11112 Background: PROgress Tracker Breast Cancer Registry is a national, ethics approved non-interventional patient-reported outcome measure (PROMs) registry, using a peer-to-peer model directed by patient advocacy group Breast Cancer Canada. Here, initial results report breast cancer survivors nature of cancer illness worry and intensity based on age, stage and molecular subtype at diagnosis. Methods: PROgress Tracker was launched in 2023, with enrollment over 10 years of Canadians with Stage 0-IV breast cancer. Participants self-refer and complete a series of validated PROMs (demographic, socioeconomic, clinical, global wellbeing) via a digital platform, capturing current status on a quarterly basis for up to 10 years. Real-world analysis assisted by AI ( January 2026; Claude [Opus 4.5], manufacturer: Anthropic; data extraction, statistical analysis with means, percentages, patient-level aggregation, stratification by clinical variables, longitudinal pattern analysis and visualization; all outputs validated against source data ) of FACT-B PROM data capture and analysis methodology was used. Results: To date, 823 participants have enrolled with 186 participating for ≥2 years. From participation start, longitudinal worry is reported using 3 factors from FACT-B PROM; hereditary risk of family members (HR), if stress impacts illness (SI), and if participant’s condition will worsen (CW). Highest degree of reported worry scores was in HR 40.4% (n = 74), SI 31.7% (n = 59) and CW at 17.4% (n = 32). Worry intensity varied by age, stage and molecular subtype. Participants diagnosed < 50 years reported higher levels in all 3 factors (HR 51% mean 2.53; SI 46.9% mean 2.24; CW 24.5% mean 1.78) to those at > 50 years (HR 37.1% mean 1.92; SI 25.9% mean 1.63; CW 14.3% mean 1.32). Stage IV participants show 66.7% high worry (CW and HR) compared to stage I at 8.5% (CW). Molecular subpopulations show higher worry in HR- / HER2- (TNBC) n = 34 (HR 48.5% mean 2.24; SI 38.2% mean 2.00; CW 17.6% mean 1.59) compared to HR+ / HER2- n = 81 (HR 37.5% mean 2.04; SI 35.4% mean 1.90; CW 17.3% mean 1.41) and HR+ / HER2+ n = 13 (HR 30.8% mean 2.08; SI 23.1% mean 1.77; CW 7.7% mean 1.38). Non-linear trajectory over time shows 24% (n = 183) experienced high worry at registry entry, declining at 12 months to 15.8% with a secondary peak at 18 months in 21.7% of participants. Conclusions: Patient-reported outcomes show the burden of worry by breast cancer survivors for hereditary risk to family and individuals’ illness. These findings offer directional insights for psychosocial screening, care resources and tailored education throughout survivorship.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy characterized by significant molecular heterogeneity with a limited range of targeted therapy options. Better resolution of the spatial interactions between tumor cells and the immune microenvironment is essential for identifying actionable vulnerabilities. Methods: Here we employed GeoMx Digital Spatial Profiling (DSP) to investigate the proteomic landscape of 72 immuno-oncology biomarkers in normal breast, primary breast cancer, and metastatic axillary lymph node tissues of treatment-naïve TNBC patients (n=29) who underwent upfront breast surgery. Results: Through comprehensive profiling, we identified the tumor suppressor protein, neurofibromin (NF1), as one of the vulnerabilities in TNBC. Spatially resolved analysis revealed that NF1 downregulation is strongly associated with Ras/Raf/MEK pathway activation. This downregulation of NF1 level was characteristic of tumor regions with a high representation of tumor infiltrating lymphocytes (TILs). Furthermore, low NF1 levels significantly correlated with reduced disease-free survival, suggesting its potential clinical utility as a biomarker. We also observed a high degree of proteomic similarity between primary breast tumors and the matched lymph node metastases. Conclusions: These findings advance our understanding of TNBC spatial proteomic profiles and suggest that targeting the NF1-Ras/Raf/MEK axis may offer novel strategy for clinical management of TNBC patients with immune “hot” tumors.

