In this cohort of 253 HL survivors who were treated with radiotherapy to the upper torso and later developed breast cancer, several breast cancer characteristics and outcomes differed significantly from those of a matched cohort of 741 patients with sporadic breast cancer. Notably, HL survivors had a greater risk of bilateral breast cancer, both synchronous and metachronous; their breast cancers were typically diagnosed at an earlier stage and were more likely to be screen detected. Although HR survivors had a greater risk of death as a result of any cause, rates of local/regional failure, metastatic failure, and death as a result of breast cancer did not differ significantly between the two groups.
Several findings are consistent with some small, single-institution studies of HL survivors that did not include comparison cohorts.11,12,16,19,20
However, the authors of a recent systematic review of these and other studies of women treated with chest irradiation for childhood, adolescent, or young adult cancer concluded that the characteristics of breast cancer in women treated with chest irradiation and the outcomes after diagnosis are similar to those of women in the general population.21
Our results do not support that conclusion.
By comparing HL survivors with patients who had sporadic breast cancer matched on race, age, and year of diagnosis, we were able to control for these characteristics, all of which are associated with HL diagnosis and with breast cancer characteristics and outcomes. For example, young age at breast cancer diagnosis has been well established in HL survivors with prior chest irradiation.7,11,12,16,19–21
The median age at breast cancer diagnosis in our cohort—42 years—is almost 20 years younger than the median age of 61 years of patients with breast cancer in the general population.21
Breast cancer in young patients is likely to display a more aggressive phenotype, to be hormone receptor negative, and to exhibit more vascular and lymphatic invasion and pathologic grade 3 features.22
Age younger than 40 years may be an independent adverse prognostic factor for time to relapse, time to distant failure, and overall survival.23,24
For similar reasons, we also controlled for race25
and year of breast cancer diagnosis,26
thereby minimizing possible bias introduced by these important confounders.
The results of our matched-cohort analysis support uncontrolled prior observations of a high incidence of both synchronous and metachronous bilateral breast cancer in patients who received radiotherapy for HL.11,12,16,20,27,28
Those series showed a bilaterality rate of 12.8% (5.5% synchronous and 7.3% metachronous).21
Among the HL survivors in our study, the rate of bilaterality at diagnosis was 6%; among those with a breast at risk, the actuarial rate of metachronous contralateral breast cancer was 18% at 5 years. In multivariable analysis, history of radiation for HL had a far greater impact on risk of metachronous contralateral breast cancer than did other patient and disease characteristics.
Although bilateral breast cancer has previously been associated with a greater risk for local recurrence and distant metastasis,29,30
we did not see higher rates of these events in our HL survivor cohort compared with the matched patients with sporadic breast cancer. However, the increased risk of developing a metachronous contralateral cancer and the potential for poorer prognosis after a contralateral cancer both support the need for close surveillance of the contralateral breast. Our findings provide important information for discussions of the option of prophylactic contralateral mastectomy in patients who had significant radiation exposure of both breasts at a young age.
