Radiation Induced Lymphopenia Is Associated With the Effective Dose to the Circulating Immune Cells in Breast Cancer.

Background: Lymphopenia is a known significant factor for treatment outcome in cancer patients, with underlying risk factor poorly understood in breast cancer. We hypothesize that the effective dose to the circulating immune cells (EDIC) which was related with lymphopenia in lung cancer will also have significant effect for radiation induced lymphopenia (RIL) in patients with breast cancer. Material and Methods: Patients treated with adjuvant radiotherapy (RT) and with complete blood tests within one week from RT end/start (post/preRT) were eligible in this study. Radiation dosimetric factors were collected retrospectively, and EDIC for each patient was calculated based on the doses to lung, heart and total body according to the model description, as previously reported. RIL was defined by the CTCAE5.0 based on postRT peripheral lymphocyte count (PLC). Linear regression was first used to test the correlation between EDIC with post/preRT PLC ratio and postRT PLC, using all these as continuous variables. Normal tissue complication probability (NTCP) was used to develop models that predict the CTCAE graded RIL from EDIC. Results: A total of 735 patients were eligible. The mean post/preRT PLC ratio was 0.66 (95% CI: 0.64-0.68) and mean EDIC of breast cancer was 1.70Gy (95% CI: 1.64-1.75). Both post/preRT PLC ratio and postRT PLC were significantly correlated with EDIC (P<0.001), with R2 of 0.246. For patients with normal preRT PLC, the post/preRT PLC ratio was better associated with EDIC, and postRT PLC was expressed as PLC preRT × (0.89 - 0.16 × EDIC). For patients with preRT lymphopenia, postRT PLC was better associated with EDIC and it was 1.1 - 0.17 × EDIC. Using binned EDIC as the dose variable, the bootstrap validated NTCPs fit the data nicely with R2 of 0.93, 0.96, and 0.94 for grade-1, grade-2, and grade-3 RIL, respectively. The corresponding EDIC to induce 50% of grade-1, grade-2 and grade-3 RIL was 1.2, 2.1 and 3.7 Gy, respectively. Conclusion: EDIC is a significant factor for RIL in patients with breast cancer, and may be used to compute the risk of lymphopenia in each individual patient with the use of the conventional NTCP modeling. External validation is needed before the EDIC can be used to guide RT plan.

Real-World Practice of Hypofractionated Radiotherapy in Patients With Invasive Breast Cancer.

PURPOSE: Application of hypofractionated radiotherapy (HFRT) is growing in patients with breast cancer (BC). This study aimed to explore a real-world practice of HFRT in early and locally advanced BC. METHODS: Patients with invasive BC between 2015 and 2019 were retrospectively reviewed. Radiotherapy (RT) was delivered by HFRT and conventionally fractionated radiotherapy (CFRT). Locoregional recurrence-free survival (LRRFS) and disease-free survival (DFS) were calculated by Kaplan-Meier curve and compared by Log-rank test. The effect of treatment modality on DFS was estimated by univariate and multivariable analyses. RESULTS: A total of 1,010 patients were included in this study, and 903 (89.4%) were treated with HFRT. At a median follow-up of 49.5 months, there was no significant difference in a 4-year cumulative incidence of LRRFS in HFRT group (1.5%) and in CFRT group (3.8%) (p = 0.23), neither in different nodal stages nor in N2-3 patients with different molecular subtypes. The 4-year DFS was 93.5% in HFRT group compared with 89.9% in CFRT group with no significant difference either (p = 0.17). Univariate and multivariable analyses also showed no significant difference in DFS between HFRT and CFRT group. However, DFS of HFRT group tended to be lower in N2-3 patients with triple negative BC compared with that of CFRT group (76.2% versus 100%). CONCLUSION: HFRT can achieve similar cumulative incidence of LRRFS and DFS in patients with BC after lumpectomy or mastectomy, and also in different nodal stage, and in locally advanced stage with different molecular subtypes.

