Researchers have revealed that the number of tumor-infiltrating lymphocytes, the state of necrosis, and mutations to the tumor-suppressor gene PBRM1 form a biomarker signature that may predict how patients with renal cell carcinoma will respond to immunotherapy, according to a novel study published by Deutsch et al in Cell Reports Medicine.
The findings suggested that patients who had the presence of tumor-infiltrating lymphocytes and the PBRM1 mutation as well as an absence of necrosis had a higher 5-year overall survival rate than patients who did not have this combination of factors.
Background
Therapies for patients with metastatic clear cell renal cell carcinoma are rapidly evolving and include immunotherapy-based regimens. However, there is currently an unmet need for biomarkers that can help match patients to the regimens most likely to help them. Such biomarkers have been investigated in lung cancer and other cancer types—but have not shown the same predictive ability in patients with renal cell carcinoma.
The classic hematoxylin- and eosin-stained (H&E) pathology slide—the gold standard for diagnosing and staging cancer in medical practices worldwide—has largely been overlooked as a possible source of biomarker information, according to the researchers.
“There are many studies investigating biomarkers for response to immunotherapy using advanced technologies that require expensive machines and experienced technicians. The ability to use information from an H&E slide, pretreatment, to predict [the] overall survival of patients receiving this therapy is extremely powerful, and is something that can be used in resource-poor settings as well,” said lead study author Julie Stein Deutsch, MD, a clinical research fellow in the Department of Dermatopathology at the Johns Hopkins University School of Medicine.
The researchers explained that immunotherapies targeting PD-1 can unleash an immune response against cancer cells and has become a vanguard of cancer therapy. However, because anti–PD-1 immunotherapies do not work in all patients, the new findings could be used to help preselect patients for the most appropriate therapies.
Study Methods and Results
In the new study, the researchers examined H&E slides from 136 samples of metastatic renal cell carcinoma pretreatment to determine whether they could identify new biomarkers from the material. The researchers analyzed 63 pretreatment biopsies obtained from patients who received first-line or later-line nivolumab; 58 biopsies from patients receiving later-line nivolumab or everolimus; and 15 biopsies from patients who were treatment-naive receiving nivolumab plus ipilimumab. The researchers scored each sample for the amount of tumor-infiltrating lymphocytes—which they called TILplus for the new study—and presence of necrosis.
Among the samples in the group of 63 biopsies—and samples from all three groups of patients who received immunotherapy—those who had immune infiltrates such as tumor-infiltrating lymphocytes, macrophages, and plasma cells that were interfacing with the tumor cells (TILplus score of 1) showed improved overall survival compared with those who lacked interfacing with the tumor cells (TILplus score of 0). The researchers noted that median overall survival was 47.9 months in those with a TILplus score of 1 vs 16 months in those with a TILplus score of 0. Further, median progression-free survival was 7.5 months in those with a TILplus score of 1 vs 2.7 months in those with a TILplus score of 0. However, the researchers stressed that TILplus scores were not associated with overall survival among patients receiving everolimus, indicating that the findings were specific to treatment with immunotherapy.
The presence of necrosis was also found to modify the benefits of having immune system infiltration in the tumor cells. In two of the study groups, patients whose tumors had necrosis that covered over 10% of the surface area were found to have a lower rate of overall survival compared with patients who had the same TILplus scores but whose tumors lacked necrosis. The researchers reiterated that combining the TILplus and necrosis scores was not predictive of outcomes for patients receiving everolimus.
“This is important, [since] traditionally, areas of necrosis are often excluded from biomarker studies because [dead tissue] can’t be used for genomic or transcriptomic [analysis],” emphasized Dr. Deutsch. “We show there is important information in that necrotic area that’s conferring some sort of negative disadvantage to patients. It’s important not to overlook these areas when you’re investigating biomarkers that predict how patients are going to do,” he added.
Finally, the researchers looked at PBRM1 mutations and found that they may have been correlated with overall survival but were not associated with TILplus scores. However, a statistical analysis of all three factors found that the combination of H&E scoring with PBRM1 mutation status stratified patients into three groups. Patients who had all three positive factors—a TILplus score of 1, necrosis score of 0, and a PBRM1 mutation—had the highest 5-year overall survival rates, patients with two of the three factors demonstrated intermediate overall survival rates, while those with only one feature had the lowest overall survival rates.
Conclusions
When investigators performed a literature search, they were unable to find other studies that used H&E features as part of tumor characterization using multimodality approaches.
“This demonstrates the underutilization of these insights in biomarker discovery for immunotherapies,” Dr. Deutsch noted.
The researchers plan to further validate their findings in larger groups of patients and potentially in prospective clinical trials.
Disclosure: The research in this study was supported by The Mark Foundation for Cancer Research, Bristol Myers Squibb, a Sidney Kimmel Cancer Center Core Grant, the National Cancer Institute, the National Institutes of Health, the Dana-Farber/Harvard Cancer Center Kidney SPORE, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, the Pan-Mass Challenge, the Hinda L. and Arthur Marcus Foundation, the Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy. For full disclosures of the study authors, visit cell.com.
