Abstract
This cohort study examines the risk of radiation-associated sarcoma in patients with breast cancer harboring germline TP53 variants.
Patients with breast cancer who carry TP53 germline variants may be at increased risk of radiation (RT)-associated secondary cancers, yet risk estimates are not well established.1,2,3 We conducted a multi-institutional cohort study to evaluate the risk of sarcoma following RT among patients with breast cancer who carry germline TP53 variants.
Methods
We identified patients who underwent primary surgical management of breast carcinoma and harbored TP53 germline variants from prospectively maintained institutional databases (OncoKB, ClinVar). The TP53 variants were classified as either likely pathogenic (PV) or of unknown significance (VUS) using the databases and literature review. The study was approved by the institutional review boards of the participating institutions and the requirement for informed consent was waived due to the retrospective and deidentified nature of the analyses. This study followed the STROBE reporting guideline.
The primary outcome was the cumulative incidence of an in-field sarcoma following breast cancer diagnosis among patients harboring TP53 PV, with death as a competing risk. A propensity score (PS)–matched control cohort was generated from a database of unselected patients with breast cancer who received adjuvant RT, using a 15:1 nearest-neighbor matching algorithm, with age, breast surgery type, and follow-up time as matching variables. The at-risk in-field region included ipsilateral thoracic organs; ipsilateral neck and thyroid were included if patients received supraclavicular node RT. Sensitivity analysis was performed using 5:1 matching with chemotherapy, receptor status, and nodal involvement as additional variables (eMethods in Supplement 1). Log-rank (Mantel-Cox) test was used to compare overall survival between groups. The significance threshold was set at P < .05 and tests were 2-sided. Analyses were performed using Prism software version 9.3.1 (GraphPad), and R version 4.1.2 (R Foundation for Statistical Computing).
Results
We identified 91 patients with breast carcinoma who harbored TP53 germline variants. Forty patients received RT (28 PV, 12 VUS) and 51 did not (41 PV, 10 VUS). Those who received RT had a higher tumor stage (T1: 57% No RT vs 35% RT; P = .04), higher number of involved axillary nodes (N0: 71% no RT vs 42% RT; P = .01), and higher-grade histologic characteristics (grade 3: 25% no RT vs 38% RT; P < .001). Median age among TP53 PV carriers who received RT was 35 (IQR, 30-45) years, and median follow-up was 14 (IQR, 8-18) years. Median age among the PS-matched control cohort was 38 (IQR, 32-43) years and median follow-up was 11 (IQR, 8-12) years (Table). Among 28 TP53 PV carriers who received RT, 3 developed a secondary in-field sarcoma (15-year risk, 8.8%; 95% CI, 1.4%-25%) compared with no events among 420 PS-matched controls (Figure, A). Results were consistent on sensitivity analysis. No in-field sarcomas were detected among 12 TP53 VUS carriers who received RT or among any of the 51 RT-naive TP53 variant carriers. The 10-year cumulative incidence of developing any secondary cancer was not significantly different between TP53 PV carriers who received RT and those who did not (22.5% [95% CI, 8.8%-40.0%] vs 38% [95% CI, 15%-61%]; P = .55) nor was overall survival in this modestly sized cohort (Figure, B). No deaths were attributable to RT-associated sarcoma.
Table. Clinical and Radiation Treatment Characteristics, Matched Controls vs TP53 Pathogenic Variant Carriers.
| Characteristic | No. (%) | P valuea | Q valueb | ||
|---|---|---|---|---|---|
| Control (noncarriers) (n = 420) | TP53 PV (n = 28) | TP53 VUS (n = 12) | |||
| Breast surgery | |||||
| Breast conservation | 150 (36) | 10 (36) | 6 (50) | >.99 | >1.00 |
| Mastectomy | 270 (64) | 18 (64) | 6 (50) | ||
| Age at diagnosis, median (IQR), y | 38 (32-43) | 35 (30-45) | 41 (37-47) | .22 | 0.38 |
| Follow-up time, median (IQR), y | 11 (8-12) | 14 (8-18) | 8.5 (5.5-11.4) | .04 | 0.13 |
| Chemotherapy receipt | 367 (87) | 23 (82) | 9 (75) | .44 | 0.62 |
| Histologic characteristics | |||||
| In situ | 13 (3.1) | 3 (11) | 2 (17) | .21 | 0.38 |
| Invasive | 406 (97) | 25 (89) | 10 (83) | ||
| Unknown | 1 (0.2) | 0 | 0 | ||
| Radiotherapy treatment characteristics | |||||
| Total dose, median (IQR), Gy | 50.4 (50.0-54.9) | 50.4 (50.0-52.6) | 51.4 (50.0-60.0) | .82 | >0.95 |
| Unknown | 58 | 12 | 0 | ||
| Regional nodal irradiation | |||||
| No | 118 (28) | 3 (11) | 5 (42) | <.001 | 0.01 |
| Yes | 244 (58) | 13 (46) | 7 (58) | ||
| Unknown | 58 (14) | 12 (43) | 0 | ||
Abbreviations: PV, likely pathogenic variant; VUS, variant of uncertain significance.
Random intercept logistic regression comparing control and TP53 pathogenic variant groups.
False discovery rate correction for multiple testing.
Figure. Secondary Cancer Risk.
A, In-field sarcoma after breast radiotherapy (RT) in TP53 pathogenic variance (PV) carriers. The 15-year cumulative incidence risk of developing an in-field sarcoma after breast RT in patients with TP53 PV was 8.8% (IQR, 1.4%-25%). The 15-year risk of the control cohort was 0.0% (P < .001). B, The 10-year cumulative risk of any secondary cancer was not significantly different between TP53 PV carriers who received RT (22.5% [95% CI, 8.8%-40.0%]) and RT-naive PV carriers (38% [95% CI, 15.4%-61%]) (P = .55). The shaded areas indicate 95% CIs.
Discussion
To our knowledge, this is the largest analysis of RT-associated cancer risk among patients with breast cancer harboring TP53 germline variants. We estimate the longitudinal risk of RT-associated sarcoma among carriers of TP53 PV to be 8.8% at 15 years—significantly increased compared with that of the general population.4,5,6 Our results highlight that TP53 PV carriers face substantial overall risk of any secondary cancers, most of which develop unrelated to RT and must be interpreted in the context of the study design. Longer-term follow-up with larger cohorts may further refine relevant risk estimates. Limitations were somewhat mitigated through comparisons between TP53 VUS carriers, RT-naive carriers, and propensity-matched cohorts, showing consistent comparative risk of in-field sarcomas across all comparisons. Thus, the iatrogenic risk of RT must be balanced against its anticipated therapeutic benefit, particularly among patients with higher-risk breast cancer presentations.
eMethods
Data Sharing Statement
References
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Supplementary Materials
eMethods
Data Sharing Statement