BRAF/MEK double blockade in refractory anaplastic pleomorphic xanthoastrocytoma

Discussion.

This case confirms that BRAFV600E mutation, harbored by two-thirds of PXAs,¹ is an interesting target for tyrosine kinase inhibition,² incites major questions on the escape mechanisms observed after BRAF-targeted therapy, which may differ in PXA and other tumor types, and provides a proof of principle for the double BRAF/MEK blockade as a therapeutic potential for PXA.

Indeed, the duration of the clinical benefit after BRAF inhibition is often limited to a few months,^3,4 partly due to paradoxical reactivation of the mitogen-activated protein kinase (MAPK) pathway by various molecular mechanisms, notably ERK reactivation.⁵ Laboratory and clinical data suggest that this resistance could be partially reversed with combined BRAF/MEK inhibition, the latter being a downstream molecule in the MAPK pathway.⁶ However, in the context of melanoma, it has been shown that the double blockade has to be initiated at the beginning of treatment, whereas it is ineffective in patients progressing after single-agent BRAF inhibition.⁷ In contrast, we demonstrate here that a BRAF/MEK double blockade provided a major clinical benefit for a patient with refractory anaplastic PXA previously treated with single-agent BRAF inhibitor. The molecular mechanisms underlying such behavioral differences need to be explored, so as to fully exploit the synergistic potential of dual or multiple inhibitions. A molecular hypothesis to be considered could be the intratumoral ratio of wild-type (wt) BRAF vs mutated BRAFV600E. Indeed, in melanomas with a wt BRAF component, the BRAF inhibition is ultimately inducing a MAPK pathway reactivation, leading to resistance and rapid tumor growth.⁸ It is noteworthy that the clinical case reported here is characterized by a fairly homogeneous expression of the mutated BRAFV600E protein (figure, B), which may explain the long duration of response.

Despite the present outcome of this case, current experiences with TKI indicate that progression will eventually occur. This is warranting the introduction of or combination with other treatment strategies, such as the combined or sequential use of MAPK inhibitors with immune checkpoint inhibitors. Indeed, murine models⁹ and human tumor samples before and after therapy from patients with metastatic melanoma^10,11 have shown that BRAF inhibition increases the expression of major histocompatibility complex molecules/tumor antigens and recruits CD8+ T cells but maintains them in a suppressed state by a concomitant increase in the expression of programmed cell death 1 (PD-1) molecule. Thus, future studies should investigate the combined use of BRAF/MEK inhibition—to attract T cells—with an anti-PD-1 monoclonal antibody aiming to upregulate their function.

Finally, considering the impressive radiologic response (figure, C), an important lesson that could be derived from this case report is the possibility to use a double BRAF/MEK inhibition as a neoadjuvant approach before surgery. Indeed, PXAs are often extended to several anatomical regions, rendering challenging a complete resection. Neoadjuvant cytoreductive therapy could potentially facilitate the surgical step and help maintain the functional integrity of the patient.