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Specific form of CYP3A7 gene associated with poor outcomes for patients with several cancer types

Among patients with breast cancer, lung cancer, or chronic lymphocytic leukaemia (CLL), those who had a specific form of the CYP3A7 gene (CYP3A7*1C) had worse outcomes compared with those who did not have CYP3A7*1C, and this may be related to how the patients metabolise, or break down, the therapeutics used to treat them.

The study was published in Cancer Research, a journal of the American Association for Cancer Research.

The CYP3A7 gene encodes an enzyme that breaks down all sorts of naturally occurring substances—such as sex steroids like oestrogen and testosterone—as well as a wide range of drugs that are used in the treatment of cancer, according to Olivia Fletcher, PhD, a senior investigator at the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research in London.

She went on to explain that the CYP3A7 gene is normally turned on in an embryo and then turned off shortly after a baby is born, but individuals who have one or more copy of the CYP3A7*1C form of the gene [the CYP3A7*1C allele] turn on their CYP3A7 gene in adult life.

To find out whether the CYP3A7*1C allele was associated with outcome for patients with breast cancer, lung cancer, or CLL, Fletcher and colleagues analysed DNA samples from 1,008 breast cancer patients, 1,142 patients with lung cancer, and 356 patients with CLL for the presence of a single nucleotide polymorphism (SNP), rs45446698.

Fletcher explained that a SNP is a type of genetic variant and that because of the way that we inherit our genetic material from our parents, we tend to inherit clusters of geneti variants.

She went on to say that rs45446698 is one of seven SNPs that cluster together, forming the CYP3A7*1C allele.

The researchers found that among the breast cancer patients, rs45446698 (and, therefore, the CYP3A7*1C allele) was associated with a 74 percent increased risk of breast cancer mortality.

Among the lung cancer patients, it was associated with a 43 percent increased risk of death from any cause, and among the CLL patients, it was associated with a 62 percent increased risk of disease progression.

Patients who were treated with a chemotherapeutic broken down by CYP3A7 tended to have worse outcomes compared with those treated with other chemotherapeutics, but the difference was not statistically significant.

“We found that individuals with breast cancer, lung cancer, or CLL who carry one or more copy of the CYP3A7*1C allele tend to have worse outcomes,” said Fletcher.

“One possibility is that these patients break down the drugs that they are given to treat their cancer too fast. However, further independent studies that replicate our findings in larger numbers of patients and rule out biases are needed before we could recommend any changes to the treatment that cancer patients with the CYP3A7*1C allele receive.”

“Even though we did not see a statistically significant difference when stratifying patients by treatment with a CYP3A7 substrate, the fact that we see the same effect in three very different cancer types suggests to me that it is more likely to be something to do with treatment than the disease itself,” added Fletcher.

“However, we are looking at ways of replicating these results in additional cohorts of patients and types of cancer, as well as overcoming the limitations of this study.”

Fletcher explained that the main limitation of the study is that the researchers used samples and clinical information collected for other studies. Therefore, they did not have the same clinical information for each patient, and the samples were collected at different time points and for patients treated with various chemotherapeutics. She also noted that the team were not able to determine how quickly the patients broke down the therapeutics they received as treatment.

Source: AACR



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