Treatment Of Bone Metastases Research Articles

Near-infrared photoimmunotherapy (NIR-PIT) of bone metastases

The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative. Radiotherapy with pain palliation can temporize bone metastases but is generally considered a short-term solution and retreatment is difficult. Surgery is often necessary, yet recovery times might exceed life expectancy. Therefore, there is a need to develop new approaches to bone metastases that are effective but minimally invasive. Near-infrared photoimmunotherapy (NIR-PIT) uses antibodies labeled with IRDye700DX (IR700) which is activated by NIR light, resulting in rapid cell membrane damage and immunogenic cell death. NIR-PIT using an anti-epidermal growth factor receptor (EGFR) antibody-IR700 conjugate in patients with recurrent head and neck cancer received qualified approval in Japan in 2020 and is now widely used there. However, no bone metastases have yet been treated. In this study, the efficacy of NIR-PIT for bone metastases was investigated using a bone metastases mouse model successfully established by caudal artery injection of a human triple-negative breast cancer cell line, MDAMB468-GFP/luc. The bone metastatic lesions were treated with NIR-PIT using the anti-EGFR antibody, panitumumab-IR700 conjugate. Bioluminescence imaging and histological evaluation showed that EGFR-targeted NIR-PIT has a therapeutic effect on bone metastatic lesions in mice. In addition, micro-CT showed that repeated NIR-PIT led to repair of metastasis-induced bone destruction and restored bone cortex continuity consistent with healing. These data suggest that NIR-PIT has the potential for clinical application in the treatment of bone metastases.

Current comprehensive understanding of denosumab (the RANKL neutralizing antibody) in the treatment of bone metastasis of malignant tumors, including pharmacological mechanism and clinical trials.

Denosumab, a fully humanized monoclonal neutralizing antibody, inhibits activation of the RANK/RANKL/OPG signaling pathway through competitive binding with RANKL, thereby inhibiting osteoclast-mediated bone resorption. Denosumab inhibits bone loss; therefore, it is used to treat metabolic bone diseases (including postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis), in clinical practice. Since then, multiple effects of denosumab have been discovered. A growing body of evidence suggests that denosumab has a variety of pharmacological activities and broad potential in clinical diseases such as osteoarthritis, bone tumors, and other autoimmune diseases. Currently, Denosumab is emerging as a treatment for patients with malignancy bone metastases, and it also shows direct or indirect anti-tumor effects in preclinical models and clinical applications. However, as an innovative drug, its clinical use for bone metastasis of malignant tumors is still insufficient, and its mechanism of action needs to be further investigated. This review systematically summarizes the pharmacological mechanism of action of denosumab and the current understanding and clinical practice of the use of denosumab for bone metastasis of malignant tumors to help clinicians and researchers deepen their understanding of denosumab.

Immunotherapy as a potential treatment approach for currently incurable bone metastasis.

Once cancer metastasizes to the bone, the prognosis of cancer patients becomes extremely poor. Unfortunately, the current most successful treatment for bone metastasis can extend their survival by only a few months. Although recent studies have revealed promising impacts of cancer immunotherapies, their treatment efficacy on bone metastatic diseases remains controversial. Therefore, in this review, we discussed (i) preclinical and clinical evidence of the immunotherapeutic strategies for cancer bone metastasis, mainly focusing on cell-based immunotherapy, cytokine-based immunotherapy, and immune checkpoint blockade, and (ii) current shortcomings of immunotherapy for bone metastasis and their potential future directions. Although the evidence on treatment efficacy and safety, as well as long-term effects, is limited, immunotherapies could induce partial or complete remissions in a few cancer patients with bone metastasis. However, there are still hurdles, such as the immunosuppressive nature of the bone marrow microenvironment and poor distribution of cell-based immunotherapies to bone, thatneed to be overcome to enhance the treatment efficacy of immunotherapies on bone metastasis. While it is apparent that further investigation is needed regarding immunotherapeutic treatment efficacy in patients with bone metastasis, this therapy may prove to be clinically novel in this subset of cancer patients.

