Molecular Changes in Breast Cancer Induced by Radiation Therapy.

PURPOSE: Breast cancer treatments are based on prognostic clinicopathologic features that form the basis for therapeutic guidelines. Although the utilization of these guidelines has decreased breast cancer-associated mortality rates over the past three decades, they are not adequate for individualized therapy. Radiation therapy (RT) is the backbone of breast cancer treatment. Although a highly successful therapeutic modality clinically, from a biological perspective, preclinical studies have shown RT to have the potential to alter tumor cell phenotype, immunogenicity, and the surrounding microenvironment, potentially changing the behavior of cancer cells and resulting in a significant variation in RT response. This review presents the recent advances in revealing the complex molecular changes induced by RT in the treatment of breast cancer and highlights the complexities of translating this information into clinically relevant tools for improved prognostic insights and the revelation of novel approaches for optimizing RT. METHODS AND MATERIALS: Current literature was reviewed with a focus on recent advances made in the elucidation of tumor-associated radiation-induced molecular changes across molecular, genetic, and proteomic bases. This review was structured with the aim of providing an up-to-date overview over the very broad and complex subject matter of radiation-induced molecular changes and radioresistance, familiarizing the reader with the broader issue at hand. RESULTS: The subject of radiation-induced molecular changes in breast cancer has been broached from various physiological focal points including that of the immune system, immunogenicity and the abscopal effect, tumor hypoxia, breast cancer classification and subtyping, molecular heterogeneity, and molecular plasticity. It is becoming increasingly apparent that breast cancer clinical subtyping alone does not adequately account for variation in RT response or radioresistance. Multiple components of the tumor microenvironment and immune system, delivered RT dose and fractionation schedules, radiation-induced bystander effects, and intrinsic tumor physiology and heterogeneity all contribute to the resultant RT outcome. CONCLUSIONS: Despite recent advances and improvements in anticancer therapies, tumor resistance remains a significant challenge. As new analytical techniques and technologies continue to provide crucial insight into the complex molecular mechanisms of breast cancer and its treatment responses, it is becoming more evident that personalized anticancer treatment regimens may be vital in overcoming radioresistance.

Excess body weight and postmenopausal breast cancer: Emerging molecular mechanisms and perspectives.

Postmenopausal, obese women have a significantly higher risk of developing estrogen receptor-positive (ER+) breast tumors, that are resistant to therapies and are associated with higher recurrence and death rates. The global prevalence of overweight/obese women has reached alarming proportions and with postmenopausal ER+ breast carcinoma (BC) having the highest incidence among the three obesity-related cancers in females (i.e., breast, endometrial and ovarian), this is of significant concern. Elucidation of the precise molecular mechanisms underlying the pro-cancerous action of obesity in ER+BC is therefore critical for disease prevention and novel treatment initiatives. Interestingly, accumulating data has shown opposing relationships between obesity and cancer in either pre- or post-menopausal women. Excess body weight is associated with an increased risk of breast cancer in postmenopausal women and a decreased risk in pre-menopausal women. Moreover, excess adiposity during early life appears to be protective against postmenopausal breast cancer, including both ER+ and ER negative BC subtypes. Overall, estrogen-dependent mechanisms have been implicated as the main driving force in obesity-related breast tumorigenesis. In the present review we discuss the epidemiologic and mechanistic aspects of association between obesity and breast tumors after menopause, mainly in the context of hormone dependency. Molecular and cellular events underlying this association present as potential avenues for both therapeutic intervention as well as the prevention of BC-promoting processes linked to excess adiposity, which is proving to be vital in an increasingly obese global population.

Safety and rapid response of dabrafenib and trametinib therapy during hyperbilirubinemia in metastatic melanoma.

This case report describes the occurrence of hyperbilirubinemia as a complication of metastatic melanoma. A 72-year-old male patient was diagnosed with BRAF V600E-mutated melanoma with metastases in the liver, lymph nodes, lungs, pancreas, and stomach. Due to a lack of clinical data and specific guidelines for the treatment of mutated metastatic melanoma patients with hyperbilirubinemia, a conference of specialists debated between initiating treatment or providing supportive care. Ultimately, the patient was started on the combination therapy of dabrafenib and trametinib. This treatment resulted in a significant therapeutic response via normalization of bilirubin levels and an impressive radiological response of metastases just one month post-treatment initiation.

Radiation-Induced Nephropathy in the Murine Model Is Ameliorated by Targeting Heparanase.