Polo-like kinase 4 (PLK4) is a key kinase regulating centriole duplication, centrosome maturation, cytokinesis and other cellular processes. Growing evidence suggests a critical role of PLK4 in the development and progression of various cancers. In many cancer types, its upregulation leads to pro-oncogenic phenotypes, while its pharmacologic inhibition leads to anticancer effects. Functionally, PLK4 affects cancer cell proliferation, growth, motility, invasion, migration, epithelial-mesenchymal transition, apoptosis and other critical oncogenic processes. In breast cancer, PLK4 is associated with centrosome amplification, aneuploidy and chromosomal instability, promoting invasive phenotypes and resistance to cancer cell death. PLK4 shows great promise as a prognostic and predictive biomarker in breast cancer. It is commonly found to be overexpressed in primary human breast cancers and is associated with poor oncologic outcomes, clinicopathologic parameters, and high-risk subtypes. Various compounds, such as CFI-400945, centrinone B, and others have been developed to inhibit PLK4 activity. Preclinical studies have shown that PLK4 inhibitors lead to decreased proliferation, growth and migration and increased breast cancer cell death. Moreover, PLK4 inhibition can serve to enhance the effects of other treatments, including radiotherapy. Clinical studies have been initiated with some of these compounds in cancer patients, including those with breast cancer. This manuscript discusses the role of PLK4 as a promising therapeutic target in breast cancer, one of the most common causes of morbidity and mortality in women.

Breast cancer is the leading cause of cancer-related morbidity and mortality in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, often resistant to therapies including radiation treatment (RT). Developing new strategies for TNBC treatment is of paramount importance. In our previous studies, we have shown that a novel drug, Polo-like kinase 4 inhibitor CFI-400945, acts synergistically with RT to enhance antiproliferative effects in TNBC. Since one of the main anticancer mechanisms of RT is deoxyribonucleic acid (DNA) damage with ensuing DNA damage response (DDR) activation, in the current study, we aimed to investigate if and how CFI-400945 modulates DDR in response to RT. Using MDA-MB-231 and MDA-MB-468 TNBC cell lines, we investigated the levels and the foci formation of γ-H2AX, Ku70 and Rad51 proteins-the markers of DNA damage, non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways, respectively. We demonstrate that RT induces sustained DNA damage that is not further meaningfully enhanced or prolonged by CFI-400945. We also observed cell-line-dependent differences in the timing of activation of NHEJ and HR pathways in response to RT, and that CFI-400945 might lead to impeding RT-induced NHEJ pathway activation or result in earlier activation of the HR pathway. Notably, despite activation of the DDR responses, DNA damage persisted for 24 or more hours after RT. While some of these observations were cell-line dependent (emphasizing known molecular heterogeneity of TNBC), we highlight that canonical DDR pathways activity in response to RT might be inefficient and modulated by drugs, such as CFI-400945-a cancer cell vulnerability that warrants further investigations for better understanding the biology of TNBC, its responses to treatment and novel drug development.

Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFITs) are key interferon-stimulated genes (ISGs), and in humans include IFIT1, IFIT2, IFIT3 and IFIT5. These proteins are primarily known for their role in the innate immune response to pathogens. However, growing evidence suggests that IFITs participate in a range of other cellular processes, including cancer development and progression. Notably, IFITs may behave in either a pro-oncogenic or tumor suppressive fashion depending on cancer types and emphasizing their potential dual function in tumorigenesis. Importantly, IFITs have shown potential to be utilized as clinical biomarkers in oncology. Their aberrant expression has been correlated with survival and other clinical outcomes, including resistance to radiotherapy, chemotherapy, targeted treatments and immunotherapy in various cancers. Additionally, they have also been reported to be a part of various clinical predictive models in cancers. This review provides an overview of the current understanding of IFIT proteins’ involvement in cancers, with an emphasis on their emerging roles as clinically relevant biomarkers.

