Diagnosis Of Metastatic Bone Disease Research Articles

Abstract 3925: Cancer-associated fibroblast-derived Dickkopf-1 impairs anti-tumor immunity in breast cancer by suppressing NK cell-mediated cytotoxicity

Abstract Despite early diagnosis, 10-20% of breast cancer patients experience metastatic disease within 5-10 years. While it is established that breast cancer cells have the capacity to evade immune responses, the mechanisms driving this evasion remain elusive. Therefore, finding ways to enhance anti-tumor immunity is crucial to improve patient outcomes. Dickkopf-1 (DKK1) is a Wnt inhibitor whose levels correlate with poor prognosis and decreased immune infiltration in various cancers. In this study, we used mice orthotopically injected with the PyMT, EO771, and 4T1 breast cancer lines. In all models, we found elevated DKK1 serum levels, and its neutralization with an αDKK1 Ab resulted in a significant reduction in primary tumor growth but also in metastatic dissemination. To identify the source of DKK1, we examined its expression in the tumor. DKK1 was detected in stromal cells with a fibroblast-like morphology but not in cancer cells or immune infiltrates. Co-staining confirmed colocalization between DKK1 and the CAF marker αSMA. To address the role of CAF-derived DKK1, we specifically deleted DKK1 in CAFs by generating FSP1CreDkk1fl/fl and αSMACreERT2Dkk1fl/fl mice. Both models showed a significant reduction in primary tumor growth while maintaining comparable serum DKK1 levels, indicating locally produced DKK1 supports tumor growth. To understand how DKK1 promotes tumor progression, we conducted bulk RNAseq of tumor cells isolated from IgG or αDKK1 treated mice. While no changes related to cell viability or cell cycle were observed, immune response-related genes were upregulated in αDKK1-treated cells. In support of this, αDKK1 did not reduce tumor growth in NSG immune-compromised mice. To pinpoint the immune cell targeted by DKK1, we depleted T, NK cells, or macrophages in WT tumor-bearing mice treated with αDKK1. Remarkably, only NK cell depletion negated αDKK1 anti-tumor effects. In vitro assays further demonstrated that rDKK1 or the presence of CAFs reduced NK cell cytotoxicity against tumor cells while αDKK1 restored it. To assess whether DKK1 levels correlated with tumor progression and immune suppression in breast cancer patients, we analyzed DKK1 serum levels and circulating NK cells at the diagnosis of metastatic bone disease and 15-18 months after standard care. DKK1 levels were significantly elevated in patients with progressive bone disease compared to those with stable disease. Importantly, NK cells from the progressive disease cohort had reduced perforin and granzyme B expression at the follow-up visit compared to baseline, indicating reduced cytotoxicity. Furthermore, rDKK1 reduced perforin in NK cells from healthy donors. In sum, our data show DKK1 is an important regulator of breast cancer progression, and we report for the first time DKK1 directly impairs NK cell cytotoxicity, creating an immune suppressive environment resistant to treatment. Citation Format: Seunghyun Lee, Biancamaria Ricci, Roberta Faccio. Cancer-associated fibroblast-derived Dickkopf-1 impairs anti-tumor immunity in breast cancer by suppressing NK cell-mediated cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3925.

Socioeconomic and insurance-related disparities in disease-specific survival among patients with metastatic bone disease.

Approximately 5% of cancer patients in the United States presented with metastatic bone disease (MBD) at diagnosis. Current study explores the disparities in survival for patients with MBD. Patients with the diagnosis of MBD at presentation for the five most common primary anatomical sites were extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset (2010-2016). Kaplan-Meier and Cox Proportional Hazard models were used to evaluate survival, and prognostic factors for each cohort. Prognostic significance of socioeconomic status (SES) and insurance status were ascertained. The five most common anatomical-sites with MBD at presentation included "lung" (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal and urothelium" (n = 7718) and "colon" (n= 3068). Lower SES was an independent risk factor for worse disease-specific survival (DSS) for patients with MBD originating from lung, prostate, breast and colon. Lack of insurance was an independent risk factor for worse DSS for MBD patients with primary tumors in lung and breast. MBD patients from the five most common primary sites demonstrated SES and insurance-related disparities in disease-specific survival. This is the first and largest study to explore SES and insurance-related disparities among patients specifically afflicted with MBD. Our findings highlight vulnerability of patients with MBD across multiple primary sites to financial toxicity.

