In the JournalsPerspective

Genetic factors influence breast cancer risk after radiotherapy for Hodgkin lymphoma

Genetic factors influence the risk for breast cancer in women who received radiotherapy for Hodgkin lymphoma, according to results of a case-only analysis published in Blood.

“Women who are treated at young ages with chest radiotherapy for Hodgkin lymphoma have a 5 to 20 times increased risk [for] breast cancer compared with the general population,” Annemieke W.J. Opstal-van Winden, PhD, epidemiologist at Netherlands Cancer Institute, and colleagues wrote. The risk [for] radiotherapy-induced breast cancer rises with increasing radiation dose and volume, but not all female Hodgkin lymphoma survivors treated with a high-dose, high-volume radiotherapy develop breast cancer. However, variation in risk may also be due to genetic factors. The high risk [for] breast cancer in this population provides an excellent opportunity to investigate the genetic basis for differential sensitivity to radiation carcinogenesis.”

The analysis by Opstal-van Winden and colleagues included 327 patients with breast cancer who underwent chest radiotherapy for Hodgkin lymphoma (median age at diagnosis, 45 years; range, 24-76) and 4,671 patients with first primary breast cancer (median age at diagnosis, 46 years; range, 22-84). Overall, researchers looked at 211,155 germline single nucleotide polymorphisms for gene-radiation interaction on breast cancer risk.

Nine SNPs had statistically significant interaction with radiotherapy on breast cancer risk, and one of those in the PVT1 oncogene achieved the Bonferroni threshold for statistical significance.

In the second step of the study, researchers conducted a nested case-control analysis that included the chest-irradiated patients with breast cancer and 491 chest-irradiated patients without breast cancer who served as Hodgkin lymphoma controls.

Median interval between Hodgkin lymphoma and diagnosis of breast cancer was 24 years (range, 9-46). Median follow-up for Hodgkin lymphoma controls was 30 years (range, 9-49).

Most Hodgkin lymphoma cases and controls (87%) received mantle field irradiation. Another 11% underwent mediastinal radiotherapy without axillary node radiotherapy.

About 50% of the patients with breast cancer after Hodgkin lymphoma, as well as 60% of the Hodgkin lymphoma controls, received chemotherapy and radiotherapy for Hodgkin lymphoma.

Researchers evaluated polygenic risk scores based on the nine radiotherapy-interacting SNPs.

Results showed that patients in the highest tertile of the radiotherapy-interaction polygenic risk score had a risk for breast cancer 1.6 times higher than patients in the lowest tertile.

Further, patients in the highest decile of the breast cancer polygenic risk score had a fourfold increased risk for radiotherapy-induced breast cancer than patients in the lowest decile.

The risk for breast cancer increased 1.4-fold per standard deviation of the breast cancer polygenic risk score, which is similar to the effect size found in the general population.

The study populations for the analysis of the radiotherapy-interaction polygenic risk score were not independent, which researchers cited as a limitation to this study.

“These results indicate that the effects of radiation exposure and common susceptibility variants, summarized in the polygenic risk score, combine approximately multiplicatively,” Opstal-van Winden and colleagues wrote. “Given the high absolute breast cancer risk in radiation-exposed women, these results have important implications for their management.” – by John DeRosier

Disclosures: The Dutch Cancer Society funded this study. The researchers report no relevant financial disclosures.

Genetic factors influence the risk for breast cancer in women who received radiotherapy for Hodgkin lymphoma, according to results of a case-only analysis published in Blood.

“Women who are treated at young ages with chest radiotherapy for Hodgkin lymphoma have a 5 to 20 times increased risk [for] breast cancer compared with the general population,” Annemieke W.J. Opstal-van Winden, PhD, epidemiologist at Netherlands Cancer Institute, and colleagues wrote. The risk [for] radiotherapy-induced breast cancer rises with increasing radiation dose and volume, but not all female Hodgkin lymphoma survivors treated with a high-dose, high-volume radiotherapy develop breast cancer. However, variation in risk may also be due to genetic factors. The high risk [for] breast cancer in this population provides an excellent opportunity to investigate the genetic basis for differential sensitivity to radiation carcinogenesis.”

