Circulating Tumor DNA-Based Testing and Actionable Findings in Patients with Advanced and Metastatic Pancreatic Adenocarcinoma.

PURPOSE: Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. MATERIALS AND METHODS: From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. RESULTS: All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. CONCLUSION: Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. IMPLICATIONS FOR PRACTICE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.

Dramatic response to modified docetaxel, cisplatin, and fluorouracil chemotherapy after immunotherapy in a patient with refractory metastatic anal cancer.

Doublet chemotherapies are the mainstay in the management of metastatic anal cancer. Immunotherapy has been incorporated into guidelines in a refractory setting. Treatment options remain limited with tumor progression beyond immunotherapy. Modified docetaxel, cisplatin, and fluorouracil (mDCF) chemotherapy, after progression postimmunotherapy, has shown a near-complete response in our patient with metastatic anal cancer. This likely is secondary to the sequence of immunotherapy followed by chemotherapy that is yielding greater than historical responses.

Trastuzumab and pertuzumab in circulating tumor DNA ERBB2-amplified HER2-positive refractory cholangiocarcinoma.

Cholangiocarcinoma is a heterogeneous and target-rich disease with differences in actionable targets. Intrahepatic and extrahepatic types of cholangiocarcinoma differ significantly in clinical presentation and underlying genetic aberrations. Research has shown that extrahepatic cholangiocarcinoma is more likely to be associated with ERBB2 (HER2) genetic aberrations. Various anti-HER2 clinical trials, case reports and other molecular studies show that HER2 is a real target in cholangiocarcinoma; however, anti-HER2 agents are still not approved for routine administration. Here, we show in a metastatic cholangiocarcinoma with ERBB2 amplification identified on liquid biopsy (circulating tumor DNA (ctDNA) testing), a dramatic response to now over 12 months of dual-anti-HER2 therapy. We also summarize the current literature on anti-HER2 therapy for cholangiocarcinoma. This would likely become another treatment option for this target-rich disease.

Feasibility of circulating tumor DNA testing in hepatocellular carcinoma.

BACKGROUND: Advancement of technologies enabling clinical assessment of circulating tumor DNA (ctDNA) are allowing for assessment of tumor specific genetic alterations in patients. This holds incredible promise for early detection of disease, serial monitoring of tumor heterogeneity, elucidation of therapeutic targets, and evaluation of treatment response and mechanisms of resistance. Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is often diagnosed late, recurs commonly, and is often diagnosed based upon imaging features alone. A comprehensive evaluation of real-time evaluation of ctDNA in patients with HCC has thus far not been undertaken. METHODS: From January 2015 to February 2018, 35 patients with biliary tract cancer (BTC) at the Mayo Clinic Comprehensive Cancer Center underwent ctDNA testing using a clinically available assay. The majority of samples were tested utilizing the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively; and in some, amplifications, fusions, and indels. RESULTS: A total of 44 samples were collected on these 35 patients, with >70% having stage 3 or 4 disease. Among all samples the median number of alterations per sample, excluding variants of undetermined significance (VUS), was 3.5, with a median allele frequency of 0.65%. A total of 122 unique genetic alterations, excluding VUS or synonymous alterations, were seen. The overall landscape of alterations is described. The top 10 genes altered in this cohort of patients, excluding VUS or synonymous alterations, were TP53 (18%), TERT (14%), CTNNB1 (13%), ARID1A (9%), MYC (5%), BRAF (4%), CCND1 (4%), CDK6 (4%), and MET (4%), and EGFR (3%). CONCLUSIONS: Herein, we describe feasibility of ctDNA testing and results from such testing in HCC patients undergoing ctDNA testing in a real-time clinical context. Patients with these cancers stand to benefit immensely from the use of ctDNA technologies, and concerted efforts at further investigation of such are critically needed.

Survival of Patients with Oligometastatic Pancreatic Ductal Adenocarcinoma Treated with Combined Modality Treatment Including Surgical Resection: A Pilot Study.

Purpose: To evaluate the overall survival of patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC; metastatic tumor <4 cm, ≤2 metastatic tumors total) receiving neoadjuvant therapy, metastasectomy and/or ablation, and primary tumor resection. Methods: We performed a case-control study from January 2005 to December 2015. Patients who underwent curative-intent surgery combined modality therapy (M1 surgery group; 6 [14%], tumor [T]3, node [N]1, and oligo-metastases [M]1) were matched 1 to 3 based on TN stage with two control groups (M0 surgery and M1 no surgery). The M0 surgery group (18 [43%], T3, N1, and M0) included patients without metastases who underwent resection. The M1 no surgery group (18 [43%], T3, N1, and M1) included patients with metastatic PDAC who received palliative chemotherapy without surgical resection. Results: Median overall survival in the M1 surgery, M0 surgery, and M1 no surgery groups was 2.7 years (95% confidence interval [CI], 0.71-3.69), 2.02 years (95% CI, 0.98-3.05), and 0.98 years (95% CI, 0.55-1.25), respectively. Eastern Cooperative Oncology Group (ECOG) status was associated with survival (p = 0.01) after univariate analysis. After adjusting for ECOG status, multivariate analysis showed M1 surgery patients had improved survival compared with M1 no surgery patients and similar survival to M0 surgery patients. Conclusion: Multimodal therapy benefitted our M1 surgery patients. A larger, prospective study of this multidisciplinary management strategy is currently under way.

A Care Process Model to Deliver 177Lu-Dotatate Peptide Receptor Radionuclide Therapy for Patients With Neuroendocrine Tumors.

Purpose: To develop a care process model for the delivery of peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-Dotatate for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: A multidisciplinary, structured PRRT process model was established. Over the last 9 months, meetings were held bi-weekly to discuss the logistics of clinical trials. Meetings are still held regularly at the Mayo Clinic Florida to discuss plans regarding commercially available PRRT treatments. The process model has evolved as we have treated patients on both clinical trials and commercial treatments. Results: An effective process model was formulated. We had 5 patients on our Expanded Access Program (EAP) clinical trial. Our ability to be a part of the EAP allowed us to understand the mechanics of how to treat these patients, and what was involved before it became commercially available. Since commercial availability of the 177Lu-Dotatate, more than 50 treatments (>20 patients) have already been completed, with several new patients getting started on treatment every week. Our nuclear medicine department receives continual requests to schedule new patients for PRRT. This can be attributed to our streamlined approach in delivering PRRT to our patients. Conclusion: A thorough procedural approach was formulated to provide patients with PRRT. Experiences and challenges led to refinement, which has allowed the process to advance. This development could lead to better patient outcomes, treatment efficiency, and a reference standard for other institutions trying to develop this at their location.