First Site Of Metastasis Research Articles

Radioembolization for treatment of uveal melanoma hepatic metastasis: Results of a phase II, single institution, prospective trial.

9535Background: The liver is the first site of metastasis in > 90% of uveal melanoma (UM) patients. Transarterial catheter directed therapies have been used to control growth of liver tumors and pr...

Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain?

The brain is the most common site of first metastasis for patients with HER2-positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBM) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the "blood-tumor" barrier is not the whole story. Using HER2-positive BCBMs as a case study, we highlight recent data from orthotopic brain metastasis models that implicate brain-specific drug resistance mechanisms in BCBMs and suggest a translational research paradigm to guide drug development for treatment of BCBMs. Clin Cancer Res; 24(8); 1795-804. ©2018 AACR.

Abstract P1-16-04: Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis

Abstract Background: Bone is the most common site of metastasis of breast cancer, and bone metastasis is associated with a high rate of skeletal-related events, all of which contribute to decreased quality of life and poor outcomes. Biological mechanisms of metastasis to bone may be unique, and identification of distinct signaling pathways and somatic mutations may provide biological insight into or rational targets for treatment of and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone only versus non-bone as first metastatic site. Methods: Tumor samples were collected from 389 patients who had metastasis and untreated primary breast cancer. In each sample, 46 or 50 cancer-related genes were selectively amplified and analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. We used Fisher's exact test to identify somatic mutations associated with bone-only first metastasis and logistic regression models to identify differences in clinicopathologic characteristics, survival, and somatic mutations between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only (“other-only first metastasis”). Results: Among the 389 patients, the first metastasis was located in bone only in 72 patients (18.5%), non-bone sites only in 223 patients (57.3%), and both in 94 patients (24.2%). Of the cancer-related genes analyzed, the most commonly mutated were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and low nuclear grade (grade 1 or 2) (all 3 comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68; respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer. Citation Format: Kono M, Fujii T, Matsuda N, Harano K, Chen H, Wathoo C, Aron JY, Tripathy D, Meric-Bernstam F, Ueno NT. Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-04.

Abstract P1-16-01: Tumor subtype concordance between breast and bone biopsies in bone only metastasis patients

Abstract Background: Bone is the most common site of metastasis in metastatic breast cancer patients. Notably, bone biopsy is considered technically challenging with concerns regarding yield and reproducibility of immunohistochemistry technique. Our goal was to assess tumor subtype concordance between breast and bone biopsies done in patients with bone only metastases. Methods: We identified patients followed at MD Anderson Cancer Center for at least 6 months from 01/01/1997 to 12/31/2015 with bone as first site of metastasis. Breast and bone biopsy immunohistochemistry was used to categorize tumor subtype with hormone receptor positive (HR+) defined as ER or PR >1%. The following four tumor subtypes were identified: luminal A-like (HR+, HER2-), luminal B-like (HR+, HER2+), triple negative (HR-, HER2-), and HER positive (HR-, HER2+). Results: We identified 805 bone only metastasis patients with positive bone biopsies, 395 (49%) of which had hormone receptor and HER2 characterization available. Of these 395 patients, 293 (74%) were luminal A-like, 44 (11%) were luminal B-like, 51 (13%) were triple negative, and 7 (2%) were HER2 positive. Of these patients, we identified 281 patients with tumor subtype data available for both primary breast biopsy and bone metastasis biopsy, of which 237 (84%) were concordant, while 44 (16%) were discordant (Table 1). Table 1. Concordance between breast and bone biopsies based on initial breast biopsy tumor subtypeBreast Biopsy Tumor Subtype (n = 281)Concordance with Bone Biopsy Tumor SubtypeDiscordant Bone Biopsy Tumor SubtypeLuminal A-like, HR+ HER2- (225/80%)Concordant: 199 (88%), Discordant: 26 (12%)10 Luminal B-like, 16 Triple negativeLuminal B-like, HR+ HER2+ (33/12%)Concordant: 19 (58%), Discordant: 14 (42%)11 Luminal A-like, 2 Triple negative, 1 HER2 positiveTriple negative, HR- HER2- (20/7%)Concordant: 16 (80%), Discordant: 4 (20%)3 Luminal A-like, 1 Luminal B-likeHER2 positive, HR- HER2+ (3/1%)Concordant: 3 (100%), Discordant: 0 (0%)NA Conclusions: When available, bone biopsy tumor subtype had significant concordance with breast biopsy tumor subtype in this large study of bone only metastasis patients. Discordant tumor subtype results were more common in patients with luminal B-like tumor subtype on initial breast biopsy. Citation Format: Parkes AM, Clifton KK, Al Awadhi A, Oke OC, Warneke CL, Litton JK, Hortobagyi GN. Tumor subtype concordance between breast and bone biopsies in bone only metastasis patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-01.

