Cleveland Clinic
Specialty Services Symposium: Medical, Surgical and Quality
June 3, 2008 InterContinental Hotel & Bank of America Conference Center | Cleveland, Ohio

Tailored Cancer Care

A Vaccine to Prevent Cancer?

While many researchers are developing tools to individualize cancer treatment, Cleveland Clinic immunologist Vincent Tuohy, PhD, wants to prevent cancer with vaccines, just as polio and measles are prevented today.  According to Dr. Tuohy, childhood vaccinations have been perhaps the biggest public health success in history, preventing hundreds of millions of cases of debilitating illnesses.

"The childhood vaccination program serves as an instruction manual for how to prevent disease," he says. And yet, for adults, just a few preventive vaccines exist - namely, for the seasonal flu and shingles.  "It's a glaring hole in our healthcare system," he says.  "We stop stimulating the immune system after childhood, but there's no good reason why that is."

Dr. Tuohy set out to create an injection that would train the immune system to prevent tumors from establishing themselves. Childhood vaccines target diseases caused by bacteria and viruses - outsiders that invade the body. But cancer cells aren't foreign invaders; they are self-cells gone bad.  The challenge for designing preventive cancer vaccines, then, is to train the immune system to recognize cancerous cells while not attacking normal, healthy cells.  To do so, Dr. Tuohy searched for protein targets that distinguish cancer cells from healthy cells.

He started with breast cancer.  Searching the literature, he struck on a possible target for a vaccine - a protein involved in milk production called alpha-lactalbumin.  The majority of breast tumors carry the protein, but normal breast tissue expresses it only during lactation. Since the vast majority of breast cancers occur after women reach age 40, Dr. Tuohy reasoned that women in this age group have a greater need to be protected from breast cancer than to preserve lactation.  He proposed that a vaccine targeting alpha-lactalbumin would protect against breast cancer with no damage to normal tissues as long as lactation is avoided.

Dr. Tuohy's lab group made a batch of an experimental vaccine that contained alpha-lactalbumin protein.  The researchers injected the vaccine into 2-month-old mice bred to be at very high risk of developing breast tumors, hoping the vaccine would train the rodents' immune systems to recognize and attack the cells carrying alpha-lactalbumin.

The strategy worked.  At 10 months of age, none of the mice receiving the vaccine had developed cancer, whereas all mice that had not received the vaccine displayed large tumors.  Further, as published in July 2010 in Nature Medicine, the vaccinated mice did not have inflammation in their breast tissue, a sign that the vaccine had not spurred a reaction against healthy tissue.

While many scientific hurdles remain and human studies are at least five years off, Dr. Tuohy is convinced that a vaccine to prevent cancer can eventually be made to work in people.  "We did it in one mammal, we can do it in another," he says.  "If we're successful, the rewards will be enormous."

With new tools and treatments, one size does not fit all.

When Jennifer Teeter was diagnosed with breast cancer, one of her big fears was of the treatment itself.  "I was terrified of chemotherapy," says the Cleveland Heights, Ohio, resident, who was treated at Cleveland Clinic in 2008.  "I had seen people go through it and I knew the side effects."  She'd lose her hair, lose weight, feel nauseous.

Ms. Teeter opted for surgery followed by radiation therapy.  A few weeks later, the 48-year-old executive assistant finally received good news: She didn't need chemotherapy after all.  A newly available test of a handful of genes in her tumor showed a very low risk that her cancer would recur if she followed the radiation with anti-estrogen therapy.  Chemotherapy was not necessary.

"The test allows us to avoid using chemotherapy when we don't need to," says Halle Moore, MD, who treated Ms. Teeter at the Taussig Cancer Institute.  "Among breast cancer patients with estrogen-sensitive tumors and no lymph node involvement, we can now omit chemotherapy for about half."

Cleveland Clinic clinicians, like Dr. Moore, are bringing exciting research results from around the country and translating them to better patient care.  Just a few years ago, oncologists didn't have tools to peer at a tumor's genetic errors.  But Dr. Moore's good news for Ms. Teeter says something about cancer care's growing sophistication, which springs from a flood of information regarding which genes malfunction in several different types of cancer.

"Research is making it increasingly clear that even within the same cancer, differences at the molecular level are critically important," explains Robert Dreicer, MD, Chairman of the Department of Solid Tumor Oncology at Cleveland Clinic.  "We are now entering an era in which therapies can be tailored to take advantage of these differences, thus providing hope that this will translate into meaningful improvement in patient outcomes."

Charting a Course

New knowledge about the genetics of lymphoma is helping patients decide on a treatment course.  In some lymphomas, white blood cells possess a genetic malfunction in which a snippet of one chromosome ends up in the wrong place, attached to a second chromosome.  The switch is known as a BCL-2 translocation.  Patients with a BCL-2 translocation have a worse prognosis than patients without it.  And now a laboratory test can determine which lymphoma patients possess the BCL-2 translocation.

