Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report
Casadei Gardini et al. BMC Cancer
Efficacy of sorafenib in BRAF-mutated non- small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type- hepatocellular carcinoma: a case report
Andrea Casadei Gardini 0
Elisa Chiadini
Luca Faloppi
Giorgia Marisi
Angelo Delmonte 0
Mario Scartozzi
Cristian Loretelli
Alessandro Lucchesi 0
Devil Oboldi
Alessandra Dubini
Giovanni Luca Frassineti 0
Paola Ulivi
0 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS , 47014 Meldola , Italy
Background: Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Case presentation: Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Conclusions: Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients.
Case report; BRAF; HCC; NSCLC; Sorafenib
Background
Sorafenib is a multi-targeted kinase inhibitor with proven
activity in renal cell carcinoma (RCC) and hepatocellular
carcinoma (HCC) [
1, 2
]. It was originally discovered as an
inhibitor of Raf-1 kinase, but was found to have an
expanded target profile with potent activity against other
kinases including BRAF, vascular endothelial growth
factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet
derived growth factor (PDGFR)-β, KIT, Flt-3, and RET. It
has a broad-spectrum efficacy in human tumor xenograft
models including NSCLC [
3, 4
].
NSCLC seemed an ideal disease in which to further
investigate sorafenib based on the frequency of RAS
mutations, particularly in adenocarcinomas [
5–7
]. Several
clinical trials have evaluated sorafenib in the treatment of
advanced NSCLC alone or in combination with
chemotherapy or targeted agents, without reaching consistent
results on efficacy [
8–11
]. Markers of sorafenib efficacy or
resistance have yet to be identified [
12–15
].
Case presentation
We present a case of a 74-year-old man smoker patient
with NSCLC with bone metastases (T2NXM1) and HCC
(BCLC stage C). The patient had a related liver cirrhosis
metabolic syndrome, good liver function (Child Pugh A5),
and reported a diabetes mellitus type II in his past medical
history. In July 2014 for chest and abdominal pain he
performed a CT scan with evidence of lung and liver lesions,
and bone metastasis. Lung biopsy performed on primary
lung lesion showed pulmonary adenocarcinoma (TTF1
positive and p40 negative) (Fig. 1a-b) and liver biopsy
showed HCC (grade 2 Edmondson) (Fig. 1c-d). As the
patient was not in good clinical conditions due to grade
2 asthenia, we decided to start with gemcitabine in
monochemotherapy in August 2014. After 2 months of
chemotherapy a further CT scan showed a disease
progression in both the lung and the liver. We decided to
initiate treatment with sorafenib with standard schedule
(400 mg bid continuously).
CT scan before therapy showed that the primary liver
lesion measured 97 mm × 98.3 mm (Fig. 2a). The
primary lung lesion measured 40.9 mm × 29.3 mm (Fig. 2d)
and the metastasis in the contralateral lung measured
27 mm × 25 mm (Fig. 2d). After 20 days we decided to
reduce the dose of sorafenib to 400 mg per day for
adverse events (hypertension grade 2 and mucositis grade
3). This dose was maintained until progression, without
adverse events. CT scan after 2 months showed partial
response in both lung lesions and stable disease in the
liver and bone lesions. CT scan after 6 months of
therapy showed partial response of the primary lung lesion
and complete response of the lung metastasis (Fig. 2e).
HCC was stable (Fig. 2b). After 13 months of therapy
CT scan (...truncated)