Abstract PD2-05: Evaluation of sentinel lymph nodes with high-frequency ultrasound: Correlations to histopathology

Abstract Purpose: The sentinel lymph node (SLN) is biopsied during breast conservation surgery (BCS) since it is the first site of metastasis for breast cancer. If malignant, axillary lymph node dissection (ALND) may be performed to remove additional nodes in and around the affected breast, limiting the spread of the malignancy. Often, ALND results in hardship for the patient in the form of further surgeries, having nodes removed that may not be malignant, and in debilitating side effects. Developing a method to analyze SLNs intraoperatively would eliminate additional surgeries and the patient's associated suffering. This research aims to develop the use of high-frequency (HF) ultrasound (20-80 MHz) as a real-time analysis method to determine SLN status during BCS. Background: HF ultrasonic data from BCS tissue specimens were gathered from 73 patients at the Huntsman Cancer Institute, Salt Lake City, UT, immediately following surgery. In addition to 349 margin specimens, data were collected from 78 SLNs, with initial results displaying high statistical measures. A limitation of the SLN analyses, however, was that pathology results were provided only on a per sample basis, whereas the ultrasonic method often tested multiple positions on a node (max = 4, avg = 1.26). Because of the mismatch between the ultrasonic measurements (per position basis) and pathology results (per specimen basis), an ambiguity existed in how to best analyze the data. The aim of this study was to examine the scope of this ambiguity by determining the differences in statistical measures obtained by analyzing the SLN data on a per position basis versus a per specimen basis given the current data available. Method: HF ultrasound parameters extracted from the data were peak density (the number of peaks in the ultrasonic spectra) and attenuation. Both parameters correlate to tissue malignancy, and were used in a multivariate analysis to provide the final results. The statistical measures for the ultrasonic test results were calculated as follows: (1) per position basis: the pathology of each position was determined by the pathology results for the entire specimen; (2) per specimen basis: only one measurement position on each node was selected, based on the highest peak density value, to correlate to the specimen pathology. Results: The analyses revealed that the HF ultrasonic data yielded an accuracy, sensitivity, and specificity of 79.6%, 76.9%, and 80.0%, respectively, for the per position basis, and 84.6%, 87.5%, and 84.3%, respectively, for the per specimen basis. The results indicate that HF ultrasound provides intraoperative detection capabilities competitive with many SLN evaluation methods currently in use, including imprint cytology, frozen-section analysis, and qRT-PCR. Detailed analyses of the SLN pathology slides from the 73-patient study are currently being conducted to improve the correlations between the ultrasound results and histopathology. Image analysis methods are being used to quantify the extent of the malignant tissue in each SLN. This will provide pathology results on a per position basis, and thus more accurate, one-to-one correlations. These correlations would significantly further the development of HF ultrasound for real-time SLN evaluation. Citation Format: Khelfa S, Factor RE, Sanjinez DA, Zambrana AF, Doyle TE. Evaluation of sentinel lymph nodes with high-frequency ultrasound: Correlations to histopathology [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD2-05.

Determinants of prolonged survival for breast cancer patient groups with leptomeningeal metastasis (LM).

