使用 mTNBC 细胞系从异位肿瘤自发转移到肝脏的异种移植模型。提供阿托伐他汀以使转移细胞敏感，然后进行化疗。通过查询 1999 年至 2019 年确诊患者的数据库，分别评估了他汀类药物使用对转移性乳腺癌女性结局的影响。

结果

阿托伐他汀对异位原发性肿瘤的肿瘤生长或化疗效果的影响有限。有趣的是，当靶向肝转移时，阿托伐他汀与多柔比星（但不是紫杉醇）相加。与野生型细胞相比，表达 E-cadherin 的休眠乳腺癌细胞对他汀类药物或化学疗法的使用具有抗性；然而，两者的结合确实导致细胞死亡增加。尽管需要前瞻性随机研究进行验证，但我们的回顾性临床分析表明，接受他汀类药物治疗的患者可能会经历更长的休眠期和总生存期；一旦肿瘤复发，他汀类药物的使用仍不会影响进展。

结论

阿托伐他汀可在辅助化疗期间使用，也可与转移性化疗联合使用以减少 mTNBC 癌症进展。这些临床前数据为开展随机研究奠定了基础。