The enzyme Manganese Superoxide Dismutase or MnSOD, encoded by the SOD2 gene is a protein that protects against oxidative damage in cells, such as the damage caused by chemotherapeutic agents, and therefore the SOD2 gene modulates the effectiveness of these therapies.

In recent years clinical trials have been conducted with breast cancer patients from different populations treated with cyclophosphamide and other adjuvant chemotherapeutic agents such as 5-fluorouracil and methotrexate. These studies have shown that polymorphisms in the SOD2 gene are related to a better response to these chemotherapeutics and therefore a better outcome of the disease, with fewer recurrences, at the same time that these genetic variants also have an implication in the toxicity of the therapy.

The polymorphism of the SOD2 gene involved in the response to chemotherapeutics such as cyclophosphamide is called p.Val16Ala or c.47A>G (referred to as rs4880 in the clinical databases). Three different studies have shown the relationship between the G allele (which consists of the substitution of a valine amino acid for an amino acid alanine in the 16th position of the protein) and the resistance to chemotherapy (worse outcome of the disease and greater number of recurrences).

A study carried out by Glynn S. A. et al. in 2010 in patients with breast cancer (248 from the United States and 340 from Norway) showed that patients carrying at least one G allele (genotype AG, Val/Ala offered greater resistance to chemotherapy than those with genotype AA. In addition, patients homozygous for the G allele (genotype GG and therefore presence of 2 alanines in the protein, Ala/Ala) still suffered a worse response than the carriers of a single variant allele, the resistance to cyclophosphamide was even higher. The Ala/Ala genotype significantly increased the risk of failure in the response to chemotherapy and the risk of recurrence of the disease.

Another study with 321 breast cancer patients from the Czech Republic conducted by Hubackova, M. et al. in 2011 corroborated the previous study showing also a negative association between the response to cyclophosphamide and the Ala/Ala genotype. In this study, patients with at least one Val allele had a better prognosis. However, in this study it was also shown that while the Val/Val genotype had a better prognosis after treatment with cyclophosphamide, patients with this genotype had greater toxic side effects than those with Ala/Ala genotype. The hypothesis of this effect is explained because in the MnSOD protein, the change of a valine amino acid to an alanine produces a protein with a more potent antioxidant effect; in this way, this genetic variant reduces the toxic effects of chemotherapeutic agents (such as cyclophosphamide, 5-fluorouracil and methotrexate) but in turn also reduces their efficacy (hence the Ala allele low response to the therapy).

A third clinical study conducted by Yao S. et al. in 2010 with 458 North American breast cancer patients who received cyclophosphamide as an adjuvant chemotherapeutic treatment confirms the results cited in the previous paragraphs. Patients with Val / Val genotype responded better to chemotherapy and left before the disease than patients with Val / Ala or Ala / Ala genotype, however, they also suffered greater toxicity (such as, development of neutropenia among other effects). adverse effects) due to a greater effect of the oxidizing chemotherapeutic agents and a lower antioxidant effect of the MnSOD protein.

The mechanism that explains these effects is that the Ala allele increases resistance to chemotherapeutic drugs because it increases the detoxifying activity and precisely the anticancer activity of these agents lies in their ability to generate reactive oxidant species that damage cancer cells. While cancer cells are damaged, benign cells are also damaged and hence the toxicity of Val/Val patients, even though their response to the disease is much better. Previous studies ""in vitro"" and ""in vivo"" have shown that efficient expression of MnSOD (like that achieved with the Ala variant) also increases resistance to other chemotherapeutics such as doxorubicin, 5-fluorouracil and methotrexate, suggesting that this polymorphism should have similar effects with these drugs.

Summarizing these three studies that are the most important to date, we can interpret that patients with Val/Val genotype (or c.47 AA if we talk about nucleotide position in DNA instead of amino acids of the protein) present a better response to chemotherapeutics such as cyclophosphamide and others but greater general toxicity, patients with Val/Ala (or AG) genotype have a lower response than Val/Val patients but also a lower toxicity, and patients with Ala/ Ala genotype (or GG) are resistant to cyclophosphamide but have much milder toxicities.

The Ala or G allele has a very high frequency in the general population, therefore, patients with Ala/Ala genotype (GG) are very frequent and therefore the failure in the treatment with these chemotherapeutic agents is usually discouraging.

Due to the compromise between the efficacy of the chemotherapy and the toxicity associated with this efficacy, it is highly recommended to perform genetic tests on breast cancer patients in order to select which type of treatment will best suit each person and thus move towards personalized therapy that would avoid unnecessary adverse effects and better clinical results.

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