Why do some patients with metastatic cancer survive much longer than others? That question (see NPR article) launched a study called NEER (Network of Enigmatic Exceptional Responders) in 2018. It included volunteers with remarkably long survival after being diagnosed with aggressive metastatic cancer (e.g. 12 years after stage IV lung cancer, 9 years after stage IV pancreatic cancer). 6 years later the first of our studies was published with some potentially useful hints.
In addition to extensive review of their clinical history we performed multiple measurements including genomic sequencing of each of the participants germline genome. Among the questions it enabled us to ask was: Is a predisposition to autoimmunity associated with outlier responses to cancer therapy? There had been previous studies of the responses to treatments with checkpoint inhibitors (like Keytruda/Pembrolizumab) that suggested that autoimmune disease (e.g. thyroiditis) or a polygenic risk score for an autoimmune diseases (e.g. psoriasis) was associated with longer survival. Would that finding generalize to patients treated with chemotherapy and would it be significant in our comparatively small study of extreme outliers?
To answer that question we used Polygenic Risk Scores, defined in prior studies rather than creating our own, to allow comparison to those prior studies to measure proclivity to autoimmunity. For contrast we picked classical autoimmune disease (e.g. thyroiditis, type 1 diabetes mellitus, psoriasis), suspected autoimmune diseases without much inflammation (e.g. multiple sclerosis) and inflammatory diseases which have different mechanisms such as Crohn’s Disease/Ulcerative Colitis (i.e. IBD).
Most intriguing in this study were three findings:
- The association of PRS scores with exceptional cancer response was at least a strong with traditional chemotherapy as in those patients who had checkpoint inhibitor treatment (i.e. treatment specifically targeting immune response). These associations were significant across a highly diverse group of cancers.
- Adding T1DM the other autoimmune diseases for which PRS scores measured with regard to cancer survival and specifically to the outliers in this study. The T2DM PRS score includes far less SNPs (locations on the genome) than any of the other PRS scores which therefore implicates far fewer loci than the other scores.
- Inflammatory bowel disease PRS worked in the opposite direction. That is, a decreased score is associated with exceptional response. Also the majority of our patients had a T1D PRS greater than the mean of typical cancer patients and a low IBD PRS at the same time.
Read the full manuscript here if you are interested in more detail about the population studied and the genes potentially implicated.
This is not the venue to speculate on mechanistic hypotheses, or implications for treatments, but suffice it to say at the very least this study suggests that exploring how to perturb the immune system, independently of the oncogenic or metastatic mechanism or tissue of original, will continue to be fertile ground for cancer research. Identifying the mechanisms driving the outcomes of high PRS autoimmune disease and low PRS inflammatory disease seems particularly exciting given these findings.
Finally a note of thanks. I’ve been fortunate in being generously funded for years by the NIH. However this kind of highly speculative, high-risk research is a bad fit for the standard grant review process. We were fortunate to have critical, philanthropic resources from the Moskovitz Fund for Precision Medicine – a fund generously established by a polymath Harvard Medical School graduate to support the study of exceptional responders to cancer treatments. Without this fund, all the genome sequencing, clinical characterizations and other ‘omics measure would not be possible. If you are interest in further supporting this work, go here.