Sex, racial/ethnic and socioeconomic disparities in patients with metastatic bone disease.

We have analyzed sex, race/ethnicity or socioeconomic disparities in the incidence of metastatic bone disease (MBD). Patients with the diagnosis of MBD at presentation for five most common primary anatomical sites was extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset. Mean incidence of MBD for different sex, racial/ethnic and socioeconomic groups were compared. The five most common anatomical sites with MBD at presentation include "lung: (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal" (n = 7718) and "colon" (n = 3068). There was an increase in incidence of MBD among cancers originating from prostate (annual percentage change [APC] 4.94), renal (APC 2.55), and colon (APC 3.21) (p < 0.05 for all). Non-Hispanic Blacks had higher incidence of MBD for prostate and breast primary sites (p < 0.001). Non-Hispanic American Indian Alaskan Native had higher incidence of MBD for cancers originating from renal (p < 0.001) and colon (p = 0.049). A higher incidence of MBD was seen in lower socioeconomic status (SES) groups for the selected sites (p < 0.001). These findings suggest that there are multiple sex-related, racial/ethnic and SES disparities in the incidence of MBD from the 5 most common primary sites. Higher incidence seen among lower SES suggests delay in diagnosis and limited access to screening modalities.

ANALGESIC EFFECT OF VARIOUS RADIOPHARMACEUTICALS IN THE COMPLEX TREATMENT OF METASTATIC BONE DISEASE

The study objective was to investigate and compare the effectiveness of different radiopharmaceuticalsin the treatment of metastatic bone disease. Cancer patients (n = 150, average age (55 ± 11.6) years, 95 females, 55 males) having gotvarious primary tumors and metastatic bone disease were given medical treatment at the Department of NuclearMedicine of the National Institute of Cancer. The 153Sm, 32Р, and 89Sr radiopharmaceutical agents produced by the«Radiopreparats» enterprise (Republic of Uzbekistan) and Radioisotope Centre Polatom (National Centre for NuclearResearch, Poland) were administered to the patients. There were cases of breast cancer (n = 75), prostate cancer(n = 45), lung cancer (n = 10), kidney cancer (n = 4), cervical cancer (n = 5), and rectosigmoid cancer (n = 11) amongthe treated subjects. In 135 patients (90 %) the bone metastases were detected by osteoscintigraphy with 99мTc- mo-nodiphosphonate. In 15 cases the diagnosis of metastatic bone disease was verified by other radiology methods. The pain intensity rating scale (LACOMED) was used to assay the analgesic effect of various radiopharma-ceuticals in metastatic bone disease. Results of treatment with 32P, 89Sr, and 153Sm were included in a comparativeanalysis procedure. It was established that the level of pain syndrome ranged from 7-8 points on the LACOMED scalebefore treatment. Upon administration of radionuclide therapy the level of pain was reduced down to 3-5 points,namely with 32P therapy it has decreased by 30.7 %, with 89Sr by 33.2 %, and with 153Sm by 41.5 % respectively. Timepattern of 153Sm analgesic effectiveness was studied depending on the number of treatment sessions. The best valueof analgesic effect of 153Sm was registered after the first treatment session with a tendency to decrease after the sec-ond and significantly lower analgesic effects after the third session. Tolerance of 153Sm was rated on the CTCNCA (v)4.3 scale. The best tolerance was peculiar to 153Sm corresponding to the «good» level according to a point assess-ment. When using 89Sr the drug tolerance was lower, not requiring however the drug discontinuation. The 32P radio-pharmaceutical featured the lowest tolerance approaching the «satisfactory» rating. In 11 patients upon that theside effects were found significantly impairing the patient's status, accordingly some extra measures were required.No decision to cancel the drug administration was made. Radionuclide therapy with 153Sm-oxabiphor agent can be used in the complex treatment of metastat-ic bone disease in cancer patients having got tumors of different localization. 153Sm-oxabiphor is the most effectiveand best tolerable radiopharmaceutical agent in the pain treatment in metastatic bone disease in comparison with32P and 89Sr preparations (р < 0.05).

