In this ancillary study to a completed clinical trial with 1,332 breast cancer patients receiving standardized treatment and follow-up, we found the C variant of SOD2, which results in better mitochondrial import, was associated with lower risk of acute hematological toxicity but with higher risk of disease recurrence or death. The effects were specific to adjuvant therapy since no significant associations were found in the observational cohort of women who did not receive adjuvant therapy. The findings are consistent with our hypothesis that high antioxidant activity protects cells from oxidative damage caused by cancer therapy, reducing drug toxicity to normal tissues but compromising treatment efficacy to cancer cells.
Among 279 women who received varied adjuvant chemotherapy, we previously reported better survival, although not statistically significant, among women with CC genotypes, compared to those with CT and TT genotypes (HR=0.70, 95% CI=0.40–1.24) (8
). A similar trend was also reported in a small study with 95 patients treated for metastatic breast cancer, where the TT genotype was associated with worse overall (HR=2.52, 95% CI=1.31–4.85) and breast cancer-specific survival (HR=1.92, 95% CI=1.03–3.57) compared to those with CC genotypes (10
). However, due to small sample size and mixed therapy modalities, neither study was able to investigate drug-specific effects. Using data from a larger number of patients receiving standardized cyclophosphamide-containing treatment, our results conflict with those previous studies: women with TC or CC genotypes had worse DFS than those with TT genotypes. Our results, nevertheless, are consistent with the recent findings from Glynn et al among breast cancer patients pooled from the United States and Norway, wherein they observed that women with CC genotypes had poorer breast cancer-specific survival than those with TT genotypes (HR=2.47, 95% CI=1.46–4.19) (1
). When analyses were restricted to a small subset of patients (n=142) who received cyclophosphamide-containing chemotherapy regimens, results were strengthened (HR=22.0, 95% CI=5.22–92.9), further refining the comparability of their results to ours, in which all patients received cyclophosphamide treatment. The small number of patients in their study may explain the higher HR and wider confidence interval than the results from our study. Moreover, both studies observed relationships between the SOD2
polymorphism and survival only among women who received adjuvant chemotherapy and not among those who did not receive treatment, supporting the hypothesis that SOD2 plays an important role in regulating chemotherapy-induced oxidative stress.
We also noted that women with CC genotypes had almost half the likelihood of developing grade 3 and 4 neutropenia, and were also less likely to develop high grade leucopenia than those with TT genotypes. These results are consistent with our previous findings among 446 women who received radiation therapy following lumpectomy for breast cancer (11
). In that study, CC genotypes were associated with reduced risk of both acute skin radiotoxicity (OR=0.61, 95% CI=0.32–1.20) and chronic skin radiotoxicity (OR=0.79, 95% CI=0.42–1.48), although the results were not statistically significant. The fact that the C allele was associated with both less toxicity and poorer survival, which would support the hypothesis that lower oxidative stress reduces cell damage in both normal and malignant tissues, strengthens our confidence in the findings.
We previously examined germline polymorphisms in other oxidative stress-related genes in relation to breast cancer treatment outcomes. Among 279 women receiving varied breast cancer therapy, those with the MPO
GG genotypes had almost a two-fold reduction in hazard of death than those with AA genotypes (HR=0.60, 95% CI=0.38–0.95) (8
). Those findings were recently validated among 453 women in this cohort (HR=0.41, 95% CI=0.21–0.77) (13
). In the same study, we also reported modifying effects of nitric oxide synthase variants on DFS after breast cancer chemotherapy (14
). Together, the growing body of evidence underscores the importance of inter-patient variations in oxidative stress metabolic capacity in determining response to breast cancer chemotherapy.
Given its position in the ROS metabolic pathway, the ultimate role of SOD2 in ROS metabolism may be complicated by other enzymes in the same pathway. Because hydrogen peroxide, the ROS intermediate produced by SOD2, can either be neutralized to non-toxic H2
O and oxygen by CAT and GPX, or be subsequently converted to potent toxic radical hypochlorous acid by MPO, increased endogenous SOD2 activity may protect against oxidative damage if activity of CAT and GPX dominates, or may lead to oxidative damage if activity of MPO dominates (). It was shown in one study that overexpression of SOD2 in breast cancer cell lines induced resistance to Adriamycin treatment (15
); while in another study high expression of SOD2 was linked to better survival among esophageal and gastric cancer patients (16
). The apparently contradictory results may reflect a shifting balance between non-toxic neutralization and oxidative radical conversion, and may provide an alternative explanation for the inconsistent findings on the SOD2
polymorphism and breast cancer survival as noted above.
Intake of exogenous antioxidants may also influence the balance between endogenous antioxidant enzymes and treatment outcomes. We previously reported associations between increased risk of premenopausal breast cancer risk and CC genotypes only among women below the median for consumption of fruits and vegetables and dietary ascorbic acid and α-tocopherol, indicating a shift towards generating potent oxidative radicals when exogenous antioxidant intake is inadequate (9
). Similarly, among men from the Physician’s Health Study who carried the more active CC genotype, high levels of antioxidants including selenium, lycopene, and α-tocopherol were associated with significantly lower risk of prostate cancer risk, but the associations were not significant among these carrying CT or TT genotypes (17
). The interactions between exogenous antioxidants and endogenous antioxidant enzyme activity may also influence cancer treatment outcomes and are currently under investigation in another study.
In summary, in an ancillary study to SWOG 8897 clinical trial, we found that the SOD2 C alleles with better mitochondrial import were associated with less acute hematological toxicity but worse disease-free survival compared to T alleles. Our findings support a beneficial role of SOD2 in reducing oxidative damage caused by cancer therapeutic drugs to normal tissues, but also provide a caveat that high endogenous antioxidant activity may compromise treatment efficacy to cancer cells. The accumulating data showing that gene variants associated with higher oxidative stress (MPO, NOS and SOD2) provide clues to identifying predictive genetic markers for commonly used breast cancer chemotherapeutic drugs by focusing on the oxidative stress pathway.