Genetic basis to an extraordinary response to Vinorelbine chemotherapy in metastatic triple negative breast cancer by Dr Lawrence Panasci in Journal of Clinical Case Reports Medical Images and Health Sciences

 Genetic basis to an extraordinary response to Vinorelbine chemotherapy in metastatic triple negative breast cancer by Dr Lawrence Panasci in Journal of Clinical Case Reports Medical Images and Health Sciences

Case report

Patients with metastatic triple negative breast cancer have a short median survival (17 months) (1). In these patients, first line chemotherapy results in less than 5% complete remissions while second or third line chemotherapy almost never results in sustained complete remission.

Two important classes of anticancer drugs utilized to treat metastatic breast cancer are: (a) vinca alkaloids such as vinorelbine and (b) taxanes such as paclitaxel (2). While these agents are effective, resistance develops quickly and patients with triple negative metastatic breast cancer have a median survival of less than 24 months after starting chemotherapy (1). The mechanism of action of the vinca alkaloids involves binding to tubulin heterodimers eventually causing dissolution of the mitotic spindle. In contrast, the taxanes bind in a different fashion reversibly to the microtubule polymer in a 1:1 stoichiometry relative to the tubulin heterodimer, within the lumen of the microtubule, enhancing the polymerization of tubulin, which is the opposite effect of vinca alkaloids (3,4,5).

Resistance to these agents has been investigated in cancer cell lines and xenograft cancer models. There are many possible mechanisms of resistance to tubulin modifying chemotherapy but the most prominent involves alteration in the tubulin proteins or microtubule-associated proteins (MAPs). Whereas increased βII-, βIII- and βIV-tubulin are associated with taxane resistance, decreased βIII-tubulin has been reported in vincaresistant cell lines (6). Mutations affecting the expression of β-tubulin isotypes have been associated with altered sensitivity to these agents. Another line of defense against cytotoxic drugs includes regulatory proteins, in particular post-translational modifications (PTMs) of tubulin which can affect regulatory protein binding and alter sensitivity to tubulin modifying agents. In particular, the MAPs (tau, stathmin, MAP2 and MAP4) have been extensively investigated as triggers for cancer resistance (3, 6,7). However, mechanism of resistance in cell lines or xenograft models often are not easily translated into the clinic hampering the development of effective methods to overcome this resistance in clinical setting.

Paclitaxel-resistant cell lines contain “hypostable” microtubules in which the equilibrium between the dimer and polymer is shifted towards the dimer. These cells display increased resistance to polymer-binding drugs like paclitaxel, and increased sensitivity to vinca alkaloids. Thus, resistance to taxanes may be associated with sensitivity to vinca alkaloid (3).

A 58-year old female with stage 4 triple negative breast cancer (ER neg, PR neg, Her2 neg) with metastases to the right axillary, mediastinum, lung and spleen was treated with 3 different chemotherapy regimens (Gemcitabine plus capecitabine, paclitaxel and pegylated liposomal doxorubicin), and eventually failed all of them. She received fourth line vinorelbine chemotherapy for 2.5 years and had a complete response which has lasted more than 5 years with no maintenance chemotherapy. She appears to be cured.

In order to determine the genetic basis of this highly unusual result, her tumor DNA was analyzed in 2 different fashions: Foundation One testing which examines 206 genes involved in possible cancer therapy options and whole exome sequencing.

For more information: JCRMHS

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