State-of-the-art imaging for diagnosis of metastatic bone disease.

Metastatic bone disease (MBD) is common—it is detected in up to 65–75% of patients with breast or prostate cancer, in over 35% of patients with lung cancer; and almost all patients with symptomatic multiple myeloma have focal lesions or a diffuse bone marrow infiltration. Metastatic bone disease can cause a variety of symptoms and is often associated with a poorer prognosis, with high social and health-care costs. Population-based cohort studies confirm significantly increased health-care utilization costs in patients presenting with cancer with MBD compared with those without MBD. The prolonged survival of patients with bone metastasis thanks to advances in therapy presents an opportunity for better treatments for this patient cohort. Early and accurate diagnosis of bone metastases is therefore crucial. The patterns and presentation of MBD are quite heterogeneous and necessitate good knowledge of the possibilities and limitations of each imaging modality. Here, we review the state-of-the-art imaging techniques, assess the need for evidence-based and cost-effective patient care pathways, and advocate multidisciplinary management based on collaborations between orthopedic surgeons, pathologists, oncologists, radiotherapists, and radiologists aimed at improving patient outcomes. Radiologists play a key role in this multidisciplinary approach to decision-making through correlating the tumor entity, the tumor biology, the impact on the surrounding tissues and progression, as well as the overall condition of the patient. This approach helps to choose the best patient-tailored imaging plan advocating a “choose wisely” strategy throughout the initial diagnosis, minimally invasive treatment procedures, as well as follow-up care plans.

Surgical treatment in bone metastases in the appendicular skeleton

IntroductionMetastatic bone disease is the most common neoplastic process that affects the skeletal system. Eighty percent of bone metastases come from carcinomas of the breast, lung, kidney, thyroid and prostate. The Katagiri scale enables an estimation of the survival of patients based on the presence or absence of visceral metastases, multiple bone metastases and functional status according to the ECOG scale. Material and methodsA retrospective, descriptive and observational study conducted between March 1, 2013 and June 30, 2015. Thirty-two patients were studied with a diagnosis of metastatic bone disease and who had undergone some type of orthopaedic surgical treatment for pathological fracture or impending fracture. Results28 cases (87.5%) presented pathological fracture and 4 cases (12.5%) impending fracture according to the Mirels score. Fifteen cases (46.875%) were treated by placing a central medullary nail+spacer in the long bone diaphysis, 15 cases (46.875%) with modular arthroplasties and 2 patients (6.25%) with forequarter amputation. Eleven patients (34.375%) died during the course of this study, all with a Katagiri greater than or equal to 4. DiscussionThe presence of a fracture in previously damaged territory is a catastrophic complication for most cancer patients. A clear understanding of the life expectancy of patients with bone metastases is of great help to prevent errors and failures in treatment.

Tratamiento quirúrgico de las metástasis óseas en el esqueleto apendicular

IntroductionMetastatic bone disease is the most common neoplastic process that affects the skeletal system. Eighty percent of bone metastases come from carcinomas of the breast, lung, kidney, thyroid and prostate. The Katagiri scale enables an estimation of the survival of patients based on the presence or absence of visceral metastases, multiple bone metastases and functional status according to the ECOG scale. Material and methodsA retrospective, descriptive and observational study conducted between March 1, 2013 and June 30, 2015. Thirty-two patients were studied with a diagnosis of metastatic bone disease and who had undergone some type of orthopaedic surgical treatment for pathological fracture or impending fracture. Results28 cases (87.5%) presented pathological fracture and 4 cases (12.5%) impending fracture according to the Mirels score. Fifteen cases (46.875%) were treated by placing a central medullary nail + spacer in the long bone diaphysis, 15 cases (46.875%) with modular arthroplasties and 2 patients (6.25%) with forequarter amputation. Eleven patients (34.375%) died during the course of this study, all with a Katagiri greater than or equal to 4. DiscussionThe presence of a fracture in previously damaged territory is a catastrophic complication for most cancer patients. A clear understanding of the life expectancy of patients with bone metastases is of great help to prevent errors and failures in treatment.

