Many Miles to Go: Targeted Treatment Based on Whole-Genome Sequencing


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Lorraine A. Chantrill, MD

We are on a learning curve. The technology is ahead of what our health-care systems can deliver. It will take time for this to become a reality.

—Lorraine A. Chantrill, MD

The ability to do genomic analysis of patients’ tumors holds great promise for revolutionizing cancer treatment, and genomics has already made some great strides. However, the Individualized Molecular Pancreatic Cancer Therapy ­(IMPaCT) trial is a cautionary tale about the hurdles involved in taking genomic profiling data to the clinical setting.

The IMPaCT trial sought to perform genomic profiling of patients with pancreatic cancer and to identify actionable genetic targets for treatment. After 93 patients were screened, 76 were eligible for profiling, and the researchers were able to identify only 22 candidate cases for a variety of reasons. And, none of these 22 patients has gone on to receive targeted therapy on the trial.

Disappointed by the results, lead author Lorraine A. Chantrill, MD, of The Kinghorn Cancer Centre, Garvan Institute of Medical Research, and The Macarthur Cancer Therapy Centre at Campbelltown Hospital, Sydney, New South Wales, Australia, said: “We are on a learning curve. The technology is ahead of what our health-care systems can deliver. It will take time for this to become a reality. At the moment, our health-care systems are not set up for this.”

Dr. Chantrill presented the IMPaCT trial results at the 2015 Annual Meeting of the American Association of Cancer Research,1 and the study was published simultaneously in Clinical Cancer Research.2

A Closer Look

Among the reasons for the failure to get patients on therapy targeted to their identified mutations were the difficulty in obtaining adequate tumor tissue for biopsy, the lag time in getting tumor tissue to the lab and back, the very short life span of pancreatic cancer patients, patients’ desire not to be randomized if they had an identifiable genetic abnormality, patients’ urgent desire to get onto treatment as quickly as possible, and the teamwork needed among the various specialties involved.

The study screened for three molecular targets: HER2 amplification, KRAS wild-type, and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). Tumor biopsies and archived tumor samples were collected from 93 patients with newly diagnosed or recurrent pancreatic cancer, and 76 were screened. Of the 76, 17 were unsuitable for tissue processing for a variety of reasons, including ineligibility, objection to randomization, and death due to pancreatic cancer.

Only 22 of those screened turned out to be candidate cases. Of these 22 patients with actionable targets identified, 6 died before results were obtained (1 suicide, 5 pancreatic cancer deaths), 1 had intercurrent prostate cancer making him ineligible, 3 could not be offered treatment due to worsening performance status, 1 withdrew consent, 1 declined consent, 2 were found to have cholangiocarcinoma on pathology and were ineligible, 1 had unacceptable liver abnormalities, 4 received chemotherapy before results were returned, and 3 resected patients are alive without disease recurrence and considered potential long-term survivors.

“Results have to be given in a meaningful time frame, considering the swift progression of pancreatic cancer and the desire patients have to start treatment immediately. We amended our study to allow patients to have one cycle of chemotherapy while waiting for results, and 75% of patients got results in less than 28 days,” she said.

Lessons Learned

In the course of the trial, several amendments were necessary, Dr. ­Chantrill explained. The first was to allow patients to have one cycle of treatment while waiting for results (at the time, gemcitabine was standard). The second was to do away with randomization. “Patients didn’t want to be randomized if they had a target identified,” Dr. Chantrill explained. The second amendment also allowed for the addition of nab-paclitaxel (Abraxane) to gemcita­bine for one cycle of chemotherapy.

“At the moment, it is still a randomized trial,” she said. Once the second amendment is passed, the IMPaCT investigators will enroll 10 more patients to start.

“The take-home message from this trial is that it is the simple things at the grass-roots level that determine whether this effort pans out: Can I get adequate tissue? Can I get the tissue to a lab in a timely fashion? Can I work with other specialists as a team to expedite this process? It’s not the bells and whistles of sophisticated technology that move this forward,” she stated.

Going Forward

A possible approach in the future that could expedite targeted molecular analysis is the use of “liquid biopsies” using circulating tumor cells or cell-free DNA. This could overcome barriers in obtaining adequate tissue samples, Dr. Chantrill said.

Going forward, a multidisciplinary team dedicated to this effort is necessary to overcome all the many hurdles. The investigators have proposed a new organizational structure that includes interventional radiologists and molecular pathologists to procure specimens more quickly and turn them around more rapidly.

“Establishing ‘biopsy teams’ is critical, as is developing an efficient yet precise pipeline to generate high-quality genomic data, and will be especially challenging for multisite trials,” she said. “We need the health-care system to align with these barriers.” ■

Disclosure: Dr. Chantrill is on an advisory board for Specialised Therapeutics Australia.

References

1. Chantrill L, Simpson S, Jones A, et al: Precision medicine for advanced pancreas cancer: The individualized molecular pancreatic cancer therapy (IMPaCT) trial. 2015 AACR Annual Meeting. Abstract CT210. Presented April 20, 2015.

2. Chantrill LA, Nagrial AM, Watson C, et al: Precision medicine for advanced pancreas cancer: The individualized molecular pancreatic cancer therapy (IMPaCT) trial. Clin Cancer Res. April 20, 2015 (early release online).

 


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