CHICAGO—Papillary thyroid cancer (PTC) is driven by mutations in the BRAF gene, but patients often show resistance to treatment with BRAF inhibitors. The mechanisms of resistance are under investigation in a neoadjuvant trial of patients before and after treatment with the BRAF inhibitor vemurafenib, according to a study presented here at the American Society of Clinical Oncology Annual Meeting (Abstract TPS6100).
As the lead author, Maria Cabanillas, MD, Assistant Professor in the Department of Endocrine Neoplasia and Hormonal Disorders at the University of Texas MD Anderson Cancer Center, explained, BRAF mutations are found in 40 percent of patients with newly diagnosed papillary thyroid cancer, but are much more prevalent in recurrent disease, ranging from 78 to 86 percent, which suggests that they play an active role in tumor progression. Among intermediate-risk patients, including those with cervical lymph node metastases, about 43 percent will have recurrent or persistent disease two years after surgery.
“Activating mutations in BRAF result in constitutive activation of MEK and subsequently ERK. ERK mediates activation of nuclear transcription factors coordinating expression of genes involved in proliferation and survival of malignant cells,” she said.
Papillary thyroid cancer usually has an excellent prognosis, especially in younger patients and in those who respond to the only effective treatment, which is surgery followed by radioactive iodine (RAI). However, more advanced stage disease at diagnosis, older age, and lack of RAI avidity are associated with a high rate of recurrence and distant metastasis, imparting a worse overall prognosis.
“Long-term outcomes depend highly on initial surgery outcome,” said Cabanillas, noting that nearly 86 percent of these patients have persistent or recurrent disease two years after surgery. “Patients at highest risk of recurrence and death are those with gross residual disease after surgery and macroscopic tumor invasion.”
BRAF mutations activate the MAPK pathway and are associated with high-risk clinicopathologic characteristics, such as extrathyroidal invasion, advanced-stage disease, lymph node metastasis, distant metastasis, loss of radioiodine uptake, and death.
Vemurafenib is an inhibitor of the activated form of the BRAF serine-threonine kinase enzyme. The drug is approved by the Food and Drug Administration for the treatment of advanced melanoma, and is currently being studied in a Phase II trial in metastatic BRAF-mutated PTC.
At the ASCO meeting, Cabanillas described the primary objective of the neoadjuvant trial, which is to assess whether changes in ERK phosphorylation response after treatment with vemurafenib correlate with clinical response at day 56 in patients with locally advanced, BRAF-mutated papillary thyroid cancer.
Secondary objectives include (1) an assessment of the safety of neoadjuvant vemurafenib in patients undergoing surgical resection of locally advanced PTC; (2) a determination of the best overall objective response of vemurafenib; (3) a description of the rates of head and neck surgery complications (hypoparathyroidism, nerve paralysis, and need for tracheal shave and/or resection); (4) a description of the rate of persistent disease at the surgical site at one year; and (5) an exploration of potential markers and mechanisms of resistance to vemurafenib.
The trial includes adult patients with incident PTC, which appears to be stage T3 or T4 on imaging or with macroscopic lymph node involvement, and those with persistent or locally recurrent PTC. BRAF V600E mutations had to be detected in the primary tumor or the recurrent, persistent tumor.
She said the plan is to enroll a total of 22 patients, and seven have been enrolled so far. Patients receive vemurafenib at 960 mg twice daily until planned surgery on day 56. After surgical resection, patients in group A (distant metastases or incomplete resection) may continue on vemurafenib until it fails. Patients in group B will discontinue vemurafenib. Patients with widely metastatic disease may continue vemurafenib.
The trial will be stopped for patients with unacceptable surgical adverse events, those who cannot undergo surgery or have a delay in time to surgery of more than four weeks from the last vemurafenib dose, or those with inadequate healing or post-op bleeding—“we will monitor the unacceptable adverse event rate and will stop the trial if that is more than 20 percent,” said Cabanillas.
The researchers will examine expression of total and phosphorylated (active) ERK protein by reverse phase protein array analysis of fresh frozen tumor biopsies, with confirmatory immunohistochemistry. They will also look at expression of activation of components of the PI3K-AKT pathway, and expression and activation of receptor tyrosine kinases, including IGF1R, EGFR, c-KIT, c-MET, and PDGFR beta. An exploratory analysis will look at other protein signaling pathways, including JAK, STAT, TGF beta-SMADs, SRC, FAK, BCL2 family, apoptotic machinery, and transcription factors.
Mutational analysis of genes in the RAS-RAF-MEK-ERK and PI3K-AKT pathways, including NRAS, KRAS, and PIK3CA, will be performed on surgical specimens or archived tissue, she continued. Immune modulation studies will include regulatory T-cell and PD-1+ T-cell analysis.
In conclusion, Cabanillas said, “This neoadjuvant trial will determine if pharmacodynamic changes in the tumor correlate with response to drug. We hope to determine whether changes in ERK phosphorylation responses after treatment with vemurafenib correlate with clinical response at day 56 in patients with locally advanced, BRAF-mutated papillary thyroid cancer.
“We will also assess the safety of neoadjuvant vemurafenib, the rate of surgical complications, persistent disease at the surgical site at one year, and the mechanisms of resistance to vemurafenib.”
‘New Departure for Papillary Thyroid Cancer’
Asked for his opinion for this article, Nick Plowman, MD, Head of the Department of Clinical Oncology at St. Bartholomew's Hospital in London, said, “The quest is on to find the mechanisms behind BRAF inhibitor resistance. This is a new departure for papillary thyroid cancer.
“It is interesting that so many papillary thyroid cancer patients carry resistant mutations to BRAF. Vemurafenib is very promising in melanoma, and may be useful in thyroid cancer.”
Plowman added: “Sorafenib is a useful drug in thyroid cancer, but we all have papillary thyroid cancer patients who do not respond and we have no other therapies for them. If a patient cannot be otherwise treated, it makes sense to look for mutations that are driving the oncogene.”
He noted that although chemotherapy is not promising for such patients, there are some data that vitamin A may cause RAI-refractory thyroid cancer to re-adapt avidity in a few patients.