Predicting origin for bone metastatic cancer using deep learning-based pathology.

Predicting origin for bone metastatic cancer using deep learning-based pathology.

Combining dual-targeted liquid metal nanoparticles with autophagy activation and mild photothermal therapy to treat metastatic breast cancer and inhibit bone destruction.

Although mild photothermal therapy (mild-PTT) avoids treatment bottleneck of the traditional PTT, the application of mild-PTT in deep and internal tumors is severely restricted due to thermal resistance, limited irradiation area and penetration depth. In addition, bone resorption caused by tumor colonization in distal bone tissue exacerbates tumor progression. Here, a strategy was developed for the treatment of bone metastasis and alleviation of bone resorption, which was based on liquid metal (LM) nanoparticle to resist thermal resistance induced by mild-PTT via autophagy activation. Briefly, LM and autophagy activator (Curcumin, Cur) were loaded into zeolitic imidazolate framework-8 (ZIF-8), which was then functionalized with hyaluronic acid/alendronate (CLALN). CLALN exhibited good photothermal performance, drug release ability under acidic environment, specifical recognition and aggregation at bone metastasis sites. CLALN combined with mild-PPT dramatically inhibited tumor progress by inducing the impaired autophagy and reduced the expression of programmed cell death ligand 1 (PD-L1) protein triggered by mild-PTT, resisting thermal resistance and alleviating the immunosuppression. Besides, CLALN combined with mild-PPT effectively alleviated osteolysis compared with only CLALN or mild-PPT. Our experiments demonstrated that this multi-functional LM-based nanoparticle combined with autophagy activation provided a promising therapeutic strategy for bone metastasis treatment. STATEMENT OF SIGNIFICANCE: Due to the limited light penetration, photothermal therapy (PTT) has limited inhibitory effect on tumor cells colonized in the bone. In addition, nonspecific heat diffusion of PTT may accidentally burn normal tissues and damage peripheral blood vessels, which can block the accumulation of drugs in deep tumors. Here, a multifunctional liquid metal based mild-PTT delivery system is designed to inhibit tumor growth and bone resorption by modulating the bone microenvironment and activating autophagy "on demand". It can overcome the treatment bottleneck of traditional PTT and improve the treatment effect of mild-PTT by resisting photothermal resistance and immune suppression. In addition, it also exhibits favorable heat/acid-responsive drug release performance and can specifically target tumor cells at the site of bone metastases.

Prognostic factors in endometrial cancer patients with bone metastasis.

This study aims to examine the pattern and prognosis of osseous involvement and the role of orthopedic surgery in patients with endometrial cancer (EC) and to evaluate the quality of life, local tumor control, and survival of patients. Between January 2011 and December 2018, a total of 14 patients (median age: 60.5 years; range, 55 to 73 years) who were surgically treated for osseous metastasis of EC and followed for minimum 12 months were retrospectively analyzed. All patients were evaluated for their primary malignancy, characteristics of bone metastasis, and type of treatment related to musculoskeletal involvement. For evaluating the functional outcomes, the Visual Analog Scale (VAS) for pain and Eastern Cooperative Oncology Group (ECOG) performance status scale were used in the pre- and postoperative period. The median follow-up was 34.5 (range, 9 to 89) months. All patients had advanced-stage disease (FIGO Stage III-IV). Four patients had solitary and 10 patients had multiple bone metastases. The mean VAS score and ECOG performance status grades improved (p<0.001 and p<0.05, respectively). The median survival after detection of bone metastasis was 61 (range, 41 to 82) months. Endometrial cancer patients with musculoskeletal pain should be investigated for the possibility of bone metastasis to tailor a prompt treatment and to achieve a better prognosis. Appropriate surgical treatment of bone metastasis may improve both pain and performance status in carefully selected patients.

Clinical Outcomes of Switching from Zoledronic Acid to Denosumab for the Management of Severe Bone Metastasis from Hepatocellular Carcinoma: A Single-Center, Open-Label, Prospective Intervention Trial.

