By: Chloe E. Atreya, MD, PhD
Each time I meet a patient with a new diagnosis of colorectal cancer with liver metastasis, I experience a hint of excitement – reminiscent of the start of a cross-country race. These are patients with a chance (albeit a small chance) of a cure if we play all our cards right and if the tumor biology is favorable. But when a 28-year-old woman came to us in August 2019 with a near-obstructing tumor in the distal transverse colon and liver masses measuring up to five centimeters, my excitement was tempered by the knowledge that heartbreak was a more likely outcome.
This mother of two toddlers was healthy up until a month prior, when she developed severe anemia, diarrhea and emesis, accompanied by a 25-pound weight loss. We initiated a usual treatment course: FOLFOX chemotherapy followed by repeat imaging. I explained that if the treatment was working, her cancer symptoms should start to improve.
Unfortunately, that’s not what happened. She was becoming progressively weaker and her CEA tumor marker was rising. Repeat imaging showed cancer growth in her liver. We decided to remove her primary colon tumor to enable further systemic therapy. The primary tumor was an aggressive, poorly differentiated adenocarcinoma, with signet ring features, measuring 10 centimeters in diameter. There was no evidence of treatment effect. This did not bode well.
Seeking a needle in the haystack
I referred the patient to the UC San Francisco Cancer Genetics and Prevention Program, but no germline mutations were identified. While the National Comprehensive Cancer Network (NCCN) Guidelines only specify genomic testing for a limited number of tumor mutations, I typically order panel testing with the hope of uncovering something rare yet actionable. In her case, the panel revealed interesting findings: a pathogenic mutation in the DNA polymerase epsilon (POLE) gene and a high tumor mutational burden (TMB). POLE mutation causes a defect in DNA replication that can produce “ultra-mutated” tumors. This is analogous to mismatch repair deficiency (dMMR), where resulting high TMB can tip off a patient’s immune system to recognize a tumor as malignant. The four percent of metastatic colorectal cancers with dMMR is currently the only subset where immunotherapy has proven efficacy.
I presented her case before the UCSF Multidisciplinary Colorectal Tumor Board. The standard recommendation would be to switch to FOLFIRI, but the chance of response after growth through first-line FOLFOX was less than 10 percent. Although we don’t usually invoke experimental options when seeking a cure, the POLE mutation with high TMB provided a rationale for trying immunotherapy. However, experience with immunotherapy for POLE mutations in colon cancer was slim, and the stakes were high.
I had a frank conversation with the patient about treatment options – including the potential for loss of disease control and severe immune-mediated toxicities. With her characteristic courage and conviction, she decided to try immunotherapy. The next possible hurdle was insurance authorization, given that POLE mutation is neither an FDA- nor an NCCN-sanctioned rationale for giving immunotherapy. Luckily, our medical judgment was not questioned.
We started her on nivolumab plus ipilimumab and, thankfully, she had no toxicities. But we were disappointed to see that her subsequent scans showed continued progression, with the dominant liver mass now measuring greater than eight centimeters. However, she suddenly was thriving – with weight gain and energy to keep up with her kids. Something did not add up.
I went back to the Tumor Board. Typically, we do not advise liver resection in the face of cancer progression. But because of the patient’s remarkable clinical improvement, we considered the possibility of pseudoprogression – a phenomenon where a tumor appears larger after immunotherapy treatment because of immune infiltration rather than actual cancer growth. Pseudoprogression is often discussed but rarely observed. Still, we decided to give her the benefit of the doubt and get the tumors out.
No one expected what happened next. Pathology reported that the resected masses were entirely mucin with inflammatory cells – signaling a robust immune response. There were no tumor cells left in the specimen. Zero. Given this amazing finding, the patient decided to pursue surveillance rather than further treatment. That was over a year ago. She continues to do well, with no signs of cancer.
When I say that miracles can happen, this is a patient who comes to mind. POLE mutations are rare, but with colorectal cancer being so common, these cases are out there – and should not be missed. It’s worth the effort to investigate this possibility for the chance to save a life. We wrote up this case along with two other examples of immunotherapy responses in UCSF patients with MMR-proficient colon cancer in a recent issue of Anticancer Research.
Dr. Atreya is a gastrointestinal oncologist and a colorectal cancer researcher with the UCSF Helen Diller Family Comprehensive Cancer Center. She also co-directs the UCSF Integrative Oncology Program at the UCSF Osher Center for Integrative Medicine.
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