The Angelina Jolie Effect

stock-photo-16854195-premiere-of-sony-pictures-salt-arrivalsAngelina Jolie’s willingness to bravely publish her saga, as she confronts the risk of a nefarious form of cancer, has focused international attention upon the phenomenon of genetic predisposition to cancer.

The term BRCA, coined by investigators from Berkeley and Europe, described an inherited predisposition to cancer. Years of research came to fruition in the early 90s when geneticist Mary-Claire King and her collaborators recognized that patients who lacked DNA repair capacity tended to accumulate chromosomal damage that ultimately lead to cancer.

The BRCA genes (1 and 2) are part of the genomic fidelity system. Just like it sounds, these DNA repair enzymes maintain the “fidelity” or trueness of your makeup. Everyday our bodies are exposed to mutations. Radon in the atmosphere, carcinogens, even our dietary intake regularly injures our chromosomes. In response, we marshal defenses that recognize, remove and repair the damaged elements before they can be transmitted to the next generation of cells. When these BRCA genes are absent or silenced, the normal wear and tear goes unrepaired. Over a lifetime, this leads to a triggering mutation and cancer.

BRCA genes are like the Zamboni machines that clean up the ice in-between periods in a hockey game. Imagine what a Stanley cup game would be like if the ice was so dug up that the players took a tumble every time they skated toward the goal.

Ms. Jolie’s chromosomes are like the ice, but her Zamboni machine isn’t working.

So why would someone like Angelina Jolie get cancer? The reason why patients with the BRCA1 or 2 mutation get breast and ovarian cancer over other types of cancer remains somewhat of a mystery. But the reason that they get cancer at all is quiet clear. They accumulate damage they can’t repair.

That being the case, what happens when we introduce DNA damage intentionally? The answer is: patients with BRCA1 and BRCA2 respond to chemotherapy often quite dramatically. It is the very fact that cells cannot repair damage, which makes them hypersensitive to DNA damaging drugs like alkylators (cytoxan), platins (cisplatin and carboplatin) and ionizing radiation (x-rays). Indeed, tumors that carry DNA repair deficiencies are among the easiest to treat with conventional cytotoxics. Thus, the very reason that these patients develop cancers is the Achilles heel that makes their tumors drug sensitive.
Interestingly, BRCA1 and BRCA2 positive patients don’t only get breast and ovarian cancer; they can also develop melanoma, lymphoma and other tumors.

The importance of the BRCA discovery has been important on many levels. First and foremost it has enabled us to develop screening techniques to identify the at-risk populations that allows them to undertake preventative measures. Second, it has granted an insight into carcinogenesis and the concept of genomic fidelity. Third, it has provided new therapeutic options for these patients and all patients with cancers that have “BRCA-ness.”

Finally, it has opened up a field of investigation that connects cancer with other long-recognized disease states like the pediatric condition Fanconi’s anemia. It only reminds us again that cancer is but one part of a continuum of human diseases.

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.

7 Responses to The Angelina Jolie Effect

  1. Elaine LaMonk says:

    Are BRCA patients at a higher risk of developing other cancers as a result of having chemotherapy and radiation?

    • robert nagourney says:

      Good point. Patients with BRCA mutations are indeed at higher risk for cancer from virtually any genotoxic insult. Even diagnostic Xrays can carry some risks. This is why breast MRI has been used in in many centers in known BRCA(+) patients to avoid overly frequent mammograms. Cancers of the prostate, pancreas and melanoma are also more common for the same reason.

  2. Elaine LaMonk says:

    What do you think about PARP inhibitors?

    • robert nagourney says:

      PARP (Poly ADP Ribose Polymerase) is an enzyme that participates in the repair single strand DNA breaks. Patients with BRCA lack Homologous Recombination Repair associated with double strand DNA breaks. When BRCA patient’s tumors are exposed to PARP inhibitors, the cells then suffer a double deficiency that can result in cell death. The phenomenon is known a synthetic lethality. These agents have been under investigation in our lab for many years and we are very interested in their application as single agents but even more so in combination with other drugs, where we have seen significant synergy.

  3. A Netherlands abstract, of a 515 women study, is supposed to be presented at the ASCO trade show this weekend that looked at women with the BRCA1 and BRCA2 mutated genes who had been diagnosed with breast cancer.

    According to the abstract, risk reducing mastectomy in BRCA1 and BRCA2 mutation carriers with a history of unilateral breast cancer significantly reduced the risk of developing breast cancer in the other breast. However, the outcome regarding overall survival is insufficiently known.

    The 10 year overall survival was 80% for the non-risk reducing mastectomy group and 90% for the risk reducing mastectomy group. The conclusions were that risk reducing mastectomy in BRCA mutation carriers with unilateral breast cancer reduces contra-laterial breast cancer incidence and is associated with improved overall survival.

    However survival was improved was not by much. Further research is needed to identify potential prognostic factors for this survival benefit.

  4. Victoria says:

    It is highly useful for me. Big thumbs up for this blog post!

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