Zoledronic acid reduces the risk of bone metastasis, but denosumab is a better option for treating bone metastases. However, few studies have evaluated the use of denosumab to treat bone metastasis originating from hepatocellular carcinoma. This study aimed to assess the clinical outcomes of switching from zoledronic acid to denosumab for treating bone metastasis in patients with hepatocellular carcinoma. This prospective study enrolled 10 patients with HCC and bone metastases. The levels of type 1 collagen cross-linked N-telopeptide (NTx) and tumor growth remained abnormal in these patients despite administration of zoledronic acid for over 3 months. We switched from zoledronic acid to 120 mg denosumab every 4 weeks and evaluated the clinical outcomes, including changes in the NTx level, pain level, and activities of daily living, as well as adverse events, after each administration. Urinary NTx clearance was normal in all patients. The average urinary NTx clearance increased from 13.2 to 21.2 nmol BCE/nmol · Cre (P = 0.54) after the switch to denosumab. Serum NTx levels were abnormal in all cases. The serum NTx level decreased from 142 nmol BCE/L to 126 nmol BCE/L (P = 0.56). The answers to questionnaires on pain and activities of daily living did not change significantly. Some patients showed elevated transaminase levels, but this was not due to the drug switch. Switching to denosumab did not show a significant change of the pain and activity of daily living for the patients with severe bone metastasis from hepatocellular carcinoma, in whom the efficacy of zoledronic acid was limited.

GLUT1-mediated magnetic liposomes for targeting bone metastatic breast cancer

Bone metastatic breast cancer is a malignant tumor in bone due to the metastasis of breast cancer, and its incidence is increasing worldwide. Treatment of cancer metastasized to bone is still a challenge because of the anticancer drugs lack target specificity. Finding an effective treatment for bone metastasis remains an urgent issue. In order to enhance the delivery of paclitaxel (PTX) to the bone metastases lesions, a novel glucose derivative was designed and synthesized in this work, which was used as liposome ligand to develop the magnetic liposome G-MLip (Glucose-modified magnetic liposome). The liposome could improve the drug formulations in the bone metastases mediated by glucose transporter 1 (GLUT1) and then target cancer cells. The PTX-loaded magnetic liposome PTX-G-MLip was prepared by the film hydration-ultrasound method. And the characterizations, such as size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis, were well evaluated. What’s more, the enhanced target ability was also investigated in vitro and in mice. The metastatic bone-targeted capacity was confirmed that the PTX concentration from PTX-G-MLip in the bone metastases lesions was markedly increased in the presence of magnetic field (MF) compared with the free PTX and other liposomes. Inspired by the enhanced targeting ability, glucose-modified magnetic liposomes could serve as an effective drug delivery system for targeting and treating bone metastases.

Osteosclerotic change as a therapeutic response to gefitinib in symptomatic non-small cell lung cancer bone metastasis

BackgroundDespite improvement in the overall survival of patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, the effects of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment on bone metastasis remain unclear. This study investigated radiological responses to gefitinib regarding bone metastasis in patients.MethodsWe treated 260 patients with NSCLC and symptomatic bone metastasis. Thirty-seven patients harboring EGFR mutation were treated with gefitinib for more than 30 days and followed up for more than 3 months (GEF group). We performed a retrospective observational study by selecting 36 cases without EGFR-TKI treatment, at least 3 months of follow-up, and at least two radiological evaluations as the control group. We assessed the best overall radiological response, interval from treatment initiation to appearance of a radiological response, and the local response maintenance rate.ResultsThe best effect in the GEF group was 98% partial response or better, which was significantly higher than the 57% observed in the control group (p < 0.001). The GEF and control groups maintained 83% and 42% local response maintenance rates at one year, respectively (p < 0.001). In the GEF with radiotherapy group, the local response maintenance rate was maintained at 92% at 1 year, while in the GEF without RT group, there was a decrease in the local response maintenance rate from 270 days.ConclusionGefitinib treatment for bone metastases in patients harboring EGFR mutation resulted in a beneficial osteosclerotic change in most patients. Combined gefitinib and radiotherapy provide long-lasting local control of bone metastases.

