Liquid Biopsies for Molecular Biology-Based Radiotherapy

Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance

Liquid Biopsies for Molecular Biology-Based Radiotherapy

Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance.</jats:p

Reining in Radiation Injury: HIF2α in the Gut

Deletion of prolyl hydroxylase domain proteins or overexpression of hypoxia-inducible factor 2α (HIF2α) in the gastrointestinal epithelium improves survival of mice after abdominal irradiation (Taniguchi et al ., this issue). </jats:p

Strategies for optimizing the response of cancer and normal tissues to radiation

Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their treatment, and the majority of these patients are treated with curative intent. Despite recent advances in the planning of radiation treatment and the delivery of image-guided radiation therapy, acute toxicity and potential long-term side effects often limit the ability to deliver a sufficient dose of radiation to control tumours locally. In the past two decades, a better understanding of the hallmarks of cancer and the discovery of specific signalling pathways by which cells respond to radiation have provided new opportunities to design molecularly targeted therapies to increase the therapeutic window of radiation therapy. Here, we review efforts to develop approaches that could improve outcomes with radiation therapy by increasing the probability of tumour cure or by decreasing normal tissue toxicity

Detecting Liquid Remnants of Solid Tumors: Circulating Tumor DNA Minimal Residual Disease

Abstract Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results suggest that ctDNA MRD could identify candidates for adjuvant therapy and measure response to such treatment. Importantly, factors such as assay type, amount of ctDNA release, and technical and biological background can affect ctDNA MRD results. Furthermore, the clinical utility of ctDNA MRD for treatment personalization remains to be fully established. Here, we review the evidence supporting the value of ctDNA MRD in solid cancers and highlight key considerations in the application of this potentially transformative biomarker. Significance: ctDNA analysis enables detection of MRD and predicts relapse after definitive treatment for solid cancers, thereby promising to revolutionize personalization of adjuvant and consolidation therapies. </jats:sec

Concurrent Imatinib and Radiation Therapy for Unresectable and Symptomatic Desmoid Tumors

Desmoid tumors are locally aggressive fibroproliferative neoplasms that can lead to pain and dysfunction due to compression of nerves and surrounding structures. Desmoid tumors often progress through medical therapy, and there is frequently a delay of multiple months before radiation can provide symptomatic relief. To achieve more rapid symptomatic relief and tumor regression for unresectable desmoid tumors causing significant morbidity such as brachial plexus impingement with loss of extremity function, we have selectively utilized a combination of imatinib and radiation therapy. Here, we retrospectively review four patients treated with concurrent imatinib and radiation therapy. The treatment was typically tolerated with minimal toxicity though one patient developed avascular necrosis of the irradiated humeral head possibly related to the combined treatment. All the patients treated have had a partial response or stable disease on imaging. Improvement of symptoms was observed in all the treated patients with a median time to relief of 2.5 months after starting radiation therapy. Concurrent radiation and imatinib may represent a viable treatment option for unresectable and symptomatic desmoid tumors where rapid relief is needed to prevent permanent loss of function

Abstract LB-167: Tumor cells, but not endothelial cells, mediate the eradication of primary cancers by radiation therapy

Abstract Radiation therapy is frequently utilized in the clinic as curative treatment for cancers, but the contribution of endothelial cells to tumor response to radiation remains controversial. Using the two highly efficient site-specific recombinases, Cre and FlpO, we have generated primary tumors in mice with different gene mutations specifically in tumor cells and stromal cells. With this dual recombinase technology, we selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. We found that deletion of Bax in endothelial cells did not affect tumor response to radiation, but Atm deletion increased radiation-induced death of tumor endothelial cells and prolonged tumor growth delay following a non-curative dose of radiation. However, following a curative dose of radiation, Atm deletion in endothelial cells did not affect growth delay of primary tumors and failed to increase local control. In contrast, deletion of Atm in tumor cells increased local control of primary tumors by radiation therapy. These results demonstrate that tumor cells rather than endothelial cells are the critical targets that regulate tumor eradication by radiation therapy. They also emphasize the importance of using primary models of cancer to study the role of stromal cells in tumor development and response to therapy. Citation Format: Everett J. Moding, Chang-Lung Lee, Katherine D. Castle, Patrick Oh, David G. Kirsch. Tumor cells, but not endothelial cells, mediate the eradication of primary cancers by radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-167. doi:10.1158/1538-7445.AM2014-LB-167</jats:p

Musculoskeletal Tumor Care Disparities Prior to Initiation of Treatment Among Newly Diagnosed Adult Patients

Purpose: We investigated care disparities and associated factors along the segments of adult musculoskeletal tumor (MST) care prior to initiation of treatment. Patients and Methods: This cohort included newly diagnosed MST patients who were referred to Stanford Medical Center for establishing care from July 2020 to April 2024. We investigated the interval from the onset of symptoms to the first appointment with a primary care provider (PCP wait-time), and the interval from first PCP appointment to obtaining the first imaging study (imaging wait-time) and to obtaining biopsy results (biopsy wait-time). Sarcoma consult wait-time was defined as the interval between referral date and consult date. We performed a survey among sarcoma physicians and non-physician staff on the perception of wait-time. Results: Among 402 eligible patients, approximately 38.5% had PCP a wait-time longer than 5 weeks, with young adults and Hispanic patients having the highest rate of such long wait-times. Approximately 20.6% of patients had an imaging wait-time longer than 5 weeks, with young adults having the highest proportion of such long wait-times. In addition, Hispanic (p = 0.02), Black (p = 0.05) and Caucasian (p = 0.02) patients had significantly higher percentages of patients with an imaging wait-time of more than 5 weeks compared to Asians. Approximately 79.3% of patients had a biopsy wait-time longer than 5 weeks, with Black and Hispanic patients having the highest percent of such long wait-times. In addition, compared to public insurance, private insurance was associated with a higher proportion of patients with PCP wait-times, imaging wait-times, sarcoma consult wait-times and biopsy wait-times longer than 5 weeks. The survey responses overwhelmingly indicated that a wait-time of more than 5 weeks was not acceptable. Conclusions: Substantial disparities in MST care related to age group, ethnicity and insurance type existed in multiple segments of the care journey prior to the initiation of treatment. Our study provides insights for practice, research and policy considerations for narrowing sarcoma care disparities