Risk and prognosis of second cutaneous melanoma after radiotherapy for breast cancer: A population-based analysis

Abstract

Radiation therapy (RT), a primary treatment for breast cancer (BC), may be associated with increased non-BC tumor risk. We aimed to examine second cutaneous melanoma (SCM) risk in BC patients who underwent RT and to assess their survival outcomes. Data from 520,977 BC patients diagnosed between 1973-2018 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Cumulative SCM incidence was estimated using the Fine-Gray competing risk model. Poisson regression analysis was conducted to calculate the standardized incidence ratio (SIR) and estimate the SCM relative risk in patients who underwent RT compared to those who did not. Overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan‒Meier method. Among the 520,977 BC patients, 243,676 (46.8%) underwent surgery and RT, while 277,301 (53.2%) only underwent surgery. Our results suggest that BC patients receiving RT had a higher SCM risk than those who did not (hazard ratio [HR] 1.40; 95% confidence interval [CI] 1.30-1.51; P < 0.001). SCM incidence was also higher in BC patients treated with RT than in the general US population (SIR 1.12; 95% CI 1.05-1.19; P < 0.05). However, SCM patients who received RT had a significantly higher 10-year survival rate than those who did not receive RT (14.90% vs 5.94%; P < 0.001). No significant difference was found in 10-year OS or 5-year CSS between SCM following RT and only primary cutaneous melanoma (OPCM), but SCM patients who did not receive RT had a significantly lower 10-year OS, with no significant difference in CSS. This study suggests an increased SCM likelihood in BC patients due to RT, although the overall risk is minimal.

Figure 1.

Comparisons of the cumulative incidence of SCM in BC survivors (A) between patients who received RT and those who did not receive RT and (B-F) SCM's pathological subtypes between patients who received RT and those who did not receive RT. Other SCMs indicate other SCM subtypes which include those not otherwise specified, except for the pathologic subtype of cutaneous melanoma described above. P values were calculated with the Fine-Gray test. RT: Radiation therapy; SCM: Second cutaneous melanoma; SSM: Superficial spreading melanoma; NM: Nodular melanoma; LMM: Lentigo maligna melanoma; ALM: Acral lentiginous melanoma; NRT: Non-radiation therapy.

Figure 2.

Dynamic SIR for SCM in (A) the age-SIR plot, (B) diagnosis time-SIR plot and (C) the latency-SIR plot; Adjusted SIR and 95% CI of developing SCM in patients treated with RT versus the US general population are plotted, as well as patients treated without RT vs the US general population, and the incidence in the background US population is represented by the black line (at y ═ 1). The detailed data of SIR are shown in Table S5. SCM: Second cutaneous melanoma; SIR: Standardized incidence ratio; RT: Radiation therapy; CI: Confidence interval; NRT: Non-radiation therapy; BC: Breast cancer.

Figure 3.

Subgroup analyses of competing regression for the risk of developing second cutaneous melanoma. The other sites of BC include axillary tail of breast and overlapping lesion of breast. Significant P values are in bold. BC: Breast cancer; RT: Radiation therapy; NRT: Non-radiation therapy; UO: Upper outer quadrant of breast; UI: Upper inner quadrant of breast; LI: Lower inner quadrant of breast; LO: Lower outer quadrant of breast; CEN: Central portion quadrant of breast; sHR: Subdistribution hazard ratio; CI: Confidence interval.

Figure 4.

Survival outcome of the SCM. (A) Survival comparison between BC patients who developed SCM after RT and BC patients who developed SCM after NRT (before PSM) and (B) between BC patients who developed SCM after RT and BC patients who developed SCM after NRT (after PSM at a ratio of 1:1); SCM patients with RT (C and E) and without RT (D and F) were matched with OPCM patients based on propensity scores at a ratio of 1:5, and survival analysis was performed. The variables matched for PSM included age at SCM diagnosis, year of SCM diagnosis, race, stage, site, histology of SCM and type of treatment for SCM. Tables S8 and S9 reveal the complete patient characteristics of SCM and OPCM before and after PSM. BC: Breast cancer; RT: Radiation therapy; SCM: Second cutaneous melanoma; OPCM: Only primary cutaneous melanoma; PSM: Propensity score matching; OS: Overall survival; CSS: Cancer specific survival; NRT: Non-radiation therapy.