Chemotherapy is a risk factor of lymphopenia before adjuvant radiotherapy in breast cancer.

BACKGROUND: Lymphopenia can decrease immune function of the host and is a known risk factor for poor prognosis in malignant tumors. Radiation induced lymphopenia was common in patients with breast cancer and was also reported to have a negative effect on long-term outcome. AIMS: Lymphopenia may be associated with baseline immune status before radiotherapy (RT). This study aimed to explore the rate and risk factors of lymphopenia before start of the adjuvant RT in patients with breast cancer. METHODS: Patients with invasive breast cancer treated from March 2015 to February 2020 and with peripheral lymphocyte counts (PLC) available within 7 days from the beginning of RT were eligible for this study. Data were presented as mean and 95% confidence interval unless otherwise specified. The risk factors of low PLC before RT were identified using univariate and multivariable linear regressions. RESULTS: A total of 1012 consecutive patients met the study criteria. The mean PLC before RT commencement was 1.58*109 /L (95%CI: 1.55-1.62*109 /L) with 15.2% (95%CI: 13.1%-17.6%) CTCAE defined lymphopenia, rendering 12.3%, 2.6%, 0.3%, and 0% for grade 1, 2, 3 and 4 respectively. Univariate and multivariable linear regression showed prior chemotherapy was the most significant risk factor (p < .001) for low PLC, while age, menopausal status and lymph node stage were not (all ps > .05). A total of 912 (90.1%, 95%CI: 88.1%-91.9%) patients had chemotherapy before adjuvant RT in this study. In patients with HR+/HER2- breast cancer, 69.0% (95%CI: 63.0%-74.5%) N0 and 98.1% (95%CI: 95.1%-99.5%) N1 had also received chemotherapy. CONCLUSIONS: Patients with breast cancer might have lymphopenia from prior chemotherapy at the start of adjuvant RT which could have negative effect on long-term outcome. It is also noted that most of the patients with HR+/HER2-, early-stage breast cancer were treated with aggressive chemotherapy without knowing the risk of chemotherapy induced lymphopenia. Future study on predictive or prognostic multigene assays is warranted to avoid unnecessary chemotherapy and subsequent lymphopenia in patients with low risk breast cancer.

Risk factors for radiation induced lymphopenia in patients with breast cancer receiving adjuvant radiotherapy.

BACKGROUND: This study aimed to investigate radiation-induced lymphopenia and its potential risk factors in patients with breast cancer receiving adjuvant radiotherapy. METHODS: Breast cancer patients received adjuvant radiotherapy (RT) at our hospital with peripheral lymphocyte counts (PLC) at pre-and immediately after RT (post-RT) were eligible. The primary endpoints were any grade of lymphopenia post-RT and nadir-PLC/pre-PLC <0.8. Patient characteristics, tumor factors, and treatment factors were collected for risk assessment. Data are presented as mean and 95% confidence interval (CI) unless otherwise specified. Matched analysis was used to compare the statistical significance between different RT techniques. RESULTS: A total of 735 consecutive patients met the study criteria. The mean PLC was 1.58×109/L before and 0.99×109/L post-RT (P<0.001). At the end of RT, 60.5% of patients had lymphopenia. Univariate and multivariable logistic analyses showed that RT technique involving RapidArc, mean lung dose, and chemotherapy were significant risk factors (P<0.05) for lymphopenia. RT technique was the only significant risk factor (P<0.05) for nadir-PLC/pre-PLC <0.8. Patients treated with RapidArc had a significantly greater reduction of PLC along with greater V5 of the lungs, even after matching mean lung dose and radiated volume. CONCLUSIONS: Lymphopenia is common in patients with breast cancer after adjuvant RT. RT technique is the only significant factor for lymphopenia and nadir-PLC/pre-PLC <0.8, suggesting the significance of RT technique choice to minimize lymphopenia and improve treatment outcomes.