Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer

Abstract

As the knowledge on cancer genetic alterations progresses, it fosters the need for more personalized therapeutic intervention in modern cancer management. Recently, mutations in KRAS, BRAF, and PIK3CA genes have emerged as important mechanisms of resistance to EGFR-targeted therapy in metastatic colorectal cancer (mCRC). Here we report the first case of a mCRC patient whose disease had progressed on standard lines of treatment and for which we devised a personalized therapeutic approach consisting of vemurafenib (ZelborafTM) and panitumumab (VectibixTM), based on the following molecular profile: BRAFV600E-mutant, amplified EGFR (double positive) and WT KRAS, WT PIK3CA, not-amplified HER2 (triple negative). This new combination therapy was well tolerated and resulted in a strong control of the disease. In particular, the vemurafenib-panitumumab combination appears to limit the typical toxicity of single agents, since no cutaneous toxic effects typically associated with vemurafenib were observed. Here we report the first clinical evidence that the combination of an anti-EGFR (panitumumab) and an inhibitor of BRAFV600E (vemurafenib) is well tolerated and results in a strong disease control in an extensively pretreated mCRC patient.

The pathomorphologist’s role in the era of personalised therapy regarding the case of colorectal tumours

“…Here mucinous and poorly differentiated cancers are dominating with metastases mostly to the lymph nodes and more rarely to the lungs [36,37]. The BRAF mutation indicates an adverse course of the disease [38], yet its prediction significance still remains an issue that requires some further research [34]. The BRAF gene, a modulator of the MAPK pathway, may become a promising target of personalised therapy as a resistance biomarker.…”

BRAF mutant colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAF/ErbB inhibitors

“…Advances made in the diagnosis and treatment of CRC have undoubtedly prolonged patient survival. However, unfavorable outcomes are still the rule for certain CRCs that are particularly aggressive [3,4]. Up to 10% of metastatic CRCs are BRAF V600E-mutated, and display a worse prognosis [3,5].…”

“…However, unfavorable outcomes are still the rule for certain CRCs that are particularly aggressive [3,4]. Up to 10% of metastatic CRCs are BRAF V600E-mutated, and display a worse prognosis [3,5]. These tumors are relatively unresponsive to currently used chemotherapy protocols [6,7], and in these cases, second-line treatment with anti-epidermal growth factor receptor (EGFR)-antibodies is rarely beneficial [8][9][10].…”

“…BRAF (along with CRAF and ARAF) belongs to a family of genes that encode serine-threonine kinases, which heterodimerize and are activated by several receptor tyrosine kinases (RTKs), such as EGFR. Together with downstream MEK and ERK proteins, RAF kinases constitute a powerful mitogen-activated protein kinase (MAPK) pathway [3,4]. The BRAF mutations found in CRC usually occur at the V600 hotspot and lead to constitutive activation of BRAF V600E , which signals as a monomer in the absence of upstream signaling through the RAS signaling pathway.…”

“…The BRAF mutations found in CRC usually occur at the V600 hotspot and lead to constitutive activation of BRAF V600E , which signals as a monomer in the absence of upstream signaling through the RAS signaling pathway. This explains at least in part the resistance of BRAF V600E CRCs to EGFR pathway blockade [11,3].…”