Association of Skin Microbiome Dynamics With Radiodermatitis in Patients With Breast Cancer

Abstract

Importance: The interindividual differences in severity of acute radiation dermatitis are not well understood. To date, the pathomechanism and interplay of microbiome and radiodermatitis before and during treatment remain largely unknown.

Objective: To assess the association of skin microbiome baseline composition and dynamics with severity of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer.

Design, setting, and participants: A longitudinal prospective pilot observational study was conducted between January 2017 and January 2019. Sequencing results were received in March 2021, and the data were analyzed from August 2021 to March 2023. This study was performed at an urban academic university cancer center. A total of 21 female patients with breast cancer after surgery were consecutively approached, of which 1 patient withdrew consent before the study started.

Exposure: Adjuvant radiotherapy for breast cancer for 7 weeks.

Main outcomes and measures: The main outcome was the association of baseline skin microbiome composition and its dynamics with the severity of radiodermatitis. A total of 360 skin microbiome samples from patients were analyzed, taken before, during, and after radiotherapy, from both the treated and contralateral healthy sides. The skin microbiome samples were analyzed using 16S (V1-V3) amplicon sequencing and quantitative polymerase chain reaction bacterial enumeration.

Results: Twenty female patients with breast cancer after surgery who underwent radiotherapy enrolled in the study had a median (range) age of 61 (37-81) years. The median (range) body mass index of the patients was 24.2 (17.6-38.4). The 16S sequencing revealed that low (<5%) relative abundance of commensal skin bacteria (Staphylococcus epidermidis, Staphylococcus hominis, Cutibacterium acnes) at baseline composition was associated with the development of severe radiodermatitis with an accuracy of 100% (sensitivity and specificity of 100%, P < .001). Furthermore, in patients with severe radiodermatitis, quantitative polymerase chain reaction bacterial enumeration revealed a general non-species-specific overgrowth of skin bacterial load before the onset of severe symptoms. Subsequently, the abundance of commensal bacteria increased in severe radiodermatitis, coinciding with a decline in total bacterial load.

Conclusions and relevance: The findings of this observational study indicated a potential mechanism associated with the skin microbiome for the pathogenesis of severe radiodermatitis, which may be a useful biomarker for personalized prevention of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer.

Figure 1.. Study Design and Radiodermatitis Severity

A, To investigate the association of skin physiology and microbiome with radiodermatitis severity, a longitudinal study with 9 visits throughout 12 weeks before, during, and after radiotherapy was conducted. B, At each visit, skin physiology and radiodermatitis severity were measured, and samples for skin microbiome analysis were taken from the affected, radiated breast and the unaffected, nonradiated breast side. All patients developed either a mild (light blue, CTCAE grade 1), moderate (dark blue, CTCAE grade 2), or severe (yellow, CTCAE grade 3) form of radiodermatitis. Severe symptoms were observed in 4 patients between visits at weeks 5 to 7. CTCAE indicates Common Terminology Criteria for Adverse Events.

Figure 2.. Low Level of Commensal Skin Bacteria at Baseline and Severe Radiodermatitis Development

Patients who develop severe radiodermatitis have a significantly lower baseline relative abundance of commensals at the affected body side (P < .001). Commensals are defined as the sum of Cutibacterium acnes, Staphylococcus epidermidis, and S hominis relative abundances in this study. Patients with severe radiodermatitis had higher relative abundances of Corynebacteriaceae species, compared with patients with mild and moderate radiodermatitis, as shown per individual (A) and group (B and C). No significant difference was found in commensals relative abundance at baseline between patients with mild and moderate radiodermatitis. The maximum Common Terminology Criteria for Adverse Events (CTCAE) severity score reached in each patient during the study period was used to group patients with mild (grade 1), moderate (grade 2), and severe (grade 3) radiodermatitis. Green and blue colors represent skin commensal species; pink, red, and orange colors represent different Corynebacteriaceae species. A sum of relative abundances of these commensals below 5% at baseline in the affected side (D) was significantly associated with the development of severe radiodermatitis with an accuracy of 100% (P < .001). The number of patients is indicated on top of the bars.

Figure 3.. Increase of Total Bacterial Load and Recovery of Commensal Skin Bacteria During Radiotherapy in Patients With Severe Radiodermatitis

A, Patients with severe radiodermatitis (yellow, Common Terminology Criteria for Adverse Events [CTCAE] grade 3) had an increase in bacterial load (measured as 16S copy numbers) as compared with their baseline values in the affected side, prior to the period with severe symptoms. B, The maximum total bacterial load increased during the early phase of the study (weeks 1-3) and was significantly higher in the affected side of patients with severe radiodermatitis, compared with mild to moderate radiodermatitis. Only the affected body side in patients with severe radiodermatitis showed an increase in bacterial load and not the unaffected side. C, The commensal frequency (defined as the sum of Cutibacterium acnes, Staphylococcus epidermidis, and Staphylococcus hominis frequencies) in patients with severe radiodermatitis recovered over time, and the median crossed 5% frequency at week 5. D, Only patients with severe dermatitis (yellow) exhibited both an increase of 16S copy numbers during weeks 1 to 3 and an increase of commensals frequency during weeks 5 to 7, compared with patients with mild (light blue) and moderate (dark blue) radiodermatitis (P < .001).