The study aimed to assess factors affecting survival of breast cancer patients suffering leptomeningeal metastasis (LM) and to compare survivals in patients with LM as the first and only site of metastases at presentation to patients with LM and metastases in other organs, along with selecting a patient group which had the best survival outcomes. Subject groups consisted of 187 patients consecutively referred during 1999-2015. A Cox proportional hazards model was used to identify factors associated with prolonged survival from LM. The Cox prognostic index was created to identify the group of patients with the most favorable prognosis. Median survival for all patients and for those with LM as the first site of metastases at presentation was 17 weeks and 1 year-survival was 15 and 16%, respectively. Factors beneficially affecting survival were: KPS ≥ 70, older age, biological subtype ER/PR+HER2-, systemic treatment, intrathecal treatment and radiation therapy. Based on these factors, 4 prognostic groups were found, with the most favorable group being 24 LM patients with median survival of 9.6months. In this group, all patients were treated systemically and all were irradiated, 88% had KPS ≥ 70, about 80% had luminal breast cancer, 75% were treated intrathecally and 58% were more than 53years old. Out of 4 prognostic groups of patients with LM, the most favorable group was selected. The median survival of breast cancer patients with the leptomeninges as the only site of metastases was comparable to those who had metastases in the leptomeninges and in other organs.

HER2 positivity in brain metastases from gastrointestinal primary malignancies.

61 Background: HER2 amplification in gastrointestinal (GI) cancers, beyond gastric cancer, is uncommon and as a result infrequently tested. In breast cancer, HER2 amplification has been associated with brain metastases (BM) with associated prognostic value and therapeutic opportunity. The purpose of this project was to determine if HER2 amplification is more frequent in GI cancer patients with brain metastases. Methods: Retrospective review of our institution’s medical record system identified all patients with GI primary malignancies who had resection of BM between 1999-2015 with tissue available. Fluorescence in-situ hybridization for HER2 amplification and immunohistochemistry for HER2 expression was performed on each sample and quantified by a board-certified pathologist. Results: Twenty-five GI cancer patients with BM were identified: 40% esophageal adenocarcinoma (AC), 12% esophageal squamous cell carcinoma (SCC), 44% colorectal AC and 4% pancreatic AC. At diagnosis 36% had metastatic disease. A BM was the isolated first site of metastasis in: 11/13 esophageal cancers, 1/11 colorectal cancers and 1/1 pancreatic cancer. Two esophageal cancer patients and one colon cancer patient had BM at diagnosis but otherwise median time to BM was 30 months (range 4-127 months). There was a median of 1 BM with a maximum of 4 lesions per patient. The most common intracranial site was the cerebellum (40%) with a median metastasis size of 27 mm (range 5-55 mm). Overall, HER2 was amplified in 24% (n=6) with 4 of these patients having paired primary tumor tissue available. None of the primary tumor tissue was HER2 amplified. No colorectal cancer patients had HER2 amplification but 67% of esophageal SCC, 30% of esophageal AC and the only pancreatic AC patient had Her2 amplified and overexpressed brain metastases. Conclusions: HER2 amplification was enriched in esophageal SCC and AC patients who developed resectable BM despite none of these patients having HER2 amplification in their primary tissue. HER2 amplification testing in esophageal cancer patients with BM (regardless of histology) may lead to additional therapeutic options, even if primary tissue was negative for HER2 amplification.

Characterization of bone only metastasis patients with respect to tumor subtypes

Metastatic breast cancer (MBC) patients with bone only metastasis (BOM) are a unique population with limited characterization. We identified patients followed at MD Anderson Cancer Center from 01/01/1997 to 12/31/2015 for at least 6 months with a BOM diagnosis as first site of metastasis. Tumor subtype (TS) was assessed by initial breast biopsy immunohistochemistry using hormonal receptor (HR) and HER2 status, with four subtypes identified: HR+/HER2−, HR+/HER2+, HR−/HER2−, HR−/HER2+. HR+ was defined as estrogen receptor or progesterone receptor ≥1%. We identified 1445 patients with BOM, 1048 with TS data available. Among these patients, the majority were HR+/HER2− (78%). Median time from breast cancer diagnosis to first bone metastasis was 2.3 years (95% CI 2.1, 2.5) and varied significantly by TS, with longer time to distant disease in HR+/HER2− patients relative to all other TS (p < .0001). Median overall survival (OS) from breast cancer diagnosis was 8.7 years (95% CI 8.0, 9.7) and varied significantly by TS with poorer OS for HR−/HER2− and HR-/HER2+ patients relative to HR+/HER2− TS (p < .0001). The 442 patients with de novo BOM disease, defined as bone metastasis diagnosis within 4 months of breast cancer diagnosis, had significantly shorter OS (p < .0001). Overall, several higher risk BOM subsets were identified in this analysis, most notably HR−/HER2+ and HR−/HER2− TS and de novo BOM patients.

Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis.

Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis.Methods: Primary tumor samples were collected before treatment from 389 patients with untreated primary breast cancer and distant metastasis at diagnosis. In each sample, 46 or 50 cancer-related genes were analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. Fisher's exact test was used to identify somatic mutations associated with bone-only first metastasis. Logistic regression models were used to identify differences in detected somatic mutations, clinicopathologic characteristics, and survival between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only (“other-only first metastasis”).Results: Among the 389 patients, 72 (18.5%) had bone-only first metastasis, 223 (57.3%) had other-only first metastasis, and 94 (24.2%) had first metastasis in both bone and non-bone sites. The most commonly mutated genes were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and lower grade (grade 1 or 2; Nottingham grading system) (all three comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68, respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001).Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis tend to have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer.

The outcome of prostate cancer patients treated with curative intent strongly depends on survival after metastatic progression

BackgroundFive-year survival in patients with localized prostate cancer (PCa) is nearly 100%, but metastatic disease still remains incurable. Clinical management of metastatic patients has become increasingly complex as novel therapeutic strategies have emerged. This study aims at evaluating the impact of the first metastatic progression on the outcome of PCa patients treated with curative intent.MethodsThe analysis was conducted using data of 913 cases of localized PCa diagnosed between 2000 and 2014. All patients were treated with curative surgery (N = 382) or radiotherapy (N = 531) with or without adjuvant therapy. All metastases were radiologically documented. The prognostic impact of the first site of metastasis on metastasis-free survival (MFS) and PCa-specific survival (PCaSS) was investigated by univariate and multivariate analyses.ResultsOne hundred and thirty-six (14.9%) patients developed a metastatic hormone-sensitive PCa and had a median PCaSS of 50.4 months after first metastatic progression. Bone (N = 50, 36.8%) and LN or locoregional (N = 52, 38.2%) metastases occurred more frequently with a median PCaSS of 39.7 and 137 months respectively (p < 0.0001). Seven patients developed visceral metastasis only (5.1%; liver, lung, brain) and 27 (19.9%) concurrent metastases; this last group was associated with the worst survival with a median value of only 17 months. Thus, each subgroup exhibited a survival after metastasis significantly different from each other. In multivariate analysis the site of the first metastasis was an independent prognostic factor for PCaSS along with Gleason score at diagnosis. The correlation between survival and first site of metastasis was confirmed separately for each therapy subgroup. Median metastasis-free survival from primary diagnosis to first metastasis was not correlated with the first site of metastasis.ConclusionsIn non-metastatic PCa patients treated with curative intent, the PCa-specific survival time depends on the time after metastatic progression rather than the time from diagnosis to metastasis. Moreover, the site of first metastasis is an independent prognostic factor for PCaSS. Our data confirm that the first metastatic event may confer a differential prognostic impact and may help in identifying patient at high risk of death supporting the treatment-decision making process following metastatic progression.

