Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report

Abstract

BackgroundGallbladder cancer typically follows an aggressive course, with chemotherapy the standard of care for advanced disease; complete remissions are rarely encountered. The epidermal growth factor receptor (EGFR) is a promising therapeutic target but the activity of single agent oral EGFR tyrosine kinase inhibitors is low. There have been no previous reports of chemotherapy plus an EGFR-tyrosine kinase inhibitor (TKI) to treat gallbladder cancer or correlations of response with the mutation status of the tyrosine kinase domain of the EGFR gene.Case presentationA 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine (1000 mg/m2) on day 1 and 8 every 21 days as well as daily erlotinib (100 mg). After four cycles of therapy, the CA 19-9 normalized and a PET/CT showed a complete remission; this response was maintained by the end of 12 cycles of therapy. Gemcitabine was then discontinued and single agent erlotinib was continued as maintenance therapy. The disease remains in good control 18 months after initiation of therapy, including 6 months on maintenance erlotinib. The only grade 3 toxicity was a typical EGFR-related skin rash. Because of the remarkable response to erlotinib plus gemcitabine, we performed tumor genotyping of the EGFR gene for response predicting mutations in exons 18, 19 and 21. This disclosed the wild-type genotype with no mutations found.ConclusionThis case report demonstrates a patient with stage IV gallbladder cancer who experienced a rarely encountered complete, prolonged response after treatment with an oral EGFR-TKI plus chemotherapy. This response occurred in the absence of an EGFR gene mutation. These observations should inform the design of clinical trials using EGFR-TKIs to treat gallbladder and other biliary tract cancers; such trials should not select patients based on EGFR mutation status.

A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

“…Although response rates in clinical studies of EGFR inhibitors across various tumor types have not been sufficiently high to warrant use in unselected patients, in a similar manner to breast cancer, durable responses have been observed at low frequencies across multiple epithelial tumor types, including cutaneous squamous cell carcinoma and gallbladder cancers (Maubec et al, 2011;Mody et al, 2010). Given that EGFR is known to play a critical role in transit-amplifying populations across various normal tissues (Schneider and Yarden, 2016), further investigation is warranted to determine whether the EGFR-associated tumorigenic program we have identified plays a role in treatment response in other tumor types.…”

Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma

“…11 Genomic correlates of extraordinary response to targeted therapeutics have been demonstrated in other contexts, 12–16 raising the possibility that a rare extreme response to erlotinib hydrochloride may result from somatic alterations in a patient’s tumor.…”

Overview of current targeted therapy in gallbladder cancer

“…A variety of therapeutic trials targeting EGFR in GBC patients have been completed, but endpoints were varied. Mody et al 137 reported a metastatic GBC case who received a combination treatment with gemcitabine (1000 mg/m 2 ) on days 1 and 8 every 21 days and daily erlotinib (100 mg). The disease remained for 18 months with no progression after 12 cycles of combination therapy followed by maintenance with only erlotinib for 6 months.…”