The analysis by Opstal-van Winden and colleagues included 327 patients with breast cancer who underwent chest radiotherapy for Hodgkin lymphoma (median age at diagnosis, 45 years; range, 24-76) and 4,671 patients with first primary breast cancer (median age at diagnosis, 46 years; range, 22-84). Overall, researchers looked at 211,155 germline single nucleotide polymorphisms for gene-radiation interaction on breast cancer risk.

Nine SNPs had statistically significant interaction with radiotherapy on breast cancer risk, and one of those in the PVT1 oncogene achieved the Bonferroni threshold for statistical significance.

In the second step of the study, researchers conducted a nested case-control analysis that included the chest-irradiated patients with breast cancer and 491 chest-irradiated patients without breast cancer who served as Hodgkin lymphoma controls.

Median interval between Hodgkin lymphoma and diagnosis of breast cancer was 24 years (range, 9-46). Median follow-up for Hodgkin lymphoma controls was 30 years (range, 9-49).

Most Hodgkin lymphoma cases and controls (87%) received mantle field irradiation. Another 11% underwent mediastinal radiotherapy without axillary node radiotherapy.

About 50% of the patients with breast cancer after Hodgkin lymphoma, as well as 60% of the Hodgkin lymphoma controls, received chemotherapy and radiotherapy for Hodgkin lymphoma.

Researchers evaluated polygenic risk scores based on the nine radiotherapy-interacting SNPs.

Results showed that patients in the highest tertile of the radiotherapy-interaction polygenic risk score had a risk for breast cancer 1.6 times higher than patients in the lowest tertile.

Further, patients in the highest decile of the breast cancer polygenic risk score had a fourfold increased risk for radiotherapy-induced breast cancer than patients in the lowest decile.

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The risk for breast cancer increased 1.4-fold per standard deviation of the breast cancer polygenic risk score, which is similar to the effect size found in the general population.

The study populations for the analysis of the radiotherapy-interaction polygenic risk score were not independent, which researchers cited as a limitation to this study.

“These results indicate that the effects of radiation exposure and common susceptibility variants, summarized in the polygenic risk score, combine approximately multiplicatively,” Opstal-van Winden and colleagues wrote. “Given the high absolute breast cancer risk in radiation-exposed women, these results have important implications for their management.” – by John DeRosier

Disclosures: The Dutch Cancer Society funded this study. The researchers report no relevant financial disclosures.

    Perspective
    Anne Blaes

    Anne Blaes

    Breast cancer is the most common second cancer in female Hodgkin lymphoma survivors. Female survivors treated with chest radiation experience the greatest risk, particularly when treated at younger ages and with mantle field radiation. The incidence of breast cancer in women treated with mantle field radiation is similar to that of women with BRCA mutations. The risk begins as early as 8 years after chest radiation and persists beyond 30 years after completion of radiation. Being able to identify those who are at highest risk for breast cancer, based on treatment-related or genetic factors, remains of utmost importance.

    Opstal-van Winden and colleagues examined 211,155 SNPs for gene-radiation interaction on breast cancer risk in patients with breast cancer who had received chest radiation for Hodgkin lymphoma and in those with a first primary breast cancer.

    Throughout their study, researchers were able to identify SNPs associated with an interaction with radiation therapy on breast cancer risk. Additionally, a polygenic risk score composed of SNPs demonstrated a higher risk for breast cancer in Hodgkin lymphoma survivors similar to that of the general population.

    Being able to identify those individuals who would be at highest risk for secondary complications such as breast cancer would allow clinicians to potentially modify therapies in an effort to reduce secondary complications. Similarly, being able to identify those at highest risk who are already survivors would also allow clinicians to pursue aggressive high-risk breast cancer screening or to consider chemoprevention. Aggressive breast cancer screening with breast MRI has been shown to improve mortality rates for Hodgkin lymphoma survivors at high risk for breast cancer. Similarly, chemoprevention with medications such as tamoxifen may be useful in decreasing the incidence of breast cancer in survivors; the results of ongoing studies (NCT01196936) are eagerly awaited.

    • Anne Blaes , MD
    • HemOnc Today Editorial Board Member
      University of Minnesota

    Disclosures: Blaes reports no relevant financial disclosures.