Although immunotherapy has improved outcomes across a growing number of cancers, its success in unselected cases of prostate cancer has been limited. According to data presented at the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium, however, investigators have identified a group of patients with early-stage prostate cancer who may represent a viable target for immune checkpoint and DNA-damaging therapies.1 Analysis of of two separate gene-expression assays has shown this subgroup of patients to be at increased risk of developing metastatic disease, but it has targetable immune biology.
These are patients with aggressive prostate cancer who relapse quickly. They should receive more treatment upfront to have a chance of cure.— Eileen Parkes, MB, PhD
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“This poor-prognostic subgroup, which represents 17% of primary prostate cancers, has chromosomal instability, upregulation of immune gene expression, and checkpoint gene expression,” said Eileen Parkes, MB, PhD, Academic Clinical Lecturer at the School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast in Northern Ireland. “These patients need early systemic treatment for their disease and may therefore represent a target population for immune checkpoint targeted therapies and/or DNA-damaging therapies for their prostate cancer.”
As Dr. Parkes reported, although more than 300,000 men die every year of prostate cancer, there are very few early-stage treatments. Treatment has been primarily hormone-based, said Dr. Parkes, who noted that early chemotherapy has recently been introduced, but with limited effect.
“Immune checkpoint inhibitors have shown minimal impact in prostate cancer, which has a low tumor mutational burden compared with diseases in which immunotherapies do well, such as melanoma and non–small cell lung cancer,” said Dr. Parkes. “With single-agent nivolumab [Opdivo], we’ve seen few or no responses, and with pembrolizumab [Keytruda], we’ve seen only partial responses in metastatic castrate-resistant prostate cancer.”
Integrative Clustering Analysis
Dr. Parkes and collaborators, Almac Diagnostics, previously developed and validated a 70-gene expression assay to identify a molecular subgroup of primary prostate cancers with biology similar to metastatic disease—the prostate cancer metastatic assay.2 Patients with the highest score on the assay demonstrated a significantly increased risk of developing metastatic disease, as well as biochemical recurrence.
“These are patients with aggressive prostate cancer who relapse quickly,” said Dr. Parkes. “They should receive more treatment upfront to have a chance of cure.”
Using data from The Cancer Genome Atlas, Dr. Parkes and colleagues then conducted an integrative clustering analysis within a cohort of primary prostate cancers, including 488 matched samples. The investigators used RNA-sequencing data and examined promoter methylation, somatic mutations, and copy number variation data. Samples were scored with the prostate cancer metastatic assay.
The clustering analysis divided the samples into four subgroups (C1, C2, C3, C4). C1 and C4, representing approximately 42% of all samples, had high metastatic scores on the prostate cancer metastatic assay. In addition, these subgroups had marked promoter hypermethylation and somatic mutations of genes known to be involved in aggressive prostate cancer. The C4 cluster was also marked by overexpression of immune genes, said Dr. Parkes.
The investigators then applied a second assay, the immune-based DNA damage–repair deficiency assay, to the cohort. This is used to identify solid tumors with loss of DNA-repair ability.3 Dr. Parkes, noted that when cells are DNA damage repair–deficient, the damaged DNA is sequestered into the cytoplasm instead of being repaired. This results in activation of the cGAS-STING pathway, which leads to expression of immune genes.4 According to Dr. Parkes, DNA damage repair deficiency is also associated with lymphocytic infiltration and upregulation of immune checkpoints. When applied to the four subgroups, the damage repair deficiency assay showed high scores for the C4 samples as well.
“These samples were genomically unstable, with high 8q gains in particular,” said Dr. Parkes. “In addition, 38% of C4 samples have TP53 mutation compared with 7% of C1 samples.”
As Dr. Parkes reported, patients in this “metastatic immune” subgroup are likely to relapse much quicker than those in other subgroups with poor survival. When compared with all other clusters, patients in the C4 subgroup had a hazard ratio for recurrence of 2.586 (95% confidence interval [CI]: 1.392–4.803; P = .003). Other factors such as Gleason score were not associated with differences in outcome.
Nevertheless, the unique biology of this particularly aggressive prostate cancer, which represents approximately 17% of all prostate cancers, may leave the door open for various treatment strategies. Assessment of immune checkpoint gene expression showed significant upregulation of programmed cell death ligand 1, cytotoxic T-lymphocyte–associated protein 4, indoleamine-pyrrole 2,3-dioxygenase, mucin domain 3, and lymphocyte-activation gene 3 in the metastatic immune subgroup.
“This is a who’s who of immune checkpoint targets, suggesting combination immunotherapy could be considered in this group,” said Dr. Parkes. “In keeping with this marked overexpression of immune checkpoints, we also saw a high rate of infiltration of white blood cells and higher expression of STING.” ■
DISCLOSURE: Dr. Parkes has received travel funding from Almac Diagnostics.
1. Reilly E, McCavigan A, Walker SM, et al: Exploration of the cGAS-STING pathway in prostate cancer. 2018 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 103. Presented January 27, 2018.
2. Walker SM, Knight LA, McCavigan AM, et al: Molecular subgroup of primary prostate cancer presenting with metastatic biology. Eur Urol 72:509-518, 2017.
3. Mulligan JM, Hill LA, Deharo S, et al: Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. J Natl Cancer Inst 106:djt335, 2014.
4. Parkes EE, Walker SM, Taggart LE, et al: Activation of STING-dependent innate immune signaling by S-phase-specific DNA damage in breast cancer. J Natl Cancer Inst 109:djw199, 2016.
Ezra Cohen, MD, PhD
Discussant for the abstract, Ezra Cohen, MD, PhD, of the University of California, San Diego, pointed out that although this subgroup may be responsive to checkpoint inhibition, it may not necessarily be anti–programmed cell death protein 1 (anti–PD-1) therapy.