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.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

8 Responses to Why do People get Cancer?

  1. Please advise of the chemotherapies/drugs used in this case. Thanks.

    • The patient is receiving the combination of Irinotecan, Doxil and Cyclophosphamide based upon her specific and unique profile of sensitvity. However, each patient is different and it is difficult to extrapolate one patient’s effective treatment to another patient.

  2. Pingback: Abstract: A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance functional analysis reveals the pathogenic one (? | Oncology Blog


    • There is no guarantee, but if you are well enough to consider further treatment and if we can easily obtain a viable tumor sample for analysis, we would profile your tumor cells to see if there were other treatment options that might provide benefit. I would be happy to discuss the specifics with you.

  4. Gosia K. says:

    I am 34 years old and I have been diagnosed with Sertoli Leydig Cell Tumour in December 2010. Do you think it can be caused by genetic mutation as some studies show there is mutation of DICER1 and sometimes BRCA genes ??

    • Dicer and Drosha are the small interfering RNA regulating enzymes. They influence gene expression through these SiRNA’s or MIr’s. These were first described in 1998 and are now recognized to regulate (totally or partially) up to 50% of all gene expression in humans. One of the leading experts in the field is Carlo Croce, PhD. The question is a fascinating one but one that I am not expert enough to answer authoritatively. You may wish to pursue the work of Dr Croce who has pioneered much of our contemporary understanding of this field. As to the BRCA role, genomic fidelity genes are fundamental to cancer. Their failure, as with BRCA 1 and 2 or Mismatch repair, render genetic mutations unrepaired and detrimental. BRCA mutations are not only associated with breast and ovary but other cancers as well. If you would like to explore the option, you might first examine family history and then, consider BRCA formal testing. This may be more than academic, for the identification of BRCA mutation would have implications for therapy through new classes of drugs known as PARP inhibitors. We are reporting some of our work in this area at the ASCO meeting in Chicago next week.

      • Gosia K. says:

        I would love to pursue the work of Dr Croce if there is any possibility. I will try to get on genetic tests in July when I will be in Poland as I am living in UK and I’m Polish. I know there was some ovarian and breast cancers in family on my mother’s side and one case of stomach cancer on my father’s side only. I also try to get on genetic tests in UK but have to speak to my gynaecological oncologist who cares of me right now in UK.

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