Introduction Prostate cancer is a leading cause of cancer death in men. Although early-stage prostate cancers can be effectively managed by surgery, radiation and/or androgen-deprivation therapies, many tumors eventually become castrate-resistant, leading to disease progression, metastasis and death. The goal of this pilot study was to gain insight into the biology of prostate cancer progression by assessing circulating tumor cells (CTCs) from 3 patient cohorts: low-volume metastatic hormone-sensitive prostate cancer (LV-mHSPC); high-volume metastatic hormone-sensitive prostate cancer (HV-mHSPC); and metastatic castrate-resistant prostate cancer (mCRPC). Materials & Methods CTCs were assessed using the epithelial-based CellSearch assay versus an epithelial-to-mesenchymal transition (EMT)-independent Parsortix assay. CTCs were also harvested from Parsortix and assessed by downstream molecular analysis using the HyCEAD mRNA multiplex assay. Specific molecular characteristics identified through HyCEAD were compared to prostate cancer data from The Cancer Genome Atlas (TCGA). Results Although no significant enumeration differences were observed between the two technologies, CellSearch was able to identify a greater number of CTCs in HV-mHSPC versus LV-mHSPC patients (p ≤ 0.05). Between the 3 patient cohorts, 17 differentially expressed genes were identified that may contribute to prostate cancer disease progression. Conclusions Taken together, our findings provide a promising panel of potential biomarkers for further investigation in order to develop a comprehensive, real-time CTC liquid biopsy strategy for the personalized clinical management of metastatic prostate cancer patients in the future.

Background/Objectives: The lack of canonical biomarkers and strategies to target radioresistance contribute to poor patient outcomes in triple-negative breast cancer (TNBC). Identifying and targeting novel radioresistance genes will benefit in enhancing radiotherapy response and treatment outcomes in TNBC patients. Methods: A genome-wide CRISPR screen was performed to identify radioresistance genes in the TNBC cell line. An in vitro clonogenic assay was used to assess the antiproliferative effects of Artemis knockout or pharmacologic inhibition of Artemis, either alone or in combination with RT. Tumor doubling time and animal survival were assessed using an in vivo xenograft model. RNA-seq analysis was performed to identify genes and pathways deregulated under Artemis knockout conditions, both alone and in combination with RT. Cellular senescence was evaluated using a β-galactosidase assay. Results: Our CRISPR screen identified Artemis as a top hit in RT-treated TNBC cells, whose depletion led to radiosensitization in TNBC. Artemis knockout significantly reduced cell proliferation and enhanced the antiproliferative effects of RT in vitro. Compared to mice-bearing control MDA-MB-231 xenografts, Artemis knockout exhibited prolonged survival that was further enhanced with RT. Bulk RNA-sequencing indicated that the antiproliferative and radiosensitization effects of Artemis depletion were mediated by the activation of cellular senescence which was confirmed with a β-galactosidase assay. Conclusions: Taken together, our results highlight the critical role of Artemis in TNBC cell proliferation and response to radiation. Our findings identify Artemis as a potential biomarker indicative of sensitivity to radiation and a putative target that could be inhibited to enhance the efficacy of RT in TNBC.

OBJECTIVE:Extracellular vesicles (EVs) have been shown to play a critical role in promoting tumorigenesis. As EV research grows, it is of importance to have standardization of isolation, quality control, characterization and validation methods across studies along with reliable references to explore troubleshooting solutions. Therefore, our objective with this Research Note was to isolate EVs from multiple breast cancer cell lines and to describe and perform protocols for validation as outlined by the list of minimal information for studies of EVs (MISEV) from the International Society for Extracellular Vesicles. RESULTS:To isolate EVs, two techniques were employed: ultracentrifugation and size exclusion chromatography. Ultracentrifugation yielded better recovery of EVs in our hands and was therefore used for further validation. In order to satisfy the MISEV requirements, protein quantification, immunoblotting of positive (CD9, CD63, TSG101) and negative (TGFβ1, β-tubulin) markers, nanoflow cytometry and electron microscopy was performed. With these experiments, we demonstrate that yield of validated EVs varied between different breast cancer cell lines. Protocols were optimized to accommodate for low levels of EVs, and various technical and troubleshooting suggestions are included for potential application to other cell types that may provide benefit to investigators interested in future EV studies.

BackgroundEmerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor.MethodsOne hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes.DiscussionSABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making.Trial registrationClinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Radioresistance is one of the barriers to developing more effective therapies against the most aggressive, triple-negative, breast cancer (TNBC) subtype. In our previous studies, we showed that inhibition of Polo-like Kinase 4 (PLK4) by a novel drug, CFI-400945 significantly enhances the anticancer effects of radiotherapy (RT) compared to single treatment alone. Here we further investigate the role of PLK4 in enhancing radiation effects in TNBC and explore mechanisms of PLK4 inhibition and radiation combinatorial antiproliferative effects. To assess cellular proliferation in response to treatments, we used colony formation assays in TNBC cell lines and patient-derived organoids (PDOs). Downregulation of PLK4 expression was achieved using siRNA silencing in TNBC cell lines. Immunofluorescence against centrin was used to assess the alteration of centriole amplification in response to treatments. We observed that inhibition of PLK4 by CFI-400945 or Centrinone B or its downregulation by siRNA, when combined with RT, resulted in a significant increase in antiproliferative effect in TNBC cells lines and PDOs compared to untreated or single-treated cells. Anticancer synergy was observed using a response matrix in PDOs treated with CFI-400945 and RT. We show that the overamplification of centrioles might be involved in the combined antiproliferative action of RT and PLK4 inhibition. Our data suggest that PLK4 is a promising target for enhancing the anticancer effects of RT in TNBC that, at least in part, is modulated by the overamplification of centrioles. These results support further mechanistic and translational studies of anti-PLK4 agents and RT as an anticancer combination treatment strategy.

Breast cancer is the most prevalent malignancy among women worldwide. Despite significant advances in treatment, it remains one of the leading causes of female mortality. The inability to effectively treat advanced and/or treatment-resistant breast cancer demonstrates the need to develop novel treatment strategies and targeted therapies. Centrosomes and their associated proteins have been shown to play key roles in the pathogenesis of breast cancer and thus represent promising targets for drug and biomarker development. Centrosomes are fundamental cellular structures in the mammalian cell that are responsible for error-free execution of cell division. Centrosome amplification and aberrant expression of its associated proteins such as Polo-like kinases (PLKs), Aurora kinases (AURKs) and Cyclin-dependent kinases (CDKs) have been observed in various cancers, including breast cancer. These aberrations in breast cancer are thought to cause improper chromosomal segregation during mitosis, leading to chromosomal instability and uncontrolled cell division, allowing cancer cells to acquire new genetic changes that result in evasion of cell death and the promotion of tumor formation. Various chemical compounds developed against PLKs and AURKs have shown meaningful antitumorigenic effects in breast cancer cells in vitro and in vivo. The mechanism of action of these inhibitors is likely related to exacerbation of numerical genomic instability, such as aneuploidy or polyploidy. Furthermore, growing evidence demonstrates enhanced antitumorigenic effects when inhibitors specific to centrosome-associated proteins are used in combination with either radiation or chemotherapy drugs in breast cancer. This review focuses on the current knowledge regarding the roles of centrosome and centrosome-associated proteins in breast cancer pathogenesis and their utility as novel targets for breast cancer treatment.

Artemis is a key nuclease involved in the non-homologous end joining repair pathway upon DNA double-stranded breaks and during V(D)J recombination. It participates in various cellular processes and cooperates with various proteins involved in tumorigenesis. Its hereditary mutations lead to several pathological conditions, such as severe combined immunodeficiency with radiation sensitivity. Recent studies suggest that Artemis deregulation plays an important role in cancer and is associated with poorer oncologic outcomes and resistance to treatment including radiotherapy, chemotherapy and targeted therapeutics. Artemis emerges as an attractive candidate for cancer prognosis and treatment. Its role in modulating sensitivity to ionizing radiation and DNA-damaging agents makes it an appealing target for drug development. Various existing drugs and novel compounds have been described to inhibit Artemis activity. This review synthesizes the up-to-date information regarding Artemis function, its role in different malignancies and its clinical utility as a potential biomarker and therapeutic target in Oncology.

