Breast cancer

The cumulative breast cancer incidence ranges from 8% to 20% by age 40 to 45 years among childhood cancer survivors and is as high as 35% by age 50 years in Hodgkin lymphoma survivors, comparable to that observed among BRCA gene variant carriers.[18,33-36]

Radiation dose and volume of breast exposed are important factors affecting risk. Specific chemotherapeutic agents, particularly alkylating agents and anthracyclines, may affect risk as well.[33,35,37]

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

Excess risk of breast cancer has been reported in survivors treated with high-dose, extended-volume radiation at age 30 years or younger.[38]

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

Data indicate that females treated with low-dose, involved-field radiation also exhibit excess breast cancer risk.[39]

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

Patients who received limited volume supradiaphragmatic radiation therapy (excluding the axillae) had a significantly lower risk of subsequent breast cancers than patients who received full mantle-field radiation therapy.[37]

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

For patients treated with radiation therapy to the chest before age 16 years, the cumulative incidence of breast cancer approaches 20% by age 45 years.[18]

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

The latency period after chest irradiation ranges from 8 to 10 years, and the risk of subsequent breast cancer increases in a linear fashion with radiation dose (P for trend < .001).[40]

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

Treatment with higher cumulative doses of alkylating agents and ovarian radiation of 5 Gy or higher (exposures predisposing to premature menopause) have been correlated with reductions in breast cancer risk, underscoring the potential contribution of hormonal stimulation on breast carcinogenesis.[37,41,42]

Breast cancer is the most common therapy-related solid SN after a previous diagnosis of Hodgkin lymphoma.[18,34] The following has been observed in female survivors of childhood Hodgkin lymphoma:

The observed number of invasive breast cancer cases among young (aged <30 years) survivors, compared with what is expected in the general population, has decreased over recent treatment eras (1970s SIR, 55.0 vs. 1990s SIR, 14.3).[36]

The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue:

The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue:

In 116 children in the CCSS cohort treated with 2 Gy to 20 Gy to the lungs (median, 14 Gy), the SIR for breast cancer was 43.6 (95% CI, 27.1–70.1).[35]

The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue:

A report of 2,492 female participants in the National Wilms Tumor Studies 1 through 4 (1969–1995) addressed the excess risk of breast cancer.[43]

The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue: › A report of 2,492 female participants in the National Wilms Tumor Studies 1 through 4 (1969–1995) addressed the excess risk of breast cancer.[43]

Sixteen of 369 women who received chest irradiation for metastatic Wilms tumor developed invasive breast cancer (cumulative risk at age 40 years, 14.8% [95% CI, 8.7%–24.5%]). The SIR of 27.6 (95% CI, 16.1–44.2) was based on 5,010 person-years of follow-up.

The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue: › A report of 2,492 female participants in the National Wilms Tumor Studies 1 through 4 (1969–1995) addressed the excess risk of breast cancer.[43]

Of the 369 patients, radiation doses to the chest were less than 12 Gy in 4%, 12 Gy in 64%, 13 Gy to 15 Gy in 19%, and more than 15 Gy in 13% of patients.

The risk of breast cancer was also increased in the following studies that used lower radiation doses to treat cancer that metastasized to the chest/lung (e.g., Wilms tumor, sarcoma) and exposed the breast tissue: › A report of 2,492 female participants in the National Wilms Tumor Studies 1 through 4 (1969–1995) addressed the excess risk of breast cancer.[43]

For all patients who developed breast cancer (with or without chest irradiation), the median age at first breast cancer diagnosis was 34.3 years (range, 15.5–48.4) and the median time from Wilms tumor diagnosis was 27.1 years (range, 7.9–35.7).

An international collaborative study pooled individual patient data from 17,903 childhood cancer survivors. The study evaluated the dose-dependent effects of individual anthracycline agents on the development of subsequent breast cancer and interactions with chest radiation therapy. There were 782 survivors (4.4%) who developed a subsequent breast cancer.[44]

An international collaborative study pooled individual patient data from 17,903 childhood cancer survivors. The study evaluated the dose-dependent effects of individual anthracycline agents on the development of subsequent breast cancer and interactions with chest radiation therapy. There were 782 survivors (4.4%) who developed a subsequent breast cancer.[44]

Doxorubicin was associated with a dose-dependent increase of subsequent breast cancer risk (HR per 100 mg/m2, 1.24; 95% CI, 1.18–1.31).