The Role of 18F-Sodium Fluoride PET/CT Bone Scans in the Diagnosis of Metastatic Bone Disease from Breast and Prostate Cancer.

We describe the role of 18F-sodium fluoride (18F-NaF) PET/CT bone scanning in the staging of breast and prostate cancer. 18F-NaF PET was initially utilized as a bone scanning agent in the 1960s and early 1970s, however, its use was restricted by the then-available γ-cameras. The advent of hybrid PET/CT cameras in the late 1990s has shown a resurgence of interest in its use and role. After a brief introduction, this paper describes the radiopharmaceutical properties, dosimetry, pharmacokinetics, and mechanism of uptake of 18F-NaF. The performance of 18F-NaF PET/CT is then compared with that of conventional bone scintigraphy using current evidence from the literature. Strengths and weaknesses of 18F-NaF PET/CT imaging are highlighted. Clinical examples of improved accuracy of diagnosis and impact on patient management are illustrated. Limitations of 18F-NaF PET/CT imaging are outlined.

Survival Rates Following Skeletal Metastases—A Twenty-Year Analysis

Introduction: The aims of this study were to establish an estimate of the prognosis and to identify the variables predictive of survival following the diagnosis of metastatic bone disease. Materials and Methods: Ninety-seven patients diagnosed with skeletal metastases confirmed by histological examination between 1991 and 2010 were selected. Data were retrospectively collected including age and sex, sites and histology of the primary tumour and skeletal metastases, presence of visceral metastases, pathological fracture, and the treatment received. Results: Ninety-three patients (95.9%) were deceased. The overall rate of survival was 47% at 6 months, 31% at one year and 10% at three years. Multivariate analysis confirmed the grade of malignancy, age and systemic therapy as independent predictors of survival. Discussion and Conclusion: The prognosis of patients with skeletal metastases should be estimated according to the site and histology of the primary tumour, grade of malignancy and age at the time of presentation.

Prostate cancer in patients from rural and suburban areas--PSA value, Gleason score and presence of metastases in bone scan.

Prostate cancer is the second most common neoplasm among men both worldwide and in Poland. In prostate cancer, bone metastasis is related to a poorer prognosis. A diagnosis of metastatic bone disease is important in prostate cancer patients prior to therapy. Prostate specific antigen (PSA) serum value is used both as a screening tool and for staging of prostate cancer. To evaluate whether there is a link between symptoms presented by patients, pain in particular, and the presence, number and location of bone metastases as assessed by bone scan scintigraphy in concordance with PSA values and Gleason scores. A group of 186 patients (aged: 68.38±6.16) diagnosed with prostate cancer, from rural and suburban areas of Małopolska province, that was directed for bone scan scintigraphy to the Nuclear Medicine Dept, John Paul II Hospital in Kraków. Analysis of all laboratory findings (including PSA value) and a biopsy were performed. Then, bone scan scintigraphy was done with the use of methylene disphosphonate (MDP) labeled with Tc-99m. In patients with a Gleason value≤7 and a PSA value≤20 ng/ml, the cutoff value for a negative bone scan with a confidence interval of 0.95 was established at a PSA value below 10 ng/ml (p<0.01). Correlations were established between PSA value and presence of metastases in bone scan (r=0.45, p=0.05), the number of metastases (r=0.66, p<0.01), and their presence in particular body regions. The correlation between PSA value and both presence and number of metastases confirms the usefulness of bone scan scintigraphy in prostate cancer staging. The cutoff value for negative bone scan with a 95% confidence interval was established at PSA=10 ng/ml.