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Background:Cutaneous melanoma can metastasise haematogenously and/or lymphogenously to form satellite/in-transit, lymph node or distant metastasis. This study aimed to determine if BRAF and NRAS mutant and wild-type tumours differ in their site of first tumour metastasis and anatomical metastatic pathway.Methods:Prospective cohort of patients with a histologically confirmed primary cutaneous melanoma at three tertiary referral centres in Melbourne, Australia from 2010 to 2015. Multinomial regression determined clinical, histological and mutational factors associated with the site of first metastasis and metastatic pathway.Results:Of 1048 patients, 306 (29%) developed metastasis over a median 4.7 year follow-up period. 73 (24%), 192 (63%) and 41 (13%) developed distant, regional lymph node and satellite/in-transit metastasis as the first site of metastasis, respectively. BRAF mutation was associated with lymph node metastasis (adjusted RRR 2.46 95% CI 1.07–5.69, P=0.04) and sentinel lymph node positivity (adjusted odds ratio [aOR] OR 1.55, 95% CI 1.14–2.10, P=0.005). BRAF mutation and NRAS mutation were associated with increased odds of developing liver metastasis (aOR 3.09, 95% CI 1.49–6.42, P=0.003; aOR 3.17, 95% CI 1.32–7.58, P=0.01) and central nervous system (CNS) metastasis (aOR 4.65, 95% CI 2.23–9.69, P<0.001; aOR 4.03, 95% CI 1.72–9.44, P=0.001). NRAS mutation was associated with lung metastasis (aOR 2.44, 95% CI 1.21–4.93, P=0.01).Conclusions:BRAF mutation was found to be associated with lymph node metastasis as first metastasis and sentinel lymph node positivity. BRAF and NRAS mutations were associated with CNS and liver metastasis and NRAS mutation with lung metastasis. If these findings are validated in additional prospective studies, a role for heightened visceral organ surveillance may be warranted in patients with tumours harbouring these somatic mutations.

Characterization of bone only metastasis (BOM) patients (pts) with respect to tumor subtypes (TS).

1072 Background: Metastatic breast cancer (MBC) pts with BOM are a unique population with limited characterization. Our goal was to characterize the TS of BOM pts, evaluating differences in sites and types of bone metastases (BM), treatment, and survival. Methods: We identified pts followed at MD Anderson Cancer Center from 01/01/1997 to 12/31/2015 for at least 6 months with a BOM diagnosis as first site of metastasis (met). TS was assessed by initial biopsy immunohistochemistry (IHC) (Table 1) with hormone receptor (HR) + defined as ER or PR &gt;10%. Results: We identified 1445 pts with BOM, 1049 with initial biopsy IHC available to group into TS (Table 1). Among BOM pts, the majority had multiple BM at diagnosis (1141/79%), most in both the axial (Ax) and appendicular (App) skeleton (53%). Of the 808 pts with BM categorized on imaging at diagnosis, the majority were lytic (389/48%), with 21% sclerotic, 18% mixed, and 12% blastic. Time from breast cancer diagnosis to first met differed significantly by TS, χ2(3) = 94.33, P&lt; .0001, with median time to met longer for pts with blastic (3.08 years; 95% CI 2.03, 4.24) versus lytic lesions (1.75 years; 95% CI 1.27, 2.17). Conclusions: BOM patients are a unique MBC subpopulation, more commonly found in luminal TS patients. Our study demonstrates prognostic differences in BOM pts specific to TS and emphasizes the need for further study of BOM patients. [Table: see text]

Patterns of disease relapse in primary extremity soft tissue sarcoma

Background Extremity soft-tissue sarcomas comprise a range of distinct histological subtypes. This study aimed to characterize the patterns of disease relapse in patients undergoing resection of primary extremity soft-tissue sarcoma. Methods All patients who had resection of primary extremity soft-tissue sarcoma at the Royal Marsden Hospital between January 2004 and January 2014 were identified from an institutional database. Results In the period examined, 556 patients underwent resection. The most common histological subtypes were undifferentiated pleomorphic sarcoma (169 patients, 30·4 per cent), well differentiated liposarcoma (63, 11·3 per cent), myxoid liposarcoma (62, 11·2 per cent), myxofibrosarcoma (54, 9·7 per cent) and leiomyosarcoma (39, 7·0 per cent). Local recurrence-free survival (LRFS) did not differ significantly between histological subtypes (P = 0·222). Distant metastasis-free survival (DMFS) and disease-specific survival (DSS) were found to differ significantly between subtypes (P < 0·001 for both DMFS and DSS), with the worst outcomes in patients with undifferentiated pleomorphic sarcoma (5-year survival rate: 56·8 (95 per cent c.i. 52·5 to 61·1) per cent for DMFS; 60·1 (55·6 to 64·6) per cent for DSS). However, on multivariable analysis, histological subtype was not found to be independently prognostic for LRFS, DMFS or DSS. Metastatic disease developed in 149 patients, with the lungs being the most common site of first metastasis (120 patients, 80·5 per cent). The site of first metastasis differed between subtypes, with extrapulmonary metastases predominant in myxoid liposarcoma (11 of 13 patients; P < 0·001). Conclusion Although histological subtype was not found to be an independent prognostic factor for oncological outcomes, the site of first metastasis differed significantly between subtypes.

