It's in the Genes

During winter, Pam Fluck becomes desperate to stay warm. Even with a space heater near her feet at work and warmers stuffed into her gloves and shoes, she still experiences constant tingling in her fingers and toes from the cold. In winter, she says, she walks like someone decades older. “I am always happy to see spring come,” she adds.

Although Fluck, 50, has been in remission from breast cancer for seven years, the damage to her peripheral nerves (called peripheral neuropathy) from the taxane she was treated with serves as a constant reminder. Taxanes, a group of cancer drugs that includes Taxol (paclitaxel) and Taxotere (docetaxel), commonly cause neuropathy in the extremities, which includes symptoms ranging from mild loss of sensation to occasional severe episodes of pain and weakness.

Not all patients react so dramatically to such treatments. In 2010, Adrienne Elder, now 73, was also treated with a taxane after she received a breast cancer diagnosis. She experienced little neuropathy, other than feeling like a string was pulled tightly around her toes and hypersensitivity in the balls of her feet, effects that diminished after about 18 months. But she did have other serious problems associated with her treatments.

Because tumors and people are very distinct genetically, the same therapy affects them differently. “I will give the same drug and same dose to different patients; one will have no neuropathy, and the other will have substantial neuropathy,” says Bryan P. Schneider, MD, associate director of the Indiana Institute for Personalized Medicine at the Indiana University Melvin and Bren Simon Cancer Center. “It’s very difficult to predict.”

To optimize cancer therapy for patients with different genetic profiles, Schneider and his colleagues are using new genetic techniques in identifying inherited gene variations connected with a particular reaction to cancer treatment. They hope to discover which patients will have the greatest benefit and fewest side effects from particular chemotherapy drugs.

“I will give the same drug and same dose to different patients; one will have no neuropathy, and the other will have substantial neuropathy.”

Schneider is attempting to identify genetic biomarkers for predicting which patients are susceptible to taxane-induced neuropathy. Such work is possible because of advances stemming from the U.S. Department of Energy’s and National Institutes of Health’s Human Genome Project (HGP), which identified the sequences of 3 billion chemical base pairs that make up human DNA. Scientists have applied that foundational work to cancer research, studying how tumors are as unique as each person and investigating which therapies will be most effective.

The HGP identified the order that the bases occur along the genome, which enables researchers such as Schneider to use an analytical tool called a genome-wide association study, or GWAS, to detect variations in inherited DNA called single nucleotide polymorphisms (SNPs).

Schneider’s team conducted a GWAS that collected genetic data from 2,204 patients with early-stage breast cancer, all of whom had received a taxane in a clinical trial. After scanning the patients’ genomes for 1.2 million SNPs, Schneider’s team reported that patients with a variation in the gene RWDD3, which helps the body deal with physiologic stress, were more likely to experience taxane-induced neuropathy.

By using a GWAS, researchers can examine hundreds of thousands of SNPs in thousands of people. Combining thousands of research subjects with, say, 1 million SNPs, helps prove that the genetic variants uncovered by a GWAS are actually linked to the disease. This type of study has limitations, however. When researchers are searching so many SNPs, they are also likely to find associations that happen by chance alone.

Another limitation of such trials, Schneider explains, is that by analyzing data from a clinical trial where multiple physicians are treating patients, researchers must rely on those investigators for vital information about patients, such as the severity of neuropathy.

Schneider’s findings could lead to a test that would help predict which women are at high risk for developing neuropathy. Such a test could help doctors and patients consider side effects earlier and make better dosage decisions.

In Fluck’s case, her neuropathy started to flare after the second of four treatments. She says that her oncologist offered to lower the dose on her last treatment in hopes of alleviating her nerve pain, but Fluck declined, saying she’d rather get it over with.

“It’s always better to know ahead of time. Even if your hands are tied and you have to use that drug anyway, you can still monitor the patient much more closely.”

Pediatric patients pose a specific challenge for researchers trying to understand the genetics of cancer. Most adult cancer patients receive a standardized dose that depends on the cancer type, stage and overall health status. Pediatric patients add complexity, says Smita Bhatia, MD, chairwoman of City of Hope’s Department of Population Sciences and director of the Center for Cancer Survivorship in Duarte, Calif.

When treating children, oncologists must determine dosages by considering the child’s height, weight and body surface area, she says. As patients get older, they may face chemotherapy-related health problems, such as second cancers, cardiac issues, bone death and stroke.

Bhatia leads a research team that has been analyzing inherited genetic variations in survivors of childhood cancer who have developed complications of treatment they received in the 1980s and 1990s. The team is focusing on a variant of the carbonyl reductase gene (CBR), which is in charge of enzymes that help the body break down anthracyclines, a common class of chemotherapy drugs. Early results suggest that survivors who carry a particular variant of the gene are more likely than those without the variant to develop congestive heart failure even when they receive low- to moderate-dose anthracyclines. Since the same chemotherapeutic agents used in children are also used in adults, her results may apply to adult patients, as well.

Bhatia says she hopes to find a predictive blood test to identify patients with the CBR gene variant. “It’s always better to know ahead of time. Even if your hands are tied and you have to use that drug anyway, you can still monitor the patient much more closely and do other things to prevent heart failure or toxicity from happening, such as using a heart protective agent,” says Bhatia. “This is where the field is going, more tests like this.”

Some genetic mutations in tumors cause people to have no response to a particular cancer therapy. For instance, a study looked at 59 mutations in 945 people for RUNX1, a gene essential for blood cell maturation. Patients with acute myeloid leukemia with RUNX1 mutations did not respond to the chemotherapy. The study authors said it was too early to use such data in clinical decision making, but if the research holds up, it could save patients from side effects of therapy that wouldn’t benefit them.

However, such genetic biomarkers help researchers understand tumor biology and may provide insight into existing or prospective drug treatments.

Schneider reminds his colleagues that no two people are the same. “If you ask a group of first-graders if people are different, they all answer ‘yes.’ Sometimes, I think doctors forget that.”