Targeting SOST using a small-molecule compound retards breast cancer bone metastasis

BackgroundBreast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis.MethodsSOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo.ResultsWe found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-β/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice.ConclusionsOur findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

Risk Factors, Patterns, and Distribution of Bone Metastases and Skeletal-Related Events in High-Risk Breast Cancer Patients

More than a quarter of breast cancer patients are at risk to develop recurrent metastases to the bone. This study was designed to identify risk factors and predilections of bone metastasis and skeletal-related events (SRE) in a population of breast cancer survivors initially diagnosed in advanced stages and with high-risks of relapse. Associated risk factors, distribution, and attainable treatment of bone metastasis and SRE were analyzed in a cohort of 1,329 breast cancer patients. The association with dependent variables was subsequently analyzed using multivariable logistic regression. Sociodemographic and adverse clinical characteristics were included as covariates of progression into bone metastasis and SREs. Of 1329 breast cancer patients, 246 patients (18.5%) were diagnosed as metastatic breast cancer in which 232 of them (94.3%) had bone metastases. Spines were the most common sites of bone metastases (25.6%). In multivariable analysis, advanced stage at diagnosis (OR=1.840, 95%CI:1.198-2.826, P=0.005), luminal subtype (OR=1.788, 95%CI:1.206-2.652, P=0.045), lobular histology (OR=1.795, 95%CI:1.012-3/184, P=0.046), positive axillary lymph node (OR=1.771, 95%CI:1.087-2.886, P=0.022), multiple metabolic comorbidities (OR=2.193, 95%CI:1.371-3.508, P=0.001), early menopause (OR=2.136, 95%CI:1.116-4.464, P=0.046) were significantly associated with risk of recurrent bone metastases. SREs occurred in 89 (68.5%) patients. Several risk factors for SREs were early menopausal age (OR=2.342, P=0.024), advanced stages (OR=1.404, P=0.039), lobular histology (OR=2.279, P=0.007), and having multiple metabolic comorbidities (OR=1.728, P=0.039). Bone metastases and SREs are relatively high in breast cancer patients diagnosed in advanced stages. Luminal subtypes, having multiple metabolic comorbidities, and lobular histology are associated with higher risks of recurrent bone metastases. Living in rural areas and advanced stage at diagnosis as a risk factors for bone metastases might represent a social gradient of care delivery.

Good clinical practice and the use of hypofractionation radiation schedules as weapons to reduce the risk of COVID-19 infections in radiation oncology unit: A mono-institutional experience.

After coronavirus disease outbreak emerged in 2019, radiotherapy departments had to adapt quickly their health system and establish new organizations and priorities. The purpose of this work is to report our experience in dealing with COVID-19 emergency, how we have reorganized our clinical activity, changed our priorities, and stressed the use of hypofractionation in the treatment of oncological diseases. The patients' circuit of first medical examinations and follow-up was reorganized; a more extensive use of hypofractionated schedules was applied; a daily triage of the patients and staff, use of personal protective equipment, hand washing, environment sanitization, social distancing and limitations for the patients' caregivers in the department, unless absolutely essential, were performed; patients with suspected or confirmed COVID-19 were treated at the end of the day. In addition, the total number of radiotherapy treatment courses, patients and sessions, in the period from February 15 to April 30, 2020, comparing the same time period in 2018 were retrospectively investigated. In particular, changes in hypofractionated schedules adopted for the treatment of breast and prostate cancer and palliative bone metastasis were analyzed. Between February 15, and April 30, 2020, an increased number of treatments was carried out: Patients treated were overall 299 compared to 284 of the same period of 2018. Stressing the use of hypofractionation, 2036 RT sessions were performed, with a mean number of fractions per course of 6.8, compared to 3566 and 12.6, respectively, in 2018. For breast cancer, the schedule in 18 fractions has been abandoned and treatment course of 13 fractions has been introduced; a 27% reduction in the use of 40.5 Gy in 15 fractions, (67 treatments in 2018-49 in 2020) was reported. An increase of 13% of stereotactic body radiation therapy for prostate cancer was showed. The use of the 20 Gy in 4 or 5 sessions for the treatment of symptomatic bone metastasis decreased of 17.5% in favor of 8 Gy-single fraction. Three patients results COVID-19 positive swab: 1 during, 2 after treatment. Only one staff member developed an asymptomatic infection. The careful application of triage, anti-contagion and protective measures, a more extensive use of hypofractionation allowed us to maintain an effective and continuous RT service with no delayed/deferred treatment as evidenced by the very low number of patients developing COVID-19 infection during or in the short period after radiotherapy. Our experience has shown how the reorganization of the ward priority, the identification of risk factors with the relative containment measures can guarantee the care of oncological patients, who are potentially at greater risk of contracting the infection.

