Potential Determinants for Radiation-Induced Lymphopenia in Patients With Breast Cancer Using Interpretable Machine Learning Approach

Abstract

Radiation-induced lymphopenia is known for its survival significance in patients with breast cancer treated with radiation therapy. This study aimed to evaluate the impact of radiotherapy on lymphocytes by applying machine learning strategies. We used Extreme Gradient Boosting (XGboost) to predict the event of lymphopenia (grade≥1) and conduced an independent validation. Then, we induced feature attribution analysis (Shapley additive explanation, SHAP) in explaining the XGboost models to explore the directional contribution of each feature to lymphopenia. Finally, we implemented the proof-of-concept clinical validation. The results showed that the XGboost models had rigorous generalization performances (accuracies 0.764 and ROC-AUC 0.841, respectively) in the independent cohort. The baseline lymphocyte counts are the most protective feature (SHAP = 5.226, direction of SHAP = -0.964). Baseline platelets and monocytes also played important protective roles. The usage of taxane only chemotherapy was less risk on lymphopenia than the combination of anthracycline and taxane. By the contribution analysis of dose, we identified that firstly lymphocytes were sensitive to a radiation dose less than 4Gy; secondly the irradiation volume was more important in promoting lymphopenia than the irradiation dose; thirdly the irradiation dose promoted the event of lymphopenia when the irradiation volume was fixed. Overall, our findings paved the way to clarifying the radiation dose volume effect. To avoid radiation-induced lymphopenia, irradiation volume should be kept to a minimum during the planning process, as long as the target coverage is not compromised.

Lymphocytopenia following adjuvant radiotherapy for breast cancer

“…Recently, a group at the University of Hong Kong published several studies that highlighted predictive factors of lymphocytopenia, including the use of VMAT, EDIC, and chemotherapy 6,8,9 . They also explored the potential determinants of radiation‐induced lymphopenia using a machine learning approach 10 . The present study analyzed standard clinical and treatment‐related factors to identify the predictive factors for lymphocytopenia.…”

“…6,8,9 They also explored the potential determinants of radiation-induced lymphopenia using a machine learning approach. 10 The present study analyzed standard clinical and treatment-related factors to identify the predictive factors for lymphocytopenia. Regression analysis revealed that regional lymph node irradiation and a lower lymphocyte count of < 1000/µL before radiotherapy were associated with severe lymphocytopenia in patients treated with and without chemotherapy.…”

“…The baseline lymphocyte count is a comprehensible factor, as indicated in previous studies. 10,14 The other three factors suggest that a larger irradiation field and more complex irradiation procedures are associated with severe lymphocytopenia, in addition to baseline lymphocyte reserve capacity.…”

“…[2][3][4][5] Among patients with breast cancer, some treatment-related factors, including prior chemotherapy, standard fraction radiotherapy (2 Gy/fraction), and the use of volumetric modulated arc therapy (VMAT) technique, have been linked to lymphocytopenia. [6][7][8] While some studies have used multifactorial models, such as the effective dose to circulating immune cells (EDIC) or machine learning approaches, 9,10 the predictive factors of lymphocytopenia are not fully understood.…”

Navigating Uncharted Waters: Could COVID-19 and/or Certain COVID-19 Vaccines Promote Malignancy?

“…Organ transplant recipients accepting an organ from a cancer survivor donor may develop malignancy because exposure to the immunosuppressant drugs that prevent organ rejection allows hidden latent metastases (transplanted with the organ) to spring to life [55]. Notably, some types of cancer treatment, such as chemotherapy, radiation, and the combination of chemotherapy and immunotherapy can also cause severe lymphopenia, which is correlated with reduced survival [50,56,57].…”