Lara C. Pullen, PhD

October 06, 2015

CHICAGO — Next-generation sequencing can potentially provide valuable information for patients with pancreatic cancer. Specifically, such sequencing of resected pancreatic adenocarcinoma specimens may pave the way for off-label use of targeted therapies. The analysis can determine common genetic mutations, thereby identifying patients for clinical trial enrollment.

"The advances that we need to make in pancreatic cancer are likely not to come from surgery but from systematic medicine," explained G. Paul Wright, MD, formerly of Michigan State University in Grand Rapids and currently a fellow at University of Pittsburgh in Pennsylvania.

Dr Wright described the results of his tissue specimen analysis at the American College of Surgeons (ACS) Clinical Congress 2015.

His team obtained 28 tissue specimens from patients who underwent resection of pancreatic adenocarcinoma from 2011 to 2014. The samples had at least 60% tumor nuclei per sample (the current laboratory standard). Next-generation sequencing was performed using the Life Technologies Ion AmpliSeq Cancer Hotspot Panel v2. The investigators used a proprietary cancer gene panel of 50 genes.

The mean age of the patients was 64.4 years (range, ±9.8 years); 64% of the patients were men; and 89% of patients were white. For the majority (96%) of patients, the cancer was of stage T3; nodal metastasis was present in 71% of patients. The R0 resection rate was 86%.

The investigators identified 75 genetic variants. Genomic sequencing revealed that 25% of samples could be matched to a US Food and Drug Administration (FDA)–approved targeted therapy. Moreover, 64% of the samples had mutations that are targeted by therapies that are currently in phase 1 clinical trials.

Multiple mutations were found in 75% of samples; the KRAS/TP53 combination was seen in 64% of samples.

Table. Incidence of Mutations

Mutation Percent
KRAS 86%
TP53 68%
CDKN2A 21%
SMAD4 21%
EGFR 7%

 

KRAS involves a complex pathway that has made the development of targeted therapies difficult. Nevertheless, five clinical trials of drugs that address this pathway are currently under way.

TP53 is the most well-known tumor suppressor gene. The p53 mutation is linked to increased responsiveness to bevacizumab (Avastin, Genentech, Inc).

CDKN2A is also a tumor suppressor gene. Palbociclib (Ibrance, Pfizer Inc), which has been approved by the FDA for the treatment of advance breast cancer, acts on this pathway. All of the CDKN2A mutations in the current study occurred in men (P = .06). This mutation also tended to occur in patients younger than 60 years (P = .06).

SMAD4 facilitates gene transcription through the TGF-β pathway. The SMAD4 gene is associated with a worse prognosis, a higher recurrence rate, and treatment failure.

EGFR is a signaling protein on the cell surface. Erlotinib is an FDA-approved drug that targets EGFR.

Precision Medicine

Pancreatic cancer is the twelfth most frequently diagnosed cancer, and as Dr Wright said when he began his talk, "Pancreatic cancer is bad.... Pancreatic cancer represents a complex disease with complex pathways."

"Kudos for you for tackling a brave new world," said discussant Susan Tsai, MD, referring to the implications that the research has for precision medicine.

Dr Wright said, "This testing is available at our institution." He emphasized his hope that such analyses might increase clinical trial enrollment. He acknowledged, however, that "the trials that are open are in advanced-stage disease." His samples were taken from patients who underwent resection.

Although Dr Tsai agreed with the research value of such a screening, she noted, "I think what is less clear is where we can target the therapeutics."

The issue of precision medicine has not yet been resolved, although the University of Pittsburgh has a targeted therapies advisory board that is designed to help patients and physicians navigate the frontier.

"I think that a lot of the sequencing ― all of them ― are in early stage," emphasized Jen Jen Yeh, MD, of the University of North Carolina at Chapel Hill, who moderated the session. "As a group, we should try and support an infrastructure to do that more," she added.

Dr Wright, Dr Tsai, and Dr Yeh have reported no relevant financial relationships.

American College of Surgeons (ACS) Clinical Congress 2015: Presented October 5, 2015.

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