e15030 Background: Programmed death-ligand 1 (PD-L1) is a predictive biomarker for immunotherapy in the treatment of non-small cell lung cancer (NSCLC). Assessing PD-L1 expression from the tumor specimen can be challenging because of tissue accessibility, heterogeneity, and dynamic changes in PD-L1 expression that may impact the status of PD-L1 during disease evolution and treatment. Hence, assessing PD-L1 status from archival tumor might not reflect its actual state on the tumor and having a real-time assessment of its expression with the use of non-invasive techniques such circulating tumor cells (CTCs) is useful. Methods: We conducted a single centre prospective study to detect CTCs in the blood of patients with stage III-IV NSCLC treated with immunotherapy using the standard CellSearch technology for CTC enumeration and the Epic Sciences technology for CTCs enumeration and assessment of PD-L1 protein expression on CTCs. CTCs were detected at baseline before treatment initiation and after 2 cycles of treatment. Study endpoints included CTCs detection and concordance between the 2 technologies, PD-L1 expression assessment on CTCs with the Epic Sciences technology, and concordance with tissue-based expression. Comparisons were made using Pearson correlation coefficient (PCC) and intraclass correlation coefficient (ICC) for count data and percentage of perfect agreement. Results: Between 2019 and 2022, 48 patients treated with immunotherapy were enrolled in the study. The mean ± standard deviation (SD) age was 66.8 ± 10.3 years, 63% were females, 42% received combination chemotherapy and immunotherapy, and 44% had adenocarcinoma histology. The tissue PD-L1 expression was high (≥50%), intermediate (1-49%), and low (<1%) in 36%, 31% and 33% of patients respectively. The mean ± SD baseline CTCs count per 7.5ml was 1.97 ± 4 with CellSearch and 1.38 ± 2.72 per ml with Epic Sciences. After 2 treatment cycles, 22% and 41% of patients had an increase in their CTCs count with CellSearch and Epic Sciences, respectively and 30% and 29% had a decrease in their CTCs. The PCC and ICC for baseline CTCs detected by CellSearch and Epic Sciences were 0.72 and 0.61, respectively and for CTCs detected after 2 cycles of treatment by the 2 technologies were -0.16 and 0.45 respectively. One patient had PD-L1 expression on their CTCs with the Epic Sciences technology and there was no association between the PD-L1 expression on CTCs and on matched tissue samples. Conclusions: This study showed a moderate to strong correlation between the 2 technologies for baseline CTCs detection and moderate to poor correlation for CTCs detection after 2 cycles of therapy. No association was found between CTCs and tissue PD-L1 expression. Future work needs to further investigate the role of PD-L1 expression on CTCs.

For patients with stage I/IIA non-small-cell lung cancer (NSCLC), surgical resection is the standard treatment. However, some of these patients are not candidates for surgery or refuse a surgical option. Definitive stereotactic ablative radiotherapy (SABR) is a standard approach in these patients. Approximately 15% of patients undergoing SABR for localized NSCLC will experience a recurrence within 2 years. Furthermore, many of these patients are deemed appropriate for SABR without a tissue diagnosis, based on the likelihood of malignancy which can be calculated by validated models. A liquid biopsy, detecting ctDNA, would be useful in early detection of recurrences, and documenting a cancer diagnosis in patients without a biopsy. This is a multi-institutional study enrolling patients with suspected stage I/IIA NSCLC and a pretreatment likelihood of malignancy of ≥60% using the validated models for patients without a tissue diagnosis, in cohort 1 (n = 45). The second cohort will consist of biopsied patients (n = 30-60). SABR will be delivered as per risk-adapted protocol. Plasma will be collected for ctDNA analysis prior to the first fraction of SABR, 24 to 72 hours after first fraction, and at 3, 6, 9, 12, 18, and 24-months. The patients will be followed up with imaging at 3, 6, 9, 12, 18, and 24-months. The primary objective is to assess whether a cancer detection liquid biopsy platform can predict recurrence of NSCLC. The secondary objectives are to assess the impact of SABR on detection rates of ctDNA in patients undergoing SABR and to correlate ctDNA positivity and pretreatment probability of malignancy (NCT05921474).

