Why do People get Cancer?

While there are a lot of reasons why people develop cancer, there is a growing recognition that a subset of patients carries genetic predispositions for the disease. Some of these genetic syndromes result in childhood cancers like the retinoblastoma gene or mutations in P53. These abnormalities are so profound that virtually all patients develop aggressive cancers at an early age. However, there is a second group of genetically driven cancers that are being encountered in young and middle aged adult patients. One of the best described is the ovarian/breast cancer syndrome associated with the BRCA 1 and 2 genes. Another group of patients carry a DNA repair deficiency known as mismatch repair or Lynch Syndrome.

Not unlike the BRCA patients, people with mismatch repair have an inability to respond to DNA damage. This failure leads to mutational events that, over the course of a lifetime, can result in cancer. We now know that the BRCA genes may provide therapeutic opportunities as the new class of drugs known as PARP inhibitors can target them. What we are now learning is that the Lynch Syndrome patients may have a similar attribute that can, in some circumstances, render them “hypersensitive” to chemotherapeutics. One such patient has been under my care for the last two years.

This charming 43-year-old patient presented with cancer of the uterus. She was managed by a gynecologic oncology service and received a combination of surgery, radiation and chemotherapy. One year later, she revealed recurrent disease in the right, lower abdomen with involvement in the liver. Impending bowel obstruction lead to surgical exploration, providing my laboratory with tissue for analysis. When I first received the tissue specimen, I was expecting recurrent uterine cancer, the same diagnosis for which she had been treated the year earlier. But, to my surprise, the patient was actually diagnosed with colon cancer. This triggered an analysis of her mismatch repair gene and provided confirmation of Lynch Syndrome.

What I found amazing was that this patient’s colon cancer was sensitive to a two-drug combination that I had never in my career administered for colon cancer. Indeed, in my published work I had consistently identified colon cancer as a bad target for this doublet. Yet, this patient’s tumor was unequivocally sensitive to the combination. Her response was as prompt as it was dramatic — a complete remission within a scant few months. And then, in follow up, her PET/CT revealed a small focus of abnormality, seemingly associated with the colon. With a negative colonoscopy, we waited an additional several months and repeated the study. This time, it was even more evident; there was clearly an abnormality in the left pelvis.

A biopsy provided an unexpected finding. It was cancer, but it wasn’t colon cancer. The patient’s original uterine cancer from two years earlier had recurred, most likely as a residual vestige of tumor from an incomplete resection two years before. The drug response profile was distinctly different, but highly consistent with a profile one might find in a patient with mismatch repair. As we prepared to treat the patient, she developed gastrointestinal bleeding, a workup for which confirmed erosion by the uterine cancer into the bowel wall. We decided to use our findings to treat the patient and initiated a three-drug combination. The patient’s tolerance was excellent and gastrointestinal bleeding stopped immediately.

She is now receiving additional courses of therapy and will be evaluated for response in the coming months. While it is too early to know how well she’ll respond, we are optimistic regarding her outcome. Among the most interesting feature of this and related cases is the fact that the genetic mutation that caused her cancer may be the same genetic mutation that makes it possible for us to treat her.