Agents used to reduce adverse effects common in cancer treatment modalities do not typically possess tumor-suppressing properties. We report that heparanase, an extracellular matrix-degrading enzyme, is a promising candidate for preventing radiation nephropathy. Heparanase promotes tumor development and progression and is upregulated in tumors found in the abdominal/pelvic cavity, whose radiation treatment may result in radiation nephropathy. Additionally, heparan sulfate degradation by heparanase has been linked to glomerular and tubular/interstitial injury in several kidney disorders. In this study, heparanase mRNA levels were measured in HK-2- and HEK-293-irradiated kidney cells and in a murine radiation nephropathy model by qRT-PCR. Roneparstat (specific heparanase inhibitor) was administered to irradiated mice, and 24 h urinary albumin was measured. Kidneys were harvested and weighed 30 weeks post-irradiation. Clinically relevant doses of ionizing radiation upregulated heparanase expression in both renal cells and mice kidneys. A murine model of abdominal radiation therapy revealed that Roneparstat abolished radiation-induced albuminuria-the hallmark of radiation nephropathy. Given the well-documented anti-cancer effects of heparanase inhibition, our findings attest this enzyme to be a unique target in cancer therapy due to its dual action. Targeting heparanase exerts not only direct anti-tumor effects but protects against radiation-induced kidney damage-the backbone of cancer therapy across a range of malignancies.

A Retrospective, Single-Institution Experience of Bullous Pemphigoid as an Adverse Effect of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors are a class of cancer treatment drugs that stimulate the immune system's ability to fight tumor cells. These drugs are monoclonal antibodies targeting im-mune-inhibiting proteins on cancer cells, such as CTLA-4 and PD-1/PD-L1. Immune checkpoint inhibitors cause many immune-related adverse events. Cutaneous toxicities are of the most common adverse effects and occur with a range of severity. Bullous Pemphigoid is a rare adverse event with a high impact on quality of life that may occur after immune checkpoint inhibitor treatment. In this article, we investigate current research on immune checkpoint inhibitors, cutaneous adverse events, and common presentations and treatments, with a specific focus on Bullous Pemphigoid, its characteristics, onset timing, and treatment. Significant findings include a negative skew in the onset of presentation. Furthermore, we describe exclusive cases.

Computational quantification and characterization of independently evolving cellular subpopulations within tumors is critical to inhibit anti-cancer therapy resistance.

BACKGROUND: Drug resistance continues to be a major limiting factor across diverse anti-cancer therapies. Contributing to the complexity of this challenge is cancer plasticity, in which one cancer subtype switches to another in response to treatment, for example, triple-negative breast cancer (TNBC) to Her2-positive breast cancer. For optimal treatment outcomes, accurate tumor diagnosis and subsequent therapeutic decisions are vital. This study assessed a novel approach to characterize treatment-induced evolutionary changes of distinct tumor cell subpopulations to identify and therapeutically exploit anticancer drug resistance. METHODS: In this research, an information-theoretic single-cell quantification strategy was developed to provide a high-resolution and individualized assessment of tumor composition for a customized treatment approach. Briefly, this single-cell quantification strategy computes cell barcodes based on at least 100,000 tumor cells from each experiment and reveals a cell-specific signaling signature (CSSS) composed of a set of ongoing processes in each cell. RESULTS: Using these CSSS-based barcodes, distinct subpopulations evolving within the tumor in response to an outside influence, like anticancer treatments, were revealed and mapped. Barcodes were further applied to assign targeted drug combinations to each individual tumor to optimize tumor response to therapy. The strategy was validated using TNBC models and patient-derived tumors known to switch phenotypes in response to radiotherapy (RT). CONCLUSIONS: We show that a barcode-guided targeted drug cocktail significantly enhances tumor response to RT and prevents regrowth of once-resistant tumors. The strategy presented herein shows promise in preventing cancer treatment resistance, with significant applicability in clinical use.

Loss of Heterozygosity of BRCA1/2 as a Predictive Marker for Talazoparib Response.