An international collaborative study pooled individual patient data from 17,903 childhood cancer survivors. The study evaluated the dose-dependent effects of individual anthracycline agents on the development of subsequent breast cancer and interactions with chest radiation therapy. There were 782 survivors (4.4%) who developed a subsequent breast cancer.[44]

There was a more-than-twofold increased risk for survivors treated with 200 mg/m2 or higher cumulative doxorubicin dose, compared with no doxorubicin (HR, 2.50 for 200–299 mg/m2; HR, 2.33 for 300–399 mg/m2; HR, 2.78 for ≥400 mg/m2).

An international collaborative study pooled individual patient data from 17,903 childhood cancer survivors. The study evaluated the dose-dependent effects of individual anthracycline agents on the development of subsequent breast cancer and interactions with chest radiation therapy. There were 782 survivors (4.4%) who developed a subsequent breast cancer.[44]

The associations were not statistically significant for daunorubicin, whereas epirubicin was associated with increased subsequent breast cancer risk (exposure yes vs. no: HR, 3.25; 95% CI, 1.59–6.63).

An international collaborative study pooled individual patient data from 17,903 childhood cancer survivors. The study evaluated the dose-dependent effects of individual anthracycline agents on the development of subsequent breast cancer and interactions with chest radiation therapy. There were 782 survivors (4.4%) who developed a subsequent breast cancer.[44]

The HRs per 100 mg/m2 of doxorubicin were 1.11 (95% CI, 1.02–1.21) for patients treated with chest radiation therapy and 1.26 (95% CI, 1.17–1.36) for patients who did not receive chest radiation therapy.

The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[33]

The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[33]

For the study group, the median age of first cancer diagnosis was 15 years and the median age at breast cancer diagnosis was 39 years.

The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[33]

The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5–6.5) and was similar for estrogen receptor–positive and estrogen receptor–negative cancers.

The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[33]

The OR per 10 Gy to the breast was higher for women who received ovarian doses less than 1 Gy (OR, 6.8; 95% CI, 3.9–12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0–6.4).

The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[33]

The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09–1.39; P < .01 for trend).

The risk of developing breast cancer after radiation therapy and chemotherapy with anthracyclines was evaluated in the CCSS. In a nested-case control study of 271 childhood cancer survivors (diagnosed between 1970–1986) who were subsequently diagnosed with breast cancer, the combination of anthracyclines and radiation therapy to the breast was associated with increased risks of breast cancer consistent with an additive interaction.[33]

There was an additive interaction between radiation therapy and anthracycline treatment. The OR was 19.1 (95% CI, 7.6–48.0) for the combined association of anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) versus 9.6 (95% CI, 4.4–20.7) without anthracycline therapy.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.

The SJLIFE study assessed subsequent breast cancer risk among 1,467 female cancer survivors and evaluated risk associated with anthracycline exposure. The study also evaluated whether surveillance imaging affects breast cancer outcomes.[25]

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › The SJLIFE study assessed subsequent breast cancer risk among 1,467 female cancer survivors and evaluated risk associated with anthracycline exposure. The study also evaluated whether surveillance imaging affects breast cancer outcomes.[25]

In women who received neither chest radiation nor anthracyclines, the cumulative incidence of breast cancer was 2% at age 35 years and 15% at age 50 years. For women who were treated with 250 mg/m2 or higher of anthracyclines, the rates were 7% at age 35 years and 46% at age 50 years.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › The SJLIFE study assessed subsequent breast cancer risk among 1,467 female cancer survivors and evaluated risk associated with anthracycline exposure. The study also evaluated whether surveillance imaging affects breast cancer outcomes.[25]

Anthracycline doses of 250 mg/m2 or higher remained significantly associated with increased risk of breast cancer in models, excluding survivors with cancer predisposition gene variants, chest radiation of 10 Gy or higher, or both.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › The SJLIFE study assessed subsequent breast cancer risk among 1,467 female cancer survivors and evaluated risk associated with anthracycline exposure. The study also evaluated whether surveillance imaging affects breast cancer outcomes.[25]

Breast cancers detected by imaging and/or prophylactic mastectomy were more likely to be in situ carcinomas, be smaller masses, have no lymph node involvement, and be treated without chemotherapy, compared with breast cancers detected by physical findings.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › The SJLIFE study assessed subsequent breast cancer risk among 1,467 female cancer survivors and evaluated risk associated with anthracycline exposure. The study also evaluated whether surveillance imaging affects breast cancer outcomes.[25]

Dual imaging with mammography and breast magnetic resonance imaging (MRI) in this cohort was a sensitive and specific approach to identify breast cancers that require less aggressive therapy than breast cancers detected by physical findings.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.

