Chemotherapy: a cause of metastases?

Can chemotherapy cause the onset of metastases or accelerate their formation?

Recent studies show chemotherapy can increase metastases

Dr. Chabner, Director of the Oncology Center of Massachusetts General Hospital, writes an interesting editorial for "The Oncologist" on a topic of great importance: can chemotherapy cause the onset of metastases or accelerate their formation?

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A recent analysis by Karagiannis and colleagues has shown, by studying breast cancer through mouse models, that many drugs that form the basis of adjuvant and neoadjuvant treatment of breast cancer (including paclitaxel and cyclophosphamide in combination with doxorubicin), induce the formation of tumor invasion sites in small blood vessels in primary cancer (TMEM, Tumor Micro-Environment of Metastasis). These TMEM sites show three significant changes characteristic of tumor invasion: infiltration of perivascular macrophages increased production by tumor cells of the MENA (Mammalian-Enabled) protein with known prometastatic potential and increased expression of TIE2, the angiopoietin receptor.

Esserman and his colleagues, who were instrumental in demonstrating the benefits of neoadjuvant chemotherapy in terms of relapse times and survival, also questioned the issue but did not reach a conclusion, as they lacked sufficient evidence.

Some questions arise about the Karagiannis study: are the models used really representative of the spectrum of human tumors? What were the levels of resistance to taxanes and other chemotherapies? What was the tumor's response to neoadjuvant therapy? Could these prometastatic sites not simply be the "remains" of a cancer site where most cancer cells have died, leaving a drug-resistant clone? Could the responses to taxanes considered prometastatic not be a transitory consequence of vascular damage, a known characteristic of taxanes' action?

However, these studies raise interesting questions: for example, in a subgroup of patients with high prometastatic potential and drug-resistant disease, could chemotherapy promote an increase in metastases and, therefore, have effects on survival? The authors show that rebastinib, a TIE2 inhibitor, blocks some prometastatic changes in their murine models. It would be useful to determine whether rebastinib can reduce recurrence rates and increase survival in breast cancer patients receiving neoadjuvant chemotherapy.

Until we have these results and a better understanding of the biological mechanisms, it makes sense to continue the current chemotherapy therapy for breast cancer.

Chabner BA. Does Chemotherapy Induce Metastases?. Oncologist. 2018 Mar;23(3):273-274.
doi: 10.1634/theoncologist.2017-0648.