Seneviratne, Danushka S.

Biological heterogeneity among different breast cancer (BC) subtypes results in markedly varying clinical outcomes. Identification and analysis of key gene biomarkers that are differentially regulated during radiation therapy (RT) may pose multiple clinical challenges for BC treatment. The purpose of the study is to identify and analyze the expression of key gene biomarkers and their networks that are differentially regulated after hypofractionated RT. Patients with BC (cT0-T2, N0, M0) were treated with hypofractionated whole breast RT 25 Gy in five fractions, 4 to 8 weeks before breast conservation surgery (BCS). Biopsy (pre-RT; n = 5) and surgical (post-RT; n = 14 or 15) BC tumor samples were used for NanoString targeted sequencing. We identified 165 and 244 differentially expressed genes (DEGs; p < 0.05) in BC tumor samples from BC patients post-RT using the nCounter BC360 and IO360 panels, respectively. Gene networks and pathway analysis revealed that RT increases the gene signature of tumor inflammation (TIS), cytotoxicity, and apoptosis, while downregulating the gene signatures of tumor cell proliferation, differentiation, and cell adhesion, and increases the claudin-low gene score. RT-induced mammary stemness and enhanced infiltration of stroma, mast, and macrophage cells in the BC tumor microenvironment (TME). Further, the nCounter IO360 (immuno-oncology) panel analysis validated the findings of BC360 and demonstrated that RT increased the myeloid inflammation signature and chemokine expression, modulated B, T, NK, and DC cell activities, and enhanced residual cancer burden (RCB) in BC tumors, thus creating an immunosuppressive TME. Collectively, RT sensitized BC tumors by increasing the gene signature of TIS, cytotoxicity, apoptosis, and mammary stemness. RT facilitated an immunosuppressive environment and increased RCB, suggesting that the therapeutic potential of RT is highly individualized for each patient based on their unique tumor biology, genetic makeup, and TME.

BNCT is a high-linear-energy transfer therapy that facilitates tumor-directed radiation delivery while largely sparing adjacent normal tissues through the biological targeting of boron compounds to tumor cells. Tumor-specific accumulation of boron with limited accretion in normal cells is the crux of successful BNCT delivery. Given this, developing novel boronated compounds with high selectivity, ease of delivery, and large boron payloads remains an area of active investigation. Furthermore, there is growing interest in exploring the immunogenic potential of BNCT. In this review, we discuss the basic radiobiological and physical aspects of BNCT, traditional and next-generation boron compounds, as well as translational studies exploring the clinical applicability of BNCT. Additionally, we delve into the immunomodulatory potential of BNCT in the era of novel boron agents and examine innovative avenues for exploiting the immunogenicity of BNCT to improve outcomes in difficult-to-treat malignancies.

BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states.

AbstractDespite advancements in local‐regional and systemic therapies, non‐small cell cancer (NSCLC) remains a leading cause of death worldwide. Among those treated with standard‐of‐care modalities, 30–60% experience disease recurrence. Carbon ion radiotherapy (CIRT) is a form of densely ionizing radiotherapy with unique physical and biological advantages over traditional photon and proton modalities. CIRT is expected to have a superior biological impact on tumors, and is believed to be less impacted by the presence of tumor hypoxia or cell cycle state. It also shows highly conformal physical dose deposition due to reduced lateral scattering of the particles, limiting the radiation dose delivered to adjacent organs at risk. To implement CIRT as a viable option in the treatment of NSCLC, technical aspects of treatment delivery – including appropriate beam arrangements, dose calculation algorithms, radiobiological models, and methods of motion management – must be thoroughly investigated. Furthermore, randomized clinical trials comparing CIRT versus traditional radiation modalities must be performed to show the benefits and risks associated with this novel treatment modality. This review discusses the rationale for utilizing CIRT in NSCLC, available clinical data to date, and the potential for future investigations that may pave the path for improving outcomes in those diagnosed with NSCLC.

Radiotherapy (RT) is one of the cornerstones in the current treatment paradigm for glioblastoma (GBM). However, little has changed in the management of GBM since the establishment of the current protocol in 2005, and the prognosis remains grim. Radioresistance is one of the hallmarks for treatment failure, and different therapeutic strategies are aimed at overcoming it. Among these strategies, nanomedicine has advantages over conventional tumor therapeutics, including improvements in drug delivery and enhanced antitumor properties. Radiosensitizing strategies using nanoparticles (NP) are actively under study and hold promise to improve the treatment response. We aim to describe the basis of nanomedicine for GBM treatment, current evidence in radiosensitization efforts using nanoparticles, and novel strategies, such as preoperative radiation, that could be synergized with nanoradiosensitizers.

Abstract Background: Multiple studies have identified an association between diagnosis of breast cancer and post-diagnosis psychological distress. Some have taken a step further, identifying predictive markers of distress in diagnosed patients and interventions to minimize post-diagnosis distress. Data regarding pre-diagnosis psychological distress and its impact on surgical decision making and clinical outcomes in the breast cancer population are limited. Here, we assessed pre-diagnosis major life stressors and breast cancer outcomes in a single-center population. Methods: Patients with newly diagnosed stage 0-3 breast cancer seen at Mayo Clinic Florida between June 11, 2018, and October 7, 2019, were included. Prior to their initial visit, patients were administered a voluntary telephone survey regarding the incidence of major life events and stressors during the 18 months preceding their diagnosis. Demographic data including age and ethnicity were also included. Subsequent clinical outcomes were obtained through retrospective chart review. Clinical outcomes were assessed with descriptive statistics. Chi-square tests were used to compare subgroups, with p &lt; 0.05 considered statistically significant. Results: Of 469 patients seen for a new breast cancer diagnosis, 222 patients completed the intake survey and met inclusion criteria. Median age was 60 (27-84) years. 80.6% of patients were white, 7.7% were black, 5.4% were Asian/Pacific Islander, and 2.3% were Latino. Over 95% endorsed having some form of social support. 51.3% reported experiencing a major life event prior to breast cancer diagnosis. Of these patients (n = 114), 43.9% denoted this stressor as family-related, as compared to 20.2% citing non-breast cancer illness, 14.9% claiming relationship stress, and 14% describing employment-related stress. Only 1.8% endorsed stress caused by financial concerns. Multiple major life events were reported by 10.8% of all included patients. Subgroup analysis of the patients with pre-diagnosis stress revealed a similar demographic distribution to the overall sample. Compared to the subgroup without pre-diagnosis stress (n = 108), there were more patients with carcinoma in situ and stage T3/T4 disease (21.1% versus 13.0%, p = 0.11) and 11.4% versus 10.2%, p = 0.77), respectively) in the subgroup with pre-diagnosis stress, although these differences were not statistically significant. More patients with pre-diagnosis stress elected to undergo mastectomy (34.2% versus 22.2%, p = 0.048) as compared to the group without stress. Conclusions: With over half of sample patients reporting pre-diagnosis major life stressors, psychological distress is prevalent prior to breast cancer diagnosis and should be considered as a factor for early intervention, such as psychological and financial counseling, during breast cancer evaluation. The sample population was predominantly white and resource-rich in terms of financial and social support, highlighting a need for characterization of pre-diagnosis psychological distress in more ethnically diverse and/or resource-limited settings. Although additional study is recommended, current data suggest possible associations between pre-diagnosis psychological distress and treatment decision making, particularly the decision to pursue mastectomy. Citation Format: Tanmayi Pai, Laura Vallow, Danushka Seneviratne, Dawn Mussallem, Lauren Cornell. Pre-diagnosis major life stressors and breast cancer outcomes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-46.