Skeletal-Related Events due to Bone Metastases from Differentiated Thyroid Cancer

In oncology, the clinical impact of metastatic bone disease is conveyed via a composite end point termed skeletal-related events (SRE), which encompasses spinal cord compression, pathological fracture, a need for external beam radiation or surgery to bone, and hypercalcemia of malignancy. An appreciation for the high incidence of SRE in other advanced cancers involving the bone has led to the approval of potent antiresorptive agents because they delay the time to the first SRE and decrease the incidence of SRE. The risk and rate of SRE after diagnosis of bone metastasis have not been described in thyroid cancer; antiresorptive agents are not routinely used. This was a retrospective review of 245 differentiated thyroid cancer patients with bone metastases identified as part of routine clinical care at Memorial Sloan-Kettering Cancer Center between 1960 and 2011. The occurrence of SRE was recorded from the initial diagnosis of bone metastasis until final follow-up or death. Seventy-eight percent of patients (192 of 245) either presented with or developed at least one SRE after the diagnosis of metastatic bone disease. The median time from identification of bone metastasis to first SRE was 5 months (excluding the 97 patients in whom first SRE occurred at the time of the bone metastasis diagnosis). Of the patients who sustained an initial SRE, 65% (120 of 192) went on to sustain a second SRE at a median of 10.7 months after the first event. SRE were frequently multiple; 39% (74 of 192) sustained three or more discrete SRE. Thyroid cancer bone metastases identified as part of routine clinical follow-up frequently cause significant and recurrent morbidity. The incidence of SRE and median time to first SRE in metastatic thyroid cancer to bone are similar to those reported in other solid tumors. Prospective clinical trials to assess the efficacy of antiresorptive agents in this population are needed.

Experts' agreement on therapy for bone metastases

Experts' agreement on therapy for bone metastases

Patterns of Bisphosphonate Use in the United States in the Treatment of Metastatic Bone Disease

Purpose The purpose of this study was to determine the incidence of metastatic bone disease (MBD), the frequency of intravenous (I.V.) bisphosphonate use and its impact on skeletal-related events (SREs), and opioid use. Patients and Methods Patients diagnosed with MBD between 2000 and 2004 were identified using 2 Thomson MarketScan® Research Databases. A total of 6783 patients, 1431 with breast cancer, fulfilled the criteria. Pain was assessed as the number of days on opioids, the strength of which was categorized according to the World Health Organization 3-step ladder for pain. Results Use of I.V. bisphosphonates steadily increased for all cancers from 17% in 2000 to 38% in 2004. For all patients, 61% received mild opioids and 35% received moderate to severe opioids at baseline. Use of I.V. bisphosphonates within the first 90 days after diagnosis of MBD was associated with a 63% decrease in SREs and reduction in use of moderate to severe opioids. Among patients with breast cancer, 10.6% received oral bisphosphonates before diagnosis of MBD, and 33.8% had pain at baseline. There was a 5.4% reduction in the use of moderate to severe opioids. Conclusion Our data support the role of I.V. bisphosphonates in decreasing SRE and improving the quality of life for patients with MBD; the result is less pain and fewer SREs. More than 73% of all patients and 53% of patients with breast cancer never receive I.V. bisphosphonate treatment. Educational measures are warranted to increase the awareness by patients and physicians of the value of I.V. bisphosphonates in MBD.