A CCSS investigation examined the breast cancer risk of 3,768 female participants who did not receive chest radiation.[45]

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › A CCSS investigation examined the breast cancer risk of 3,768 female participants who did not receive chest radiation.[45]

A fourfold excess risk (SIR, 4.0; 95% CI, 3.0–5.3) of breast cancer was observed compared with rates in the general population.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › A CCSS investigation examined the breast cancer risk of 3,768 female participants who did not receive chest radiation.[45]

Breast cancer risk was highest among survivors of sarcoma (SIR, 5.3; 95% CI, 3.6–7.8) and leukemia (SIR, 4.1; 95% CI, 2.4–6.9), for whom the cumulative incidence of breast cancer was estimated to be 5.8% and 6.3%, respectively, by age 45 years.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › A CCSS investigation examined the breast cancer risk of 3,768 female participants who did not receive chest radiation.[45]

Treatment with alkylating agents and anthracyclines increased the risk of breast cancer in a dose-dependent manner.

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.

CCSS investigators also examined SN risk among 7,448 participants who were treated with chemotherapy only.[12]

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › CCSS investigators also examined SN risk among 7,448 participants who were treated with chemotherapy only.[12]

Breast cancer incidence was 4.6-fold greater than what would be expected in the general population (SIR, 4.6; 95% CI, 3.5–6.0).

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › CCSS investigators also examined SN risk among 7,448 participants who were treated with chemotherapy only.[12]

A linear dose response was demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m2; 95% CI, 1.2–1.6).

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age.

DCOG-LATER investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[13]

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › DCOG-LATER investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[13]

Survivors treated with doxorubicin exhibited a dose-dependent increased risk of breast cancer (HR, 3.1; 95% CI, 1.4–6.5 among survivors treated with anthracycline doses of 250 mg/m2 or higher).

Childhood cancer survivors not exposed to chest radiation also have an increased risk of breast cancer at a young age. › DCOG-LATER investigators evaluated the contribution of chemotherapy to solid cancer risk in a large cohort of childhood cancer survivors diagnosed between 1963 and 2001.[13]

The doxorubicin–breast cancer dose response was stronger for survivors of Li-Fraumeni–associated cancers (leukemia, CNS, and sarcomas other than Ewing) than for survivors of other cancers.

A SEER Program–based study evaluated trends in surgical management and the 5- and 10-year cumulative incidence of contralateral breast cancer among women who were treated with radiation therapy for Hodgkin lymphoma before age 30 years and diagnosed with a subsequent breast cancer between 1990 and 2016.[46]

A SEER Program–based study evaluated trends in surgical management and the 5- and 10-year cumulative incidence of contralateral breast cancer among women who were treated with radiation therapy for Hodgkin lymphoma before age 30 years and diagnosed with a subsequent breast cancer between 1990 and 2016.[46]

Overall, 263 (89.2%) women presented with unilateral breast cancer, 50 of whom (19.0%) underwent breast-conserving surgery and 213 of whom (81.0%) underwent mastectomy (40.5% bilateral).

A SEER Program–based study evaluated trends in surgical management and the 5- and 10-year cumulative incidence of contralateral breast cancer among women who were treated with radiation therapy for Hodgkin lymphoma before age 30 years and diagnosed with a subsequent breast cancer between 1990 and 2016.[46]

The 5-year incidence of contralateral breast cancer in women who underwent unilateral surgery was 9.4% (95% CI, 5.6%–15.4%), increasing to 20.2% (95% CI, 13.7%–29.2%) at 10 years and 29.9% (95% CI, 20.8%–41.9%) at 15 years. This finding underscores the importance of ongoing breast cancer surveillance and consideration of prophylactic mastectomy.