The IlluminOss® System: a solution in elderly patients with upper limbs bone metastases.

The IlluminOss® System (IS) based on photodynamic bone stabilization (PBS) is a recent option in between the minimally invasive surgical techniques available to treat bone metastases when medical or radiation therapy is neither effective nor indicated, and major surgery is not possible. In this study, the results obtained using IS in the treatment of impending fractures or bone metastases of the upper limb have been analyzed in terms of improvement in pain, quality of life and recovery of function. Between January 2017 and October 2019, 8 patients over 65 years old with impending fractures or pathological fractures or myeloma of the upper limb have been treated in our institute with IS. All patients were assessed about pain, general health and function of the affected limb before surgery and 1, 3, 6 (consistent with survival) months after the procedure. Mean VAS score improved from 8.88 before surgery to 1.00 six months after surgery, mean Karnofsky index improved at 1 and 3 months post-operative follow-up, and Musculoskeletal Tumor Society Score (MSTS) raised from 44.6 before surgery to 74.7 six months after surgery. Moreover, good reduction and stable fixation of the osteolytic lesion were achieved in all patients, and no complications were found. Numerous studies have been reported in the literature on the use of this system in osteoporotic elderly fractures, whereas only few articles are currently available regarding its use in the treatment of bone metastases or pathological fractures. From our study PBS seems to be an effective solution in the management of bone metastases or myeloma in both pathological fractures and impending upper limb fractures in patients with low life expectancy.

PSAT164 Incidence and Severity of Hypocalcemia in Association with Antiresorptive Therapy in Cancer Patients with Bone Metastasis: An Integrated Health Network Experience

