Molecularly Guided Therapy in Pancreatic Cancer: Untapped Potential and the 'Bright Future' Ahead

Will Pass

March 11, 2020

Molecularly guided treatments may extend survival by more than a year for patients with pancreatic cancer who have actionable molecular alterations, according to a retrospective analysis of almost 2000 patients in the Know Your Tumor registry.

While patients with actionable alterations remain in the minority, experts suggest the study's results provide a ray of hope for treating a cancer that has historically been associated with a poor prognosis and disappointing clinical trials.

Patients with actionable molecular alterations who received matched therapies had a median overall survival of 2.58 years, compared with 1.51 years for those who received unmatched therapies, reported lead author Michael J. Pishvaian, MD, PhD, of MD Anderson Cancer Center in Houston, and colleagues.

"Our study provides strong rationale that tumor-based molecular profiling for patients with pancreatic cancer should be routinely performed and encourages prospective clinical trials based on this or similar platforms," the investigators wrote in Lancet Oncology.

In an accompanying comment, Jörg Kleeff, MD, and Christoph W. Michalski, MD, of Martin-Luther University Halle-Wittenberg in Germany, supported this conclusion, calling the study "an encouraging starting point for a structured investigation of molecularly matched therapies."

The authors also highlighted the untapped potential the trial uncovered, noting that only 4% of patients received a molecularly matched therapy, even though one-quarter had actionable alterations.

"These findings are important in that they define an estimation of the current number of potentially actionable targets and in that they provide a — rather disappointing — real-world assessment of the number of patients who actually received molecularly targeted treatment," Kleeff and Michalski wrote.

They went on to describe a list of unanswered questions in the field, ranging from ethical dilemmas that may be encountered when choosing between targeted trials and chemotherapy for patients with targetable alterations, to more tangible subjects, such as genome sequencing techniques and therapeutic timing.

Their comment and the related study were published simultaneously with a series of pancreatic cancer articles in Lancet journals, which includes:

According to the authors of the therapeutic review, treatments for pancreatic cancer have "a bright future."

"There is more optimism now than ever before that advances will be made by combining chemotherapy more effectively with agents that target the unique features of pancreatic ductal adenocarcinoma tumors," the authors wrote. "The next 5-10 years should deliver major improvements in outcomes through the use of novel agents that specifically target pathological signaling pathways and genetic alterations."

In an interview, Dana B. Cardin, MD, of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., shared this favorable outlook, which she said is particularly needed for a condition that has generally been left behind by the new era of personalized oncology treatments.

"There's been a lot of frustration on the part of patients and doctors and everyone in the research community that there have been a lot of other tumor types [in which] learning about genetic changes in cancer cells has really revolutionized how patients are being treated," Cardin said. "That is something that has really been elusive in pancreas cancer."

The retrospective study by Pishvaian and colleagues serves as proof-of-concept by showing that large-scale genomic testing can also identify personalized treatments for patients with pancreatic cancer, Cardin said.

"When you do find them, even when it's a small percentage of patients that may have actionable mutations, it really can make a huge difference in the outcomes for those patients," she said. "We have to get rid of this sense of futility. If you're not trying to look for those things, then you're not ever going to find them."

Regardless of whether a personalized treatment is available for a particular patient, Cardin emphasized the importance of a positive and active clinical mindset, as data suggest that existing supportive strategies can have a significant impact on patient health.

"We can make a difference for these patients," Cardin said, "but we're only going to make a difference if we try."

Cardin, a National Comprehensive Cancer Network panelist for pancreatic cancer, went on to explain how outcomes in the control arm of pancreatic cancer clinical trials have been improving over the past decade, even though the standard control drug, gemcitabine, has stayed the same.

"It doesn't mean that gemcitabine is better than it used to be," Cardin said. "It probably means that we're treating more patients, and we're also doing a better job of supporting those patients." She identified growth factors, nutritional support, and enzyme supplements as key ancillary treatments for those who need them.

Pishvaian and colleagues' study was funded by Pancreatic Cancer Action Network and Perthera. The investigators disclosed relationships with Perthera and other companies. Kleeff, Michalski, and Cardin have disclosed no relevant financial relationships.

Lancet Oncol. Published online March 2, 2020. Abstract, Comment

Lancet Oncol. 2020;21:PE135-E145. Abstract

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