Patients with triple-negative breast cancer (TNBC) have an increased propensity to develop lung metastasis. Our previous studies demonstrated that stem-like ALDH hi CD44 + breast cancer cells interact with lung-derived soluble factors, resulting in enhanced migration and lung metastasis particularly in TNBC models. We have also observed that the presence of a primary TNBC tumor can ‘prime’ the lung microenvironment in preparation for metastasis. In this study, we hypothesized that soluble lung-derived factors secreted in the presence of a primary TNBC tumor can influence stemness/plasticity of breast cancer cells. Using an ex vivo pulmonary metastasis assay (PuMA), we observed that the lung microenvironment supports colonization and growth of ALDH hi CD44 + TNBC cells, potentially via interactions with lung-derived FGF2. Exposure of TNBC cells to lung-conditioned media (LCM) generated from mice bearing TNBC primary tumors (tbLCM) significantly enhanced the proportion of ALDH hi CD44 + cells compared to control or LCM from tumor-naïve mice (tnLCM). Further analysis using a human cancer stem cell qPCR array revealed that, relative to tnLCM or control, exposure of TNBC cells to tbLCM leads to downregulation of the transcription factor and putative tumor suppressor Dachshund homolog 1 (DACH1), a downstream regulator of FGF2. In addition, inhibition of DACH1 using siRNA or treatment with recombinant FGF2 enhanced the ALDH hi CD44 + phenotype. Taken together, our findings suggest that the FGF2-DACH1 signaling axis supports stemness/plasticity of TNBC cells in the lung microenvironment and lays the foundation for future evaluation of FGF2 as a potential novel therapeutic target for treatment or prevention of breast cancer metastasis to the lung.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity amongst trauma patients. Its treatment is focused on minimizing progression to secondary injury. Administration of propranolol for TBI maydecrease mortality and improve functional outcomes. However, it is our sense that its use has not been universally adopted due to low certainty evidence. The literature was reviewed to explore the mechanism of propranolol as a therapeutic intervention in TBI to guide future clinical investigations. Medline, Embase, and Scopus were searched for studies that investigated the effect of propranolol on TBI in animal models from inception until June 6, 2023. All routes of administration for propranolol were included and the following outcomes were evaluated: cognitive functions, physiological and immunological responses. Screening and data extraction were done independently and in duplicate. The risk of bias for each individual study was assessed using the SYCLE’s risk of bias tool for animal studies. Three hundred twenty-three citations were identified and 14 studies met our eligibility criteria. The data suggests that propranolol may improve post-TBI cognitive and motor function by increasing cerebral perfusion, reducing neural injury, cell death, leukocyte mobilization and p-tau accumulation in animal models. Propranolol may also attenuate TBI-induced immunodeficiency and provide cardioprotective effects by mitigating damage to the myocardium caused by oxidative stress. This systematic review demonstrates that propranolol may be therapeutic in TBI by improving cognitive and motor function while regulating T lymphocyte response and levels of myocardial reactive oxygen species. Oral or intravenous injection of propranolol following TBI is associated with improved cerebral perfusion, reduced neuroinflammation, reduced immunodeficiency, and cardio-neuroprotection in preclinical studies. Oral or intravenous injection of propranolol following TBI is associated with improved cerebral perfusion, reduced neuroinflammation, reduced immunodeficiency, and cardio-neuroprotection in preclinical studies.

Breast cancer is a prominent cause of cancer diagnosis and death in women globally, with over 90% of deaths being attributed to complications that arise from metastasis. One of the common locations for breast cancer metastasis is the lung, which is associated with significant morbidity and mortality. Curative treatments for metastatic breast cancer patients are not available and the molecular mechanisms that underlie lung metastasis are not fully understood. In order to better treat these patients, identifying events that occur both prior to and during metastatic spread to the lung is essential. Several studies have demonstrated that breast cancer-derived extracellular vesicles secreted from the primary breast tumor play a key role in establishing the lung pre-metastatic niche to support colonization of metastatic tumor cells. In this review, we summarize recent work supporting the influence of extracellular vesicles on stromal components of the lung to construct the pre-metastatic niche and support metastasis. Furthermore, we discuss the potential clinical applications of utilizing extracellular vesicles for diagnosis and treatment. Together, this review highlights the dynamic nature of extracellular vesicles, their roles in breast cancer metastasis to the lung, and their value as potential biomarkers and therapeutics for cancer prevention.

