Breast Cancer–Specific Survival Worse Among Survivors of Childhood or Young Adult Primary Cancer Treated With Radiotherapy

Candice A. Sauder, MD

Premenopausal women with breast cancer who were previously treated with radiotherapy for a primary childhood, adolescent, or young adult cancer were found to have worse breast cancer–specific survival (BCSS), according to results from a study published in Cancer Epidemiology, Biomarkers & Prevention.¹

After comparing the impact of secondary malignancies to patients with primary breast cancer, investigators noted an overall higher hazard of breast cancer-related death in patients with secondary breast cancers (HR, 1.98; 95% CI, 1.77-2.23), as well as in all subgroups examined. Moreover, investigators noted significant interactions by race and ethnicity (P = .02), age group (P <.001), and stage at diagnosis (P <.001).

Associations were found to be most distinct in Hispanic and Asian/Pacific Islander patients, in younger women (ages 12-39), and in those with earlier American Joint Committee on Cancer stage of disease. Moreover, additional associations seemed to be more pronounced in patients with lymph node–negative disease, although this was not determined to be of statistical significance (P = .06).

In both cohorts, large tumor size and lymph node involvement indicated worse BCSS. ER-/PR-negative and triple-negative tumors additionally worsened survival outcomes, though HER2 negativity only appeared to negatively affect outcomes in patients with primary breast cancers only (HR, 1.31; 95% CI, 1.22-1.40).

“Our results suggest that BCSS is significantly decreased among all survivors of childhood, adolescent, and young adult cancer who were treated with radiation therapy and then develop breast cancer, even in the setting of early-stage breast cancer and other characteristics that are considered good prognostic factors,” Candice A. Sauder, MD, a surgical oncologist at the University of California Davis Comprehensive Cancer Center and first author on the study, stated in a press release.² “As such, we may need to tailor our treatment strategy for women with a second primary breast cancer.”

Radiotherapy is considered to be an important aspect of multidisciplinary therapy that is utilized in the treatment of common adolescent and young adult and childhood cancers, including Hodgkin lymphoma, sarcomas, and breast cancer, according to the study authors. Despite its established role in the treatment paradigm for these malignancies, it has been established that this approach carries with it a strong risk factor for secondary breast malignancies, especially when used in patients with childhood or adolescent and young adult cancer.

In the study, investigators sought to develop a better understanding of how radiation used to treat primary malignancies impacts the clinical characteristics of secondary breast malignancies developed in the premenopausal setting.

To do this, investigators evaluated data from the large, population-based California Cancer Registry to take a closer look at demographic and clinical characteristics and BCSS survival in premenopausal patients with secondary breast malignancies versus similar aged patients with primary breast cancer. For their analysis, investigators included female patients who were between the ages of 12 and 50 during the period of January 1, 1988 through December 31, 2014. After excluding patients with unknown dates of diagnosis/follow-up, investigators were left with a population of 107,751 patients who had a first and only breast cancer, along with 1,147 patients with a secondary malignancy following radiotherapy for their primary disease.

The cohort of patients who had developed a secondary malignancy were more likely to be non-Hispanic black (10.3% vs 7.4%) or Hispanic (26.4% vs 22.2%) and between the ages of 35 years and 45 years. They were also more likely to have earlier-stage tumors (stage I, 45.5% vs 33.4%), as well as higher-grade disease (grade III, 49.3% vs 39.5%). A lack of lymph node involvement (65.7% vs 53.4%) and estrogen receptor (ER) and progesterone receptor (PR) negativity (ER, 36.2% vs 22.2%; PR, 41.8% vs 26.8%) were additionally associated with the secondary malignancy cohort.

With regard to treatment, the secondary malignancy cohort was found to be less likely to receive treatment with chemotherapy (55.4%) compared with the primary malignancy cohort (62.2%); the same was found to be true with radiation (26.3% vs 45.5%). However, the secondary malignancy cohort was found to be more likely to get a mastectomy than the primary malignancy cohort, at 63.0% versus 50.2%, respectively.

The multivariate logistic regression model revealed that while non-Hispanic black patients were more likely to have a secondary breast malignancy than non-Hispanic white patients (odds ratio [OR], 1.35; 95% CI, 1.11-1.66), Asian and Pacific Islander patients were less likely to develop a secondary malignancy (OR, 0.76; 95% CI, 0.63-0.92). Additionally, secondary cancers were more likely to be diagnosed at an earlier tumor size (T3 vs T1a; OR, 0.38; 95% CI, 0.28-0.52) and without lymph node involvement (positive vs negative; OR, 0.58; 95% CI, 0.51-0.67); however, these malignancies were more likely to be ER and PR negative (OR, 1.76; 95% CI, 1.52-2.03) and be of a higher grade (grade III vs 1; OR, 1.76; 95% CI, 1.41-2.21).

Additional results from 2 separate multivariate Cox models for patients with primary and secondary breast cancer showed that for primary breast cancer, non-Hispanic black patients had worse BCSS (HR, 1.41; 95% CI, 1.34-1.47) and non-Hispanic Asian/Pacific Islander (HR, 0.89; 95% CI, 0.85-0.94) and Hispanic (HR, 0.96; 95% CI, 0.92-0.99) patients experienced improved BCSS versus non-Hispanic white patients. For secondary breast cancer, Hispanic patients were found to have worse BCSS (HR, 1.38; 95% CI, 1.02-1.87) versus non-Hispanic white patients. Asian/Pacific Islander women had similar BSCC compared with their non-Hispanic white counterparts.

The associations for non-Hispanic black patients were comparable to that of primary breast cancers; however, the HR for these patients with secondary breast cancer was no found to be statistically significant potentially because of the smaller size of the secondary malignancy population, according to the study authors.

“We found that the negative impact of second primary breast cancer among women previously treated with radiation was particularly strong in subgroups of patients [who] have superior survival after primary breast cancer,” Sauter added in the release. “It will be important to prospectively evaluate how certain treatments, such as specific radiation fields or chemotherapeutic agents, can affect second primary breast cancer outcomes.”

After considering these significant decreases in survival, investigators concluded that factors such as tumor genetic make-up and prior treatments should be further evaluated to better determine whether treatment should be augmented with novel PARP and CDK 4/6 inhibitors.

References:

1. Sauder CAM, Li Q, Othieno A, et al. Characteristics and outcomes for secondary breast cancer in childhood, adolescent, and young adult cancer survivors treated with radiation. Cancer Epidemiol Biomarkers Prev. Published online September 2020. doi:10.1158/1055-9965.EPI-20-0260
2. Radiation treatment for childhood or young adult primary cancer linked to worse breast cancer-specific survival. News release. UC Davis Health. August 26, 2020. Accessed September 8, 2020. https://bit.ly/2R36IX7.