Abstract Introduction Antiresorptive therapy (ArT) has been known to decrease the risk of skeletal-related events (SRE), such as bone pain and pathological fractures, in cancer patients with bone metastasis (BM). While beneficial, ArT may cause adverse effects in this population including hypocalcemia, which can be severe and life-threatening. We examined the incidence, severity, and risk factors for hypocalcemia associated with the use of ArT to treat BM in cancer patients. Methods We conducted a retrospective review of the electronic medical records of adult patients with advanced cancer complicated by BM who were treated at our institution between January 2016 and November 2020. Our primary aim was to compare the incidence and severity of hypocalcemia with the use of IV Zoledronic acid (ZA), a bisphosphonate, vs SQ Denosumab (DM), a RANKL inhibitor, to treat BM in cancer patients.Our secondary aim was to compare risk factors associated with severe hypocalcemia (defined as albumin-corrected serum calcium &amp;lt; 7 mg/dL). Inclusion criteria were patients aged 19-99 years with a history of cancer with known BM, who received either ZA or DM. Results We reviewed 860 EMRs of patients treated within the specified period. 392 patients met inclusion criteria, among them, 297 (76%) and 95 (24%) received DM and ZA, respectively. There were no between-group differences in age, ethnicity, or weight. The median patient age was 71 years (range: 27–96). There were, however, between-group differences in gender (p=0.01) and cancer diagnoses (p=0.03). Females comprised 53.9% of the DM group vs. 40% of the ZA group. The top three cancer diagnoses were (DM vs ZA groups): breast (40.1% vs 26.3%), prostate (25.9% vs 40%), and lung cancer (17.8% vs 15.8%). Overall incidence of hypocalcemia was 48.8% (n=144) and 45.3% (n= 43) with the use of DM and ZA, respectively (p=NS). Severe hypocalcemia was more frequently observed with the use of DM vs ZA (6.6% vs 1.1%, p &amp;lt;0.05). Median (IQR) corrected serum calcium concentration following ArT (when trending calcium for the individual patient) was 8.4 (7.9-8.8) and 8.6 (8.2-8.8) mg/dL for DM a ZA groups, respectively (p=0.1). There were no between-group differences in risk factors for hypocalcemia, such as renal function (eGFR), concentrations of 25-hydroxy vitamin D, albumin, phosphorus, magnesium, or TSH. However, there was a between-group difference in the concentration of alkaline phosphatase (median 83 vs 101 IU/L for DM vs ZA, p= 0.02). There were no between-group differences in the type of BM (osteolytic vs osteoblastic, p=0.9) Conclusion: Severe hypocalcemia was significantly more common with the use of DM compared to ZA for the treatment of BM in cancer patients treated at our institution. Our study was limited by its retrospective design and the between-group differences in gender distribution and cancer diagnoses. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Evaluating and Optimizing Prognostic Modeling for Patients Undergoing Stereotactic Body Radiotherapy for Bone Metastases

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) holds an expanding role in the treatment of bone metastases. As compared to conventional external beam radiation (cEBRT), SBRT may be best applied to specific subsets of patients with more favorable prognosis and may prolong survival time. This calls into question the generalizability of survival estimates from prognostic models built from more general patient populations treated with cEBRT. We investigate the external validity of three such models for patients treated with bone-directed SBRT and identify approaches to optimize prognostication for this population. <h3>Materials/Methods</h3> Patients treated with SBRT for bone metastases from 1/2017-12/2019 at 3 radiation oncology facilities were identified through retrospective electronic medical record review. Demographic, disease, and treatment data were collected, including the covariates of 3 previously-validated models built in populations that excluded SBRT: the 27-item Bone Metastases Ensemble Trees for Survival (BMETS) machine-learning model and 2 Cox regression models—Chow's 3-item (C-3) and Westhoff's 2-item (W-2) tools. Individualized estimates for risk of death at various time points after consultation were obtained using each model. Time-dependent area under the curve (tAUC), calibration plots, and Brier scores evaluated model discrimination, calibration, and overall performance when each model was applied to the SBRT validation set. <h3>Results</h3> A total of 192 sites in 168 patients were included. Patients were 65.5% male; 74% white, 17% black and 8% other; with median age of 63 years (range: 18-92), and median Karnofsky Performance Status of 90 (range: 50-100). Histologies were prostate (31%), lung (15%), breast (10%), and other (44%). Estimated median overall survival was 3.3 years. BMETS tAUC was 0.73, 0.81, and 0.81 at 6, 9, and 12 months, with significant outperformance (p<0.05) of C-3 and W-2 models by the 12-month time point (tAUC 0.71 and 0.75, respectively). Calibration plots showed overestimation of risk of death in all 3 models. Brier scores for BMETS, C-3 and W-2 were respectively 0.24, 0.28 and 0.25 at 12 months; the simple baseline model from the Kaplan-Meier curve estimate (Brier score 0.19) outperformed all 3 models. Subsequent analyses identified variables absent from the 3 models strongly predictive of survival in the SBRT cohort, including number of metastatic lesions. <h3>Conclusion</h3> When applied to an SBRT cohort, BMETS maintained excellent discrimination at time points >6 months, outperforming C-2 and W-3 models. Yet, each model underestimated specific survival probabilities, suggesting that tools built from non-SBRT populations may be poorly calibrated for SBRT and supporting use of SBRT-specific prognostic tools. To address this, we have modified the BMETS web platform to permit for users to select for SBRT and non-SBRT specific survival predictions.