Several prognostic characteristics and tumor features were more favorable in the HL survivors than in their matched peers with sporadic breast cancer. Although a family history of breast cancer has been shown to increase the risk of developing breast cancer in patients who received radiotherapy for HL,27,31
we found that breast cancer in a first-degree relative was less common in the HL survivors who developed breast cancer than in the patients with sporadic breast cancer. The HL survivors were also diagnosed at an earlier stage (stage 0 or 1) and were less likely to have lymph node involvement. This difference in stage distribution is likely associated with the greater frequency of screen-detected cancers in the HL survivor cohort. Since the association between radiotherapy for HL and the increased risk of breast cancer was clearly established,7,11,32
awareness and guidelines for early detection, primarily with initiation of early routine mammograms, have been promoted for HL survivors. Most breast tumors that develop after HL are detectable by mammography,13,14
and implementation of routine screening has increased the proportion of patients diagnosed at earlier stages.16
Despite the greater frequency of screen-detected tumors and earlier stage at diagnosis in our HL survivor cohort, these women did not have better breast cancer outcomes than their peers with sporadic breast cancer. Rates of local failure and metastatic failure were similar in the two groups, controlling for patient and disease characteristics and treatment. The rate of death from breast cancer was somewhat elevated in the HL survivors, but this difference was not statistically significant. In addition to the disease characteristics available in our study, breast cancer outcomes may be associated with tumor genes and other markers that differ between radiation-induced and sporadic breast cancers, predisposing the former to more aggressive disease.33
In the HL survivors, breast cancer treatment options were undoubtedly constrained by prior exposure to chest irradiation and, in some, to systemic chemotherapy. In a small, retrospective study comparing women with breast cancer after either HL or non-Hodgkin's lymphoma with women with sporadic breast cancer matched for age, stage, and year of diagnosis, 5-year disease-free survival was only 54% in the lymphoma survivors compared with 91% in the comparison group.34
The investigators speculated that this disparity in outcome was associated with differences in treatment and, specifically, with the underuse of anthracycline-based chemotherapy in HL survivors.
All-cause mortality and the rate of non–breast cancer death were significantly greater in HL survivors than in their matched peers with sporadic breast cancer. These results reinforce prior evidence that young cancer survivors—specifically women who received chest irradiation for HL—are at an elevated risk of death from other second tumors and from noncancer causes.2,35
Survivors of HL face an increased risk of cardiac death, most commonly related to acceleration of coronary disease after mediastinal irradiation, particularly in the presence of other coronary risk factors.36
Treatment of HL with anthracycline-containing chemotherapy may also contribute to the risk of heart disease.37
A recent registry-based comparison of patients with breast cancer with and without a history of radiation for HL found that women in the former group had a seven-fold greater risk of death as a result of other cancers and an elevated risk of death from heart disease.38
More than half of the HL survivors in our study were diagnosed with HL before 1980; therefore, they were likely exposed to the most radical attempts to cure HL with radiation alone by maximizing both the dose and the volume of radiation. It is encouraging that the modern approach to the cure of HL utilizes significantly lower doses of radiation, and most treatments to the upper body lymph nodes now avoid most or all of the breast.8,39
Several studies demonstrate that avoiding treatment of the axillae significantly reduces the risk of breast cancer in HL survivors.6,8
Contemporary, effective treatment regimens for HL have markedly reduced the amount of both chemotherapy and radiation administered to patients.40
Several limitations of our analysis warrant mention. The study cohorts were identified from selected tertiary academic medical centers that see a high volume of both HL and breast cancer patients. If women seen in community-based settings differ with regard to personal factors, disease characteristics, and the treatment they receive, the generalizability of our findings may be limited. Although we were able to identify deaths as a result of breast cancer, we had limited information about other causes of death. Thus, we could not clearly distinguish deaths that were a result of noncancer causes from deaths that were a result of secondary malignancies other than breast cancer, such as lung cancer and non-Hodgkin's lymphoma, both of which are seen at an elevated rate in HL survivors.3
Our results are mostly relevant to patients treated for HL in the era when radiation therapy alone was the dominant form of curative therapy and was used with high radiation doses that almost always included both breasts and the heart. This practice has changed radically, and the reduced exposure of these organs is likely to change the risk profile for long-term complications. Thus, it may be inappropriate to alarm patients who are scheduled for modern, reduced radiation with the experience from radical radiotherapy of 3 to almost 5 decades past. However, our findings are informative for the thousands of HL survivors who remain at risk of long-term complications from their original treatment, underscoring the importance of regular screening for breast cancer and for comorbid conditions. Healthy lifestyle, cessation of smoking, early detection, and treatment of high blood pressure and hyperlipidemia, along with regular breast imaging, should all be part of standard education and follow-up for HL survivors.