BACKGROUND/AIM: Tumor cell lines are essential tools in understanding the molecular mechanisms underlying cancer biology and therapeutic responses. Poly (ADP-ribose) polymerase inhibitors (PARPi) kill tumor cells harboring pathogenic mutations of BRCA DNA repair-associated genes 1/2 (BRCA1/2) and are approved to treat ovarian and metastatic breast cancer. Loss of heterozygosity (LOH) of the wild-type BRCA1/2 locus is suspected to increase cellular response to PARPi. To better elucidate the molecular mechanisms underlying PARPi sensitivity and resistance, this study assessed the responses of various pathogenic BRCA1/2-mutant cell lines to the PARPi talazoparib. MATERIALS AND METHODS: Mutant cell lines were extracted and cultured from four surgically resected, human breast cancer specimens with different pathogenic BRCA1/2, one normal breast specimen and one ovarian cancer specimen. Mutation analysis was performed on all cell lines using genomic DNA extraction and polymerase chain reaction. Following treatment with talazoparib, cell growth was assessed using tetrazolium salt and half-maximal inhibitory concentration values were determined. RESULTS: A partial correlation between different variants of pathogenic BRCA1/2 mutation and talazoparib susceptibility was found, with five of the cell lines exhibiting sensitivity to talazoparib. The most sensitive cell-line to talazoparib had LOH for BRCA1, while the breast cancer cell line harboring BRCA2 LOH was resistant to talazoparib. CONCLUSION: This study suggests that LOH does not necessarily correlate with PARPi efficacy. These results lay a foundation for future studies to utilize these novel cell lines to further elucidate the underlying molecular mechanisms of PARPi resistance and reveal new potential drug targets.

Modified bi-weekly cetuximab-cisplatin and 5-FU/leucovorin based regimen for effective treatment of recurrent/metastatic head and neck squamous cell carcinoma to reduce chemotherapy exposure of patients.

BACKGROUND: The standard chemotherapy treatment protocol for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) requires as long as 56 days of hospitalization over six months. Where the 5-Fluorouracil (5-FU) pump is available, most treatment will be on outpatient bases, however patients will still be under chemotherapy treatment for a comparable period of time (around 50 days). AIM: A modified protocol was assessed to decrease hospitalization and/or chemotherapy treatment time without sacrificing outcomes, to potentially increase patient quality of life. METHODS AND RESULTS: A retrospective analysis (2005-2018) of recurrent/metastatic HNSCC patients with a modified treatment protocol was performed. Treatment consisted of cisplatin, cetuximab, 5-fluorouracil bolus and leucovorin administered on day 1 of a 2-week cycle, and a continuous infusion of 5-fluorouracil on days 1-2 of the cycle. Outcomes were measured by progression-free survival, overall survival, and patient hospitalization time. Analysis was done using the Kaplan-Meier survival function curve. The study cohort consisted of 27 patients. The modified treatment protocol resulted in a median progression-free survival of nine months and median overall survival of 14 months, while hospitalization time was reduced by almost 80% in the first six months of treatment. CONCLUSIONS: Modification of the cisplatin, cetuximab, 5-FU and leucovorin protocol to a bi-weekly regimen utilizing alternative drug delivery methods, significantly reduced patient hospitalization from 56 days to 12 days in the first 6 months of treatment. This was achieved without compromising treatment outcome, while significantly reducing the days patients were exposed to chemotherapy, and thus potentially improving quality of life.

Dermatomyositis Associated with Lung Cancer: A Brief Review of the Current Literature and Retrospective Single Institution Experience.

Dermatomyositis is a rare inflammatory myopathy that is often related to lung cancer. In this retrospective observational study, we analyzed data from patients diagnosed with lung cancer at Soroka University Medical Center between January 2017 and July 2021. A total of 689 patients with lung cancer were included in this study, 97 of whom had small cell lung cancer and 592 had non-small cell lung cancer. We identified a single patient (60-year-old female) who presented with signs and symptoms of dermatomyositis, which was later confirmed to be associated with lung cancer as a paraneoplastic syndrome. Both our study and a recent review of the literature illustrate the temporal link between dermatomyositis and lung cancer, as well as reinforce the need for heightened cancer screenings in DM patients.

Clinical Applicability of the Proliferation Marker Thymidine Kinase 1 in Head and Neck Cancer Patients.

BACKGROUND/AIM: Prognostic factors serve as a vital tool in the treatment of patients with head and neck cancer (HNC). The aim of this study was to evaluate the clinical potential of Thymidine-kinase-1 (TK1) marker in the prognosis of HNC patients. PATIENTS AND METHODS: We evaluated 366 blood samples from 278 HNC patients and 88 healthy controls, using an ELISA assay. Correlations of TK1 levels with disease stage, lymph node involvement and response to radiation therapy, were determined. RESULTS: In HNC patients, TK1 levels were significantly higher compared to healthy controls. Significantly higher TK1 levels were demonstrated in node positive cases and in advanced disease stages compared to node negative and early disease stages. Levels were higher prior to radiation and decreased significantly thereafter, in patients responding to treatment. Increasing levels of TK1 post-radiation were indicative of recurrence or of non-response to treatment, while decreasing levels indicated a positive response. CONCLUSION: TK1 is a tumor marker in HNC patients with the ability to assess response to therapy. High or increasing levels correlated to a poor prognosis, whereas low levels correlated to an overall increased survival.