Predictors of Early Polymetastasis after Comprehensive Local Therapy for Synchronous Oligometastatic NSCLC

<h3>Purpose/Objective(s)</h3> While comprehensive local treatment of non-small cell lung cancer (NSCLC) oligometastatic disease (OMD) has thus far yielded promising results, challenges remain in selecting patients with a more localized oligometastatic phenotype, as opposed to those with a large subclinical systemic disease burden. We sought to identify clinical variables that predict for early polymetastatic progression after definitive local treatment to all sites of disease for synchronous oligometastatic NSCLC. <h3>Materials/Methods</h3> From 2010-2019, 2884 patients with metastatic NSCLC were treated at a single cancer center. Patients who presented with synchronous OMD, defined as 1-5 distant metastases at diagnosis of NSCLC, and who had definitive local treatment of the primary and each metastatic lesion were retrospectively identified and included for analysis. The Kaplan-Meier method was used to calculate endpoints of freedom from polymetastasis (FFPM), defined as disease recurrence with >5 new/growing lesions, as well as freedom from new metastasis (FFNM), progression-free survival (PFS), and overall survival (OS). Multivariate Cox analyses were performed on variables with significant association on univariate analyses. Patients with and without early polymetastatic progression (within 1 year of completing local treatment) were compared using Fisher's exact test and Welch's t-test. <h3>Results</h3> A cohort of 84 NSCLC patients with synchronous OMD and definitive treatment to every site of disease was identified. Median follow up was 25.4 months. 2-year FFPM, FFNM, PFS, and OS were 55.0%, 27.8%, 20.9% and 55.1%, respectively. On multivariate analysis, N2 stage (vs. N0, HR 5.10, 95%CI 2.30 – 11.32, p < 0.001), number of metastases (HR 1.61, 95%CI 1.08 – 2.38, p = 0.018), and bone metastasis (HR 6.84, 95%CI 2.41 - 19.47, p < 0.001) were associated with FFPM, while no variable maintained a significant association with FFNM. N2 stage (HR 1.91, 95%CI 1.06-3.44, p = 0.031) and brain metastasis (HR 1.98, 95%CI 1.07-3.67, p=0.029) were associated with PFS. N2 stage (HR 2.79, 95%CI 1.47-5.32, p = 0.002) and age (HR 1.06, 95%CI 1.03 – 1.09, p < 0.001) were associated with OS. When comparing the 20 patients with polymetastasis within 1 year and 55 with FFPM > 1 year (excluding patients with <1 year follow up), patients with early polymetastasis were more likely to have N2 disease (45% vs. 10.9%, p = 0.009) and bone metastasis (30% vs. 3.6%, p = 0.004). <h3>Conclusion</h3> For NSCLC patients undergoing comprehensive local treatment for synchronous OMD, bone metastasis, N stage, and number of metastases are associated with early polymetastatic progression, likely reflecting the disparate biologies among patients with synchronous OMD as well as the difficulty of identifying small bone metastases with typical imaging studies. Strategies to intensify upfront imaging and systemic treatment may benefit this subset of patients.

Onset of MRONJ in Breast Cancer Patients after Switching from Low to High Dose of Bone Modifying Agents Due to Bone Metastases Development: A Single Center Retrospective Cohort Study

