British researchers have developed a new 44-gene assay known as DNA-damaging immune response (DDIR) that independently predicted benefit from neoadjuvant chemotherapy in some esophageal tumors. The test may help stratify patients and select more effective treatments based on neoadjuvant immune response before surgery.
Positivity to the test was associated with improved relapse-free survival (hazard ratio 0.61, 95% CI 0.38-0.98, P=0.042) and overall survival (HR 0.52, 95% CI 0.31-0.88, P=0.015). DDIR-positive patients also had a higher pathological response rate of 16.7% versus 6.8% (P=0.033), a lower nodal burden (P=0.026), and reduced margin involvement (P=0.007).
“Overall, the DDIR assay enables treatment selection and patient stratification in esophagogastric adenocarcinoma and may improve response to therapy, resection rates, and survival in this poor prognostic disease,” Richard C. Turkington, MBBS, PhD, of Queen’s University Belfast, and colleagues wrote in Gut.
“Our work opens the way for a precision oncology approach in the treatment of resectable oesophageal cancer,” Turkington told MedPage Today in an email.
DDIR positivity strongly correlated with an inflammatory microenvironment characterized by CD8-positive tumor-infiltrating lymphocytes (TILs) and high expressions of programmed cell death ligand 1 (PD-L1) expression, the researchers reported.
Earlier this year, MedPage Today reported that T-cell–inflamed gene-expression profiling, programmed death-ligand 1 (PD-L1) expression, and tumor mutational burden could predict clinical efficacy with the anti-PD-L1 antibody pembrolizumab across a diverse set of 20 solid tumors.
Those researchers noted that esophageal adenocarcinoma has risen six-fold in the Western world over the past 40 years, with the highest incidence occurring in the U.K. Neoadjuvant therapy followed by surgery cures fewer than half of resectable esophageal adenocarcinoma patients, and response rates to platinum-based neoadjuvant therapy are low at 15%.
Recently, DNA repair biology has sparked renewed interest because of its involvement in the immune response to cancer. Molecular landscape studies have identified a subgroup of tumors with impaired DNA damage response, which may spare ineffective therapy in patients unlikely to respond.
The U.K. researchers examined prechemotherapy endoscopic biopsies from 273 patients with resectable esophageal cancer who received neoadjuvant chemotherapy followed by surgical resection. These samples were collected at four British centers in the Oesophageal Cancer Clinical and Molecular Stratification consortium during 2003 to 2014. Among the specimens, 66 (24%) were DDIR-positive and 207 (76%) were DDIR-negative. The median age of patients overall was about 65 years, and those age 70 and older accounted for 36.4% of DDIR-positive tumors versus 22.7% of DDIR-negative tumors. In both groups, more than 80% of patients were male.
In addition to older age, DDIR positivity was also associated with reduced lymph node and circumferential resection margin and a more proximal tumor site. When assessed beside clinical factors available at diagnosis, DDIR status demonstrated superior prognostic ability versus standard clinico-pathological factors. But application of the test to patients who did not receive neoadjuvant therapy showed no difference in survival according to DDIR status, indicating that the assay may not be prognostic in its own right but only in the context of DNA-damaging therapy, the researchers explained.
They said they anticipate that future insights into the molecular biology of DDIR will lead to novel combinations of conventional therapy and DNA repair inhibitors or immunotherapy, but stressed the need for further validation in a prospective randomized controlled trial dataset.
“A technique like this is helpful because it can prevent the use of therapy that would ultimately prove ineffective and still come at a price of high morbidity,” Brandon G. Smaglo, MD, of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston, told MedPage Today. “On the other hand, if a patient’s tumor falls into the category where treatment will fail, there is no alternative suggested. Patients would be told, essentially, there is nothing to do. I think this would be a hard pill to swallow.”
Smaglo agreed that the longer-term utility of this type of technique likely lies in combination with other approaches, “to really determine what tumor responds to what. In other words, being able to test tumors upfront, direct some to chemotherapy, others to some alternative neoadjuvant treatment such as radiation or immunotherapy perhaps, or even others directly to surgery.” But in order to do that, he added, effective alternatives to standard neoadjuvant therapy need to be established.
Limitations of the current study, Turkington and co-authors said, included its reliance on a retrospective cohort, which may have influenced survival outcomes owing to the absence of standardized follow-up procedures. In addition, all cohort patients received neoadjuvant platinum-based chemotherapy resection, and further validation is required in another sample set treated with this modality.
Furthermore, the researchers said, since high intratumoral heterogeneity has correlated with response to neoadjuvant therapy in esophageal cancer, there may be limitations to using just a single biopsy to develop a predictive biomarker. In addition, the limited amount of tissue available from biopsies precluded using these samples to analyze TIL and PD-L1 expression. Matched resection specimens were used, but neoadjuvant chemotherapy could have influenced both TIL levels and PD-L1 expression in these specimens.
The response rate of 16.7% in DDIR-positive patients was comparable to that in some unselected retrospective and clinical trial cohorts and thus may limit the assay’s usefulness as a tool to assess pathological response after neoadjuvant therapy, the team added. Conversely, the 6.8% response in DDIR-negative patients may not be low enough to discourage the use of neoadjuvant cisplatin-based chemotherapy in this patient population.
This work was funded in part by Belfast Health and Social Care Trust Gastrointestinal Cancer Research Fund, Almac Diagnostics, the Medical Research Council, Cancer Research UK, the HSC Research and Development Division of the Public Health Agency in Northern Ireland, the National Institute for Health Research, Cambridge Biomedical Research Centre, and Invest Northern Ireland.
Turkington reported having no competing interests; several co-authors are employees of Almac Diagnostics Ltd. and several reported patent declarations.