For those who do, their oncologist may suggest different treatment, says John Sweetenham, MD, Vice Chair for Clinical Research at the Taussig Cancer Institute.  "The blunt, one-size-fits-all approach to treatment is giving way to a more individualized approach," he says.

Another new genetic test can help doctors steer their pediatric cancer patients away from a treatment that may do more harm than good.  For children with acute lymphoblastic leukemia, a mainstay drug called thiopurine 6-mercaptopurine can help patients live longer.  But in a subset of children the drug also can suppress bone marrow function.  Now there's a test for a gene involved in metabolizing the drug. For patients with low gene activity, the test steers clinicians away from prescribing the drug, protecting children from this dangerous side effect.

Although just a few such tests are available now, many more are being developed.  And they're desperately needed: According to a 2008 report from the National Institutes of Health (NIH), prescribed cancer treatments are effective for only 25 percent of cancer patients.  That is, a whopping 75 percent of cancer patients may be receiving drugs - often with harsh side effects - that do little to beat back their cancer.  And cancer isn't the only disease with such a poor record.  Commonly prescribed medications for diseases such as diabetes, depression and asthma are effective for only approximately 60 percent of patients, according to the NIH report.  The report also said that, although a small number of important genomic tests have reached the market, "early expectations for the field have not yet materialized."

Charis Eng, MD, PhD, Chair of the Genomic Medicine Institute and Director of the Center for Personalized Genetic Healthcare at Cleveland Clinic, agrees that expectations for genomic medicine have been sky-high.  But she's optimistic that the past decade of basic science has laid the groundwork for an explosion in individualized information for cancer patients and their physicians.

"Genomic medicine, drawing from both genetics and genomics knowledge, is obviously the tool we need to individualize oncology," she says.  "It will help us be proactive and personalize prevention measures for those at high risk of cancer, while also helping us individualize drug treatment and surgery decisions."

Cancer is different from other diseases, such as diabetes.  Some gene alterations occur only in the cancer cells, not the patient's normal cells.  Dr. Eng says that testing for those gene alterations or tumor signatures will drive more and more cancer treatment decisions in the future.

There is a different type of genetic alteration that occurs in every cell of a patient's body and can be passed on through families.  Because of research in the past decade, looking at the set of genes a person has inherited from his or her parents can now help steer some individuals toward more aggressive screening for cancer, detecting cancers at early and curable states, as well as tailoring prevention.

Colon cancer, for instance, can run in families, triggered by inherited gene alterations.  About 3 percent to 10 percent of colon cancer cases fall in this category, according to Dr. Eng.  The most common hereditary colon cancer syndrome in adults is Lynch syndrome. If an individual has family members with colon cancer or any other Lynch syndrome cancers (endometrial or ovarian), a genetic test can determine if they, too, are at high risk.  The test looks for telltale genetic mutations that define Lynch syndrome. These mutations affect the ability to repair minor damage to DNA. Humans possess a whole set of genes to fix such damage, but in Lynch syndrome, the damage can accumulate unchecked, leading to colon, ovarian and endometrial cancers.  "The most reliable way of comprehensively searching for Lynch syndrome is to look for problems with the repair proteins in the colon cancer cells.  At Cleveland Clinic, because of multidisciplinary efforts from several institutes - Taussig, Digestive Diseases Institute, Pathology and Lab Medicine, Genomic Medicine Institute - all colon cancers removed on the main campus are tested," says Dr. Eng.

"We catch 80 percent of all Lynch syndrome in this manner," she adds.  Patients who have a positive test are contacted and referred to a genetics clinic.  She recommends that individuals with the Lynch syndrome gene begin screening for colon and endometrial cancers much earlier and more often than recommended for the general population.  "Polyps turn into cancer very quickly in people with Lynch syndrome," Dr. Eng says.  "You can call this tailored screening for cancer."

Testing for Lynch syndrome mutations can drive treatment decisions as well.  The standard chemotherapy drug 5-FU is not effective for colon cancer patients with Lynch syndrome (or for colon cancer patients with the same mutation that is not inherited, as in Lynch syndrome, but is limited to their cancer cells).  Patients with the mutation can avoid a round of debilitating 5-FU treatment and choose a different treatment instead.

As for the near future, Dr. Eng expects whole-genome sequencing to become commonplace in medical care.  A whole-genome sequence reads every letter of DNA in a person's genetic code, highlighting possible trouble spots that lead to increased risk for cancer or other diseases.  The cost of this, too, is dropping rapidly - Dr. Eng says that a whole-genome sequence now costs just $2,000 in the research setting at Cleveland Clinic and other academic institutions.  But doctors have only a nascent understanding of that mass of information.  "We need to wisely understand what it all means, and wisely use that information to guide prevention and treatment," she says.

As for Ms. Teeter, she's convinced of the wisdom and benefit of tailored treatment.  "I was lucky. When I got my test results, I got to hear what I wanted to hear," she says.  "If I had been diagnosed a few years earlier, in all likelihood we would have opted for chemotherapy."



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