Abstract
Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer.
Highlights
Pancreatic cancer is an aggressive malignancy with one of the worst outcomes among all solid malignancies [1]
We highlight the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was treated with DNA damaging agents based on the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient’s surgically resected tumor
Contrary to the expected median survival of 3 months for pancreatic cancer patients who progress on gemcitabine, this individual is virtually symptom-free for 3 years after progression to the first-line chemotherapy
Summary
Pancreatic cancer is an aggressive malignancy with one of the worst outcomes among all solid malignancies [1]. Metastatic stages, pancreatic cancer can almost never be controlled by any of the available therapeutic options, mirrored by an extremely low estimated 5-year survival rate of
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