Frontline Cancer: Knowledge is power; Leveraging genetic cancer predispositions

FRONTLINE CANCER:

When cancer hits home, people want to know why. Cancer risk involves many well-understood environmental injuries such as cigarette smoke or overexposure to sunlight, but there is a complex interplay between environmental exposures, genetic backgrounds, and sometimes, just bad luck that can spur the development of all cancers.

Fortunately, our ability to discover inherited genetic differences that increase cancer risk, including site and type of cancer, has grown exponentially over the past few years, along with our understanding of the familial and genetic basis of cancer.

Celebrities have helped demystify familial aspects of cancer, such as when Angelina Jolie announced she had a mutation in the BRCA1 gene, putting her at risk for hereditary breast and ovarian cancer (HBOC). This risk is usually from a deleterious mutation in a single gene that is easy to detect, and detection has revealed these mutations to be far more common than previously suspected.

The good news is that the genes do not completely define our destinies, and not every person who carries a mutation in the family will get cancer, known as “penetrance.”

Another familial predisposition to cancer of the colon, uterus, ovaries, and a few other organs is called Lynch syndrome. This disease was personal to Rick Boland, M.D., who recently joined the UC San Diego Moores Cancer Center as a special advisor for the hereditary cancer program. He was among the first to recognize this entity; he thought the cancer deaths of several of his own family members in their 20s probably had a genetic explanation, which he then began researching.

By the 1980s he gave a name to this familial syndrome, followed by the discovery of the first Lynch gene (MSH2) by Richard Kolodner, Ph.D., Director of Ludwig Institute for Cancer Research, UCSD. What became immediately clear was that the biology and clinical behavior of neoplasia in this syndrome was strikingly different than other familial and non-familial cancer.

For example, colon cancer emerged from premalignant polyps at warp speed, making it exceedingly difficult to detect and resect with standard colonoscopic screening guidelines (every 5-10 years). This phenomenon led to the germline syndrome’s initial name — hereditary nonpolyposis colorectal cancer, which uniquely suggested that these cancers didn’t evolve from premalignant polyps.

Actually, they do usually begin as polyps, but the nature of this disease causes a 100-fold increase in mutation accumulation rate, so the polyps grow from undetectable to invasive cancer in just a few months, thereby missed by traditional interval screening exams.

In a clinical study to determine optimal screening, patients at high risk for colorectal cancer enrolled into a surveillance program of colonoscopy every 3 years. After the discovery of the Lynch syndrome genes, the investigators determined which patients had the syndrome and found that a 3-year surveillance interval was insufficient to prevent cancer deaths in those with this syndrome, whereas it was effective in the other high risk patients.

Revising guidelines in the Lynch syndrome group to annual surveillance virtually eliminated the excess colon cancer risk and death.

Rick actually identified a unique mutation of MSH2 in the DNA from his cousin, and a new era began for his family. Following decades in which most mutation carriers in his family died of cancer, the current mutation carriers have had more cancers, but remarkably no one in his family has died from cancer due to vigilant surveillance prompted by knowledge of the mutation.

Knowing who carries the mutation has permitted broader awareness of the extent of this syndrome. Remarkably, with the availability of simple testing measures, even the aggressive asbestos-related malignant mesothelioma was added to the Lynch syndrome cancer spectrum last year. This required guideline updates and planned National Comprehensive Cancer Network (NCCN) panel restructuring, led by UCSD colleague and panel vice chair, Samir Gupta, M.D., to keep pace with the rapidly evolving landscape of this hereditary cancer complex.

Likewise, the list of cancer types associated with other familial mutations is expanding; for example, the BRCA2 mutation, which is mostly associated with breast and ovary cancer, is now unequivocally linked to increased risks of aggressive prostate and pancreatic cancer. Knowing makes a difference and having this information not only helps optimize prevention, but also can lead to transformative precision and immune therapy in cancer patients with identified “germline mutations.”

Initially, it was difficult and expensive to do the appropriate genetic testing process for familial cancers. However, now it is relatively inexpensive and simpler with remote web-based genetic education and counseling being developed, including through recent national SU2C initiatives in pancreas cancer co-led by investigators at Moores and a handful of other NCI-designated comprehensive cancer centers in several states.

Accurate and cost-effective testing of others in the family, a process referred to as “cascade” testing, permits us to focus on effective prevention agents and interception. Getting the best information has permitted physicians to target preventive measures to those who will benefit from them, and not overburden family members who do not carry the mutation, typically half of the at-risk family.

Recent studies have shown that more than 1 of every 300 people in the U.S. population have Lynch syndrome (!), but fewer than 5 percent know it. We cannot advise people at elevated cancer risk to seek beneficial preventive measures unless we know who needs them. Having overcome much of the anxiety and embarrassment associated with familial cancer syndromes, we have yet to implement optimal testing. Giving the precise transformative therapy and preventive care needed for germline syndromes will make a difference in the lives of our patients and families.

Thanks to Rick Boland, M.D., who has a long and successful track record of research specifically in hereditary diseases, and who provided content and insights for this article. In subsequent columns, we will discuss some of the evolving developments in the area of the familial basis of cancer. Each cancer is linked to different cancer predisposing genes, and each new discovery leads to new ideas about prevention and new drugs for treatment.

— Scott M. Lippman, M.D. is director of UC San Diego Moores Cancer Center. You can reach him by e-mail at mcc-dir-lippman@ucsd.edu