Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer

• Published in: British journal of cancer 2021-10, Vol.125 (9), p.1285-1298
• Main Authors: Marti, Juan Luis Gomez, Beckwitt, Colin H., Clark, Amanda M., Wells, Alan
• Format: Article
• Language: English
• Subjects: 631/67/1347; 631/67/322; Animal models; Animals; Atorvastatin; Atorvastatin - administration & dosage; Atorvastatin - pharmacology; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cell death; Cell Line, Tumor; Chemotherapy; Dormancy; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Drug Resistance; Drug Synergism; E-cadherin; Epidemiology; Female; Humans; Liver; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Metastases; Metastasis; Mice; Molecular Medicine; Oncology; Paclitaxel; Prospective Studies; Receptor, ErbB-2 - genetics; Retrospective Studies; Statins; Survival Analysis; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01529-0

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.