Site of metastasis and breast cancer mortality: a Danish nationwide registry-based cohort study.

Survival among patients with metastatic breast cancer may vary according to the site of metastasis and receptor status. We used Danish nationwide medical registries to establish a cohort of patients with metastatic breast cancer (870 with de novo metastatic disease and 3518 with recurrent disease with distant metastasis) diagnosed during 1997-2011. We examined 1-year and >1 to 5-year mortality associated with first site of metastasis and receptor expression status of the primary tumor. Cox proportional regression was used to compute confounder-adjusted mortality rate ratios (MRRs) associated with site of metastasis, stratified by receptor status. Overall 1-year and >1 to 5-year mortality risks were 36 and 69%, respectively. Risk of death within 1 year was highest for brain-only (62%) and liver-only (43%) involvement and nearly the same for patients with lung-only (32%), bone-only (32%) involvement, and other/combination of sites (34%). Using bone-only metastasis as reference, women with brain-only metastasis had more than two-fold increased risk of dying. The adjusted MRR for women with liver-only metastasis also was increased, though less pronounced. Patients with lung-only [adjusted MRR 0.9 (95% confidence interval (CI) 0.8, 1.1)] or other metastases [adjusted MRR 1.0 (95% CI 0.9, 1.2)] had similar mortality as patients with bone-only metastasis. Positive hormonal receptor status was a favorable prognostic factor. Metastatic breast cancer has a serious prognosis. Patients with brain-only metastasis had the highest mortality. Positive hormonal receptor status on the primary tumor was a favorable prognostic factor for all metastatic sites.

Patterns of disease relapse in primary extremity soft-tissue sarcoma.

Extremity soft-tissue sarcomas comprise a range of distinct histological subtypes. This study aimed to characterize the patterns of disease relapse in patients undergoing resection of primary extremity soft-tissue sarcoma. All patients who had resection of primary extremity soft-tissue sarcoma at the Royal Marsden Hospital between January 2004 and January 2014 were identified from an institutional database. In the period examined, 556 patients underwent resection. The most common histological subtypes were undifferentiated pleomorphic sarcoma (169 patients, 30·4 per cent), well differentiated liposarcoma (63, 11·3 per cent), myxoid liposarcoma (62, 11·2 per cent), myxofibrosarcoma (54, 9·7percent) and leiomyosarcoma (39, 7·0 per cent). Local recurrence-free survival (LRFS) did not differ significantly between histological subtypes (P = 0·222). Distant metastasis-free survival (DMFS) and disease-specific survival (DSS) were found to differ significantly between subtypes (P < 0·001 for both DMFS and DSS), with the worst outcomes in patients with undifferentiated pleomorphic sarcoma (5-year survival rate: 56·8 (95 per cent c.i. 52·5 to 61·1) per cent for DMFS; 60·1 (55·6 to 64·6) per cent for DSS). However, on multivariable analysis, histological subtype was not found to be independently prognostic for LRFS, DMFS or DSS. Metastatic disease developed in 149 patients, with the lungs being the most common site of first metastasis (120 patients, 80·5 per cent). The site of first metastasis differed between subtypes, with extrapulmonary metastases predominant in myxoid liposarcoma (11 of 13 patients; P < 0·001). Although histological subtype was not found to be an independent prognostic factor for oncological outcomes, the site of first metastasis differed significantly between subtypes.

Relation between primary tumor FDG avidity and site of first distant metastasis in patients with breast cancer