Background: Medication-Related Osteonecrosis of the Jaw (MRONJ) is an adverse drug reaction mainly associated to bone modifying agents (BMAs). Breast cancer (BC) is the most frequent cancer worldwide. Its therapy can cause cancer treatment-induced bone loss (CTIBL), commonly treated with BMAs. The aims of this retrospective study are: to describe characteristics of BC patients under BMAs for CTIBL; to record any switch to high-dose BMAs; to assess MRONJ onset and to identify any factors associated with it. Patients: Authors included patients referred for MRONJ prevention to the Unit of Oral Medicine (University Hospital of Palermo). Results: Fourteen female BC patients under low-dose BMAs for CTIBL were eligible (mean age 66.6 years). Four patients switched to high-dose BMAs for bone metastases. In two of the four, MRONJ developed: one case, in the mandible (risedronate for 48 months then Xgeva® for 60 months); the other case, in the maxilla (Prolia® for 20 months then zoledronate for 16 months). Conclusion: It can be theorized that BC patients under BMAs for CTIBL are likely to have MRONJ risk similar to osteo-metabolic patients. These patients need more careful monitoring of oral health since they may switch, for preventing or treating bone metastases, to heavier BMAs therapy, thus increasing their risk of MRONJ.

Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis.

Simple SummaryThe pro-inflammatory cytokine, IL1β, plays a pivotal role in breast cancer bone metastasis. Inhibiting IL-1 signalling with the IL1β specific antibody, Canakinumab, or the IL1R1 antagonist Anakinra almost eliminates bone metastases but has adverse effects on tumours growing outside of the bone and immune regulation. This current study demonstrated that pharmacological inhibition of other members of the IL-1 signalling pathway Caspase-1, IL1β and IL1R reduced migration and invasion of E0771 and Py8119 cells in vitro and also reduced spontaneous metastasis and metastatic outgrowth of breast cancer in the bone, in vivo. Interestingly, targeting IRAK1 had no anti-tumour effects. Importantly, inhibiting Caspase-1 reduces bone metastasis without adversely affecting tumours outside of bone or immune cell regulation, suggesting that targeting immediately upstream of IL1β may be a good therapeutic strategy for treating patients with breast-cancer-induced bone disease.Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.

Role of Interleukin-1 family in bone metastasis of prostate cancer.

Prostate cancer (PCa) is one of the most fatal diseases in male patients with high bone metastatic potential. Bone metastasis severely shortens overall survival and brings skeletal-related events (SREs) which reduces the life quality of patients, and this situation is currently regarded as irreversible and incurable. The progression and metastasis of PCa are found to be closely associated with inflammatory cytokines and chemokines. As pivotal members of inflammatory cytokines, Interleukin-1 (IL-1) family plays a crucial role in this process. Elevated expression of IL-1 family was detected in PCa patients with bone metastasis, and accumulating evidences proved that IL-1 family could exert vital effects on the progression and bone metastasis of many cancers, while some members have dual effects. In this review, we discuss the role of IL-1 family in the bone metastasis of PCa. Furthermore, we demonstrate that many members of IL-1 family could act as pivotal biomarkers to predict the clinical stage and prognosis of PCa patients. More importantly, we have elucidated the role of IL-1 family in the bone metastasis of PCa, which could provide potential targets for the treatment of PCa bone metastasis and probable directions for future research.

Ra-223 induces clustered DNA damage and inhibits cell survival in several prostate cancer cell lines

The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in prostate cancer. The alpha-particle emitter Ra-223, targets regions undergoing active bone remodeling and strongly binds to bone hydroxyapatite (HAp). However, the toxicity mechanism and properties of Ra-223 binding to hydroxyapatite are not fully understood. By exposing 2D and 3D (spheroid) prostate cancer cell models to free and HAp-bound Ra-223 we here studied cell toxicity, apoptosis and formation and repair of DNA double-strand breaks (DSBs). The rapid binding with a high affinity of Ra-223 to bone-like HAp structures was evident (KD= 19.2 × 10−18 M) and almost no dissociation was detected within 24 h. Importantly, there was no significant uptake of Ra-223 in cells. The Ra-223 alpha-particle decay produced track-like distributions of the DNA damage response proteins 53BP1 and ɣH2AX induced high amounts of clustered DSBs in prostate cancer cells and activated DSB repair through non-homologous end-joining (NHEJ). Ra-223 inhibited growth of prostate cancer cells, independent of cell type, and induced high levels of apoptosis. In summary, we suggest the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by α-particles.