345 POSTER Nomograms to predict outcome after preoperative chemotherapy for breast cancer

Background: Complications from skeletal-related events (SREs) constitute a challenge in the care of patients with metastatic bone disease (MBD) that originated from any type of malignancy.Objective: The purpose of this article was to compare the efficacy of clodronate, pamidronate, and zoledronate with that of placebo in reducing morbidity and overall mortality in cancer patients with MBD.Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched (from inception to January 2009) to retrieve randomized clinical trials that evaluated the bisphosphonates of interest. The search included articles published in English, French, Italian, Portugese, and Spanish. Patients with a definite (ie, biopsy-proven) diagnosis of MBD were included in the analysis. We extracted and combined data from studies that reported the number of patients with SREs and mortality data. A random-effects, meta-analytic model was applied in all calculations. The Jadad scale was used to assess the quality of study reporting.Results: The literature search identified 62 potential full-text studies; 44 of these studies were excluded and 18 were evaluated. The mean (SD) quality of reporting of the included studies was 57.8% (22.6%), or 2.89/5 (1.1/5). Each of the 3 drugs was found to be more effective than placebo in preventing all SREs in cancer patients with MBD. The relative risk of developing SREs was 0.70 (95% CI, 0.61–0.81; N = 1211) for zoledronate, 0.81 (95% CI, 0.73–0.91; N = 2251) for pamidronate, and 0.87 (95% CI, 0.75–1.00; N = 681) for clodronate. However, no clear advantage of one drug over the others was observed (CIs overlapped substantially). None of the bisphosphonates was more beneficial than placebo in reducing the number of deaths in the course of the trials (P = NS).Conclusion: Clodronate, pamidronate, and zoled-ronate were associated with reductions in morbidity in cancer patients with MBD with regard to preventing SREs, but were not associated with a reduction in overall mortality.

17. A method comparison study to compare a shorter versus a longer scanning time for bone scans in the diagnosis of metastatic bone disease

17. A method comparison study to compare a shorter versus a longer scanning time for bone scans in the diagnosis of metastatic bone disease

Treatment of metastatic adenocarcinoma of the pelvis and the extremities.

Cancer is the second leading cause of death in the United States; in 1991, 23.7 per cent (514,657) of the total number of deaths were cancer-related126. The rate of survival has improved over the last three decades; the five-year rate of survival from the time of diagnosis has increased by 20 and 30 per cent for breast and prostate carcinoma, respectively, since 1963126. Bone is the third most common site for distant metastases from adenocarcinoma, second only to the lung and the liver. Bone metastases were the first presentation of carcinoma in 23 per cent of 429 previously undiagnosed patients19. Although not always clinically evident, there is bone involvement at the time of autopsy in as many as 85 per cent of patients who die from carcinoma of the breast, prostate, or lung66,114. Breast (32 per cent), prostate (36 per cent), and lung carcinoma (14 per cent) are the most commonly reported types in the United States126. Of these adenocarcinomas, lung cancer contributes to 33 per cent of the deaths of men and to 24 per cent of those of women126. Radionuclide imaging demonstrated bone metastases in 590 (63 per cent) of 933 patients diagnosed with a primary adenocarcinoma, with 789 (85 per cent) of these patients having metastases secondary to breast, lung, or prostate carcinoma115. The most frequent sites of bone metastases are the vertebrae, pelvis, ribs, femora, and skull. The duration of survival after the diagnosis of metastatic bone disease often depends on the histological characteristics of the primary carcinoma. Patients who have metastatic bone disease secondary to breast carcinoma have a better prognosis for survival (thirty-four months) than do those who have metastatic bone disease secondary to carcinoma of the prostate …

Skeletal Scintimaging and Radiography in the Diagnosis and Management of Pagefs Disease

Experiences in sue of skeletal scintimaging, primarily with 99mTc EHDP, is reported in 108 patients with Paget's disease. The results are compared with other reports and suggest that the mean age of this sample at the time of initial diagnosis and study is somewhat younger than patients in series reported in the literature. In correlation of scintimaging with skeletal radiography only approximately 67% of lesions are seen with the latter. Lesions seen only on scintimaging primarily are associated with early symptomatic lesions and lesions seen only on radiography with older sclerotic "burned out" type lesions. Scintimaging reveals a relatively low incidence of monostotic distribution of lesions, and is superior to skeletal radiography for diagnosis of metastatic bone disease. Qualitative skeletal scintimaging is valuable for objective assessments of therapeutic management by new modes of therapy while clinical radiography is not.