Breast cancer (BC) is the most common cancer in women. Primary systemic therapy (PST) or neoadjuvant therapy, is used in nonmetastatic breast cancer to treat systemic disease earlier, decrease tumour bulk ideally to a complete pathological response, and reduce the extent of surgery.

There exist some clinical studies associating MTHFR gene allele T and p53 gene allele Pro with toxicity due to chemotherapy in patients of breast cancer and other type of cancerous malignancies, such as hematological malignancies.

MTHFR gene codifies for an enzyme called Methylene Tetrahydrofolate Reductase. MTHFR regulates the pool of intracellular folates for nucleic acid and protein synthesis. Defficiencies in MTHFR protein can lead to defficiencies in DNA repair and polypeptide production, specially in situations where the celular structures are being damaged, for exemple during chemotherapy. Several studies has shown the relationship between MTHFR genetic polymorphisms and toxicity in response to certain drugs.

Clinical studies of Enríquez-Hernández et al. in 2010 with 50 breast cancer patients and those done by Guillem et al. in 2007 with 145 patients of breast cancer and other hematological malignancies (e.g. autologous stem cell transplantation, leukemia, etc.) treated with chemotherapeutic adjuvants such as cyclophosphamide and others (5-fluoracil and methotrexate) showed an association between MTHFR gene polymorphism and a major risk of developing severe side effects (leukopenia, gastrointestinal toxicity, hepatotoxicity, myelodysplasia and acute myeloid leukemia) and other less severe effects (nausea, mucositis, astenia and diarrea).

The polymorphisms related with the chemotherapy-induced side effects described in the MTHFR gene are the following: c.665G>A (or named with the code rs1801133 in clinical data bases) and c.1286T>G (or rs1801131 in clinical data bases).

For the c.665G>A, the AA genotypes on patients treated with chemotherapeutics (such as cyclophosphamide) have an increased risk of developing severe acute toxicity, and patients with the GA genotype have an elevated risk but in a lesser extent than the AA patients.

In a similar way, for the c.1286T>G, the TT genotypes on patients treated with chemotherapeutics have an increased risk of developing severe acute toxicity than the risk suffered by TG or GG patients.

MTHFR polymorphisms could be related to chemotherapeutic severe side effects probably because DNA repair is impaired in circumstances where it is strongly required to restore the important DNA damage caused.

Although both polymorphisms in MTHFR gene are generally associated with risk of toxicity both for breast cancer chemotherapy and for the treatment of other hematologic malignancies (e.g. autologous stem cell transplantation, leukemia, etc.), Guillem et al. proposed that the c.665G>A SNP is more linked to toxicity after breast cancer chemotherapy and the c.1286T>G is more linked to toxicity after hematologic malignancies chemotherapy.

In addition to this two polymorphisms (SNPs) taken independently, there is a risk combinations (or haplotypes) between the two MTHFR SNPs described by Guillem et al. For chemotherapy in breast cancer patients, those presenting the combination c.665A+c.1286T (AT) have a increased risk of side effects, and for chemotherapy in hematological malignancies, the combination or haplotype c.665G+c.1286G (GG) have been associated with an increased risk.

Although these two clinical trials has been conducted mainly for the adjuvant chemotherapeutic cyclophophamide, in the studies another chemotherapeutics adjuvants were tested, such as 5-fluorouracil and methotrexate, and it seems that the conclusions obtained for the treatment with cyclophosphamide can be extrapolated to these other chemotherapeutics.

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