PDF file - 1147KB, 2 x 106 MDA-MB-231 or MDA-MB-435 cells were injected into 6- to 7-week-old female NOD/SCID or nu/nu mice via mammary fat pad. The control cohort (n=4) received weekly saline subcutaneous injections, while three other cohorts (n=4 per group) received rHuEPO doses of 300U/kg, 600U/kg or 1200U/kg. (A-D) Data from MDA-MB-231 breast cancer cells in NOD/SCID mice. (E-H) Results from MDA-MB-435 breast cancer cells injected into nude (nu/nu) mice. (A,E) Primary tumor growth of human breast cancer cells injected into mice over time. EPO treatment was initiated at 3 weeks post injection (black arrow). Data are presented as mean SEM. (B,F) Incidence of lung metastasis (% of mice in each treatment group that developed metastases). (C,G) Size (diameter) of lung metastases scored. Data are presented as mean SEM. (D,H) Number of lung metastases observed. Data are presented as the mean SEM. For all panels, # denotes a statistically significant difference relative to the untreated control cohort (p<0.05).

Resistance to protein tyrosine kinase inhibitors (TKIs) presents a significant challenge in therapeutic target development for cancers such as triple-negative breast cancer (TNBC), where conventional therapies are ineffective at combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth factor receptor) and c-Met are potential targets for treatment. However, targeted anti-EGFR and anti-c-Met therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that adaptive responses in regulatory kinase networks within the EGFR and c-Met signaling axes contribute to the development of acquired erlotinib and cabozantinib resistance. To test this, we developed two separate models for cabozantinib and erlotinib resistance using the MDA-MB-231 and MDA-MB-468 cell lines, respectively. We observed that erlotinib- or cabozantinib-resistant cell lines demonstrate enhanced cell proliferation, migration, invasion, and activation of EGFR or c-Met downstream signaling (respectively). Using a SILAC (Stable Isotope Labeling of Amino acids in Cell Culture)-labeled quantitative mass spectrometry proteomics approach, we assessed the effects of erlotinib or cabozantinib resistance on the phosphoproteome, proteome, and kinome. Using this integrated proteomics approach, we identified several potential kinase mediators of cabozantinib resistance and confirmed the contribution of AKT1 to erlotinib resistance in TNBC-resistant cell lines.

Background With the shift towards person-centered care (PCC) in oncology, there is a need for parallel evolution of oncology education programs to prepare the next generation of health professionals to deliver effective PCC. These programs should be designed utilizing perspectives from individuals who have lived experience with cancer to ensure that changes to education curricula translate to improved PCC in the clinic. Objectives Our goal was to identify existing literature describing such programs as well as identify gaps for further development. Methods Keywords were agreed upon and searched across Ovid Medline, Ovid Embase, ERIC, Google Scholar, and MedEdPORTAL databases. Duplicates were removed, unique articles were screened for relevance by title and abstract, and a full text review of each article was completed for validation. Included articles describe methods for involving people with cancer in developing and/or delivering oncology-focused education programs. Results In total, 15 articles describing 12 unique oncology education programs from 7 different countries were identified, reviewed, and summarized. These programs involved learners undertaking undergraduate medical education, postgraduate medical education, continuing medical education, or training as nurses or radiation therapists. Current literature indicates that classroom-based sessions, experiential or simulated learning modalities, and/or asynchronous online modules can all feasibly be created with the integration of perspectives/narratives of people with cancer. Furthermore, involving people with cancer directly in the design and/or delivery of these education programs may contribute to improved patient experiences. Conclusions Including the perspectives of people with cancer directly in oncology curriculum development and delivery can improve established pedagogical approaches and enhance learner confidence and competency in delivering PCC. We provide recommendations for stepwise implementation of patient perspectives into oncology education, with the hope that future programs will better prepare and motivate learners to provide PCC aimed at improving cancer care, quality of life, and disease outcomes.