NEW YORK (Reuters Health) – A newly developed genomic-risk scoring system may significantly improve outcome predictions for patients with idiopathic pulmonary fibrosis (IPF) compared with clinical parameters alone, researchers say.
“IPF is a lethal disease with a variable and unpredictable course,” Dr. Jose Herazo-Maya of Yale School of Medicine in New Haven, Connecticut told Reuters Health.
“In a previous study we identified outcome-predictive genes in the peripheral blood of patients with IPF,” he said by email. “In this study, we measured the expression of 52 genes in the peripheral blood and developed a score that allowed us to classify them into high-risk and low-risk patients.”
Dr. Herazo-Maya and colleagues recruited 425 participants from six academic centers in the U.S., UK and Germany. The participants’ mean age at enrollment varied from 67 to 70, depending on the center; most (65% to 89%) were men.
The team collected peripheral blood mononuclear cells or whole blood at baseline from all participants, and from 98 (23%) during four to six years of follow-up.
After assessing the 52-gene signatures, the researchers used the Scoring Algorithm for Molecular Subphenotypes (SAMS), which they developed, to classify patients as low- or high-risk, based on the signature.
As reported in The Lancet Respiratory Medicine, online September 20, low-risk and high-risk patients in each cohort had significant differences in mortality or transplant-free survival (hazard ratio range, 2.03 to 4.37). Pooling the data revealed similarly elevated HRs for high-risk patients (2.18 for mortality and 2.04 for transplant-free survival).
Adding 52-gene risk profiles to the Gender, Age, and Physiology index (which uses clinical variables to stage mortality risk) significantly improved its predictive accuracy, according to the authors.
Risk profiles tended not to change in untreated patients, but temporal changes in SAMS scores, as assessed in two of the cohorts (Pittsburgh and Yale patients), were associated with changes in forced vital capacity. For example, some high-risk patients had a reversal of their genomic risk profile after antifibrotic therapy was started.
A simultaneous increase in “up score” and decrease in “down score” (these scores reflect gene-signature patterns relative to median values) was predictive of decreased transplant-free survival (HR, 3.18) in the Pittsburgh cohort. In contrast, a simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant improvement in forced vital capacity in the Yale cohort.
Taken together, the findings “may be very important for prioritization of transplant or stratifying patients in drug studies,” Dr. Herazo-Maya said.
“Based on the current lung allocation score, many IPF patients should be referred for transplant evaluation, and many end up being eligible for lung transplantation,” he noted. “However, our data suggests that patients with a high-risk genomic profile may require this evaluation urgently, while many others do not require lung transplantation even three to five years after diagnosis.”
“Thus, incorporating 52-gene risk profiles in the evaluation of IPF patients may enhance the precision of lung transplantation referral – avoiding delays in transplants for those who need it early, and delaying those who may not need it,” Dr. Herazo-Maya concluded.
Coauthor Dr. Naftali Kaminski, also of Yale, cautioned in the same email, “while the outcome prediction was based on over 400 patients in six cohorts, the observations on temporal changes and potential response to therapy were obtained on only a small subset of patients, and further prospective studies are needed to determine whether (the score) also predicts response to therapy.”
“We are aiming to perform (such)studies to validate the observation that a beneficial shift in the patient’s genetic risk profile is indicative of potential response to therapy,” she said, “and (assess) whether this response is specific to any of the FDA-approved drugs.”
Dr. Martin Kolb of McMaster University in Hamilton, Ontario, coauthor of a related editorial, told Reuters Health by email, “This work shows quite consistent expression profiles of a good number of genes across six centers, (with) very robust methodology.”
“However, it still needs work and prospective studies to translate this into clinical management of IPF,” he concluded. “That’s why my (editorial) comment says ‘we are getting closer, but are not there yet.’”
Three study authors have patents related to pulmonary fibrosis biomarkers, and many report stock options and fees from industry.
SOURCES: http://bit.ly/2ymTpcK and http://bit.ly/2kiHp5S
Lancet Respir Med 2017.
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