BC remains a challenging cancer. The rationale for this study was based on the demonstration of a potential role for BRAF and KRAS signaling pathways in the carcinogenesis of BC. Results from this study reveal interesting activity for selumetinib as a single agent in this patient population with metastatic BC that included patients (39%) with prior exposure to systemic therapy. There were three objective responses and another 14 patients with meaningful SD. Additionally, both mPFS and mOS compare favorably with published historical controls.2–5
Consistent with the PFS and response results was the target lesion decrease in 52% of patients as shown in .
Selumetinib was fairly well tolerated with predominantly GI and cutaneous toxicities. Fourteen percent of treated patients required dose reduction for grade 3 diarrhea, fatigue, rash, or cellulitis. We did not observe any ocular toxicity with this MEK inhibitor.
In our population, no patients had a BRAF
V600E mutation, and a there was a low occurrence (approximately 8%) of KRAS
G12/13X mutations. Although other published studies suggest these mutations can be found in up to 60% of patients with BC,17–20
our study is the only prospective analysis of BRAF
mutational status in this patient population in the United States. Several published studies suggest that the presence of an activating mutation of BRAF
in cancer cell lines predicts sensitivity to MEK inhibition in vitro. In our study and despite the presence of several patients who experienced clinical benefit, there were no BRAF
V600E mutations. Of note, our study included a larger proportion of patients with intrahepatic disease compared with the general population of BC patients. This could limit the generalizability of our findings, including the interpretation of the molecular correlates, especially the mutational analyses.
Another finding in our study was the lack of a clear correlation between pERK or pAKT immunostaining and mPFS. Interestingly, patients with pERK score lower than 1 included 80% of patients whose disease progressed and none of the patients who experienced objective response. In addition, OS was lower in patients in whom pERK immunostaining was absent. Patients with pERK ≥ 1 or pAKT ≥ 1 had an improved but not statistically significant survival advantage. These findings raise the possibility that pERK and/or pAKT may have prognostic but not predictive relevance and suggest that tumor sample AKT activity may not predict resistance. We recognize that immunohistochemistry is qualitative and that staining can be heterogeneous. However, it is important to note that the agreement in scores between the independent observers was high and tissue samples were available from 95% of study patients, including every patient who experienced objective response or whose disease progressed. Given the exploratory nature of the correlative analyses and the limitation of such analyses in the setting of a small sample size, additional studies using robust and more objective measures are needed to confirm this potentially important finding. Finally, sequential biopsies in patients on therapy were not available to confirm pharmacodynamic inhibition of ERK activation.
Given the absence of clear predictors from the correlative studies presented, several other mechanisms may explain the interesting activity noted with selumetinib in BC. Alternative genetic or epigenetic alterations for this malignancy, such as activation as a result of BRAF
gene mutations at other nucleotide positions or newly described MEK
are certainly possible. A recent study identified transcriptional pathway signatures that could predict for MEK addiction and response to selumetinib with no absolute correlation with mutational or phosphoprotein markers of BRAF/MEK, RAS, or PI3K.25
Finally, immune modulation can potentially explain the observed activity of selumetinib, including the documented nonfluid weight gain. Selumetinib has been previously shown to inhibit secretion of interleukin (IL) -626
as well as of other cytokines including IL-1 and tumor necrosis factor. IL-1, IL-6, and tumor necrosis factor have all been implicated in the origins of cachexia in cancer.27–29
Cholangiocarcinoma cells constitutively secrete IL-6, a vital cytokine for cholangiocarcinogenesis, with a major role on survival signaling pathways and growth of these cells,30,31
and inhibition of IL-6 has been shown to attenuate growth of cholangiocarcinoma cell lines.32
A review of published results on selumetinib in various malignancies revealed few reported responses,15,33–38
specifically in melanoma (< 5%),36
lung cancer (5%),38
and thyroid cancer (< 3%).35
In our study, 12% of patients experienced objective responses, and 56% experienced prolonged SD; the majority of those with prolonged SD had target lesion decrease. Our study fell short of achieving the number of responses required to consider moving forward with single-agent selumetinib in patients with BC. One may argue that our choice of primary end point was not optimal, and our target response rate may have been ambitious. Nonetheless, with the presence of preliminary evidence of activity for selumetinib, development of this agent is warranted in combination with other promising agents, such as inhibitors of epidermal growth factor receptor39
In conclusion, MEK inhibition with selumetinib was well tolerated and shows evidence of promising activity in BC. Correlative studies confirming the potential negative predictive value of absence of ERK phosphorylation and identifying new positive predictors of clinical response are needed to better understand the mechanisms of activity and to better select patients for treatment. The results of the present study suggest that selumetinib monotherapy has clinical activity in BC and may represent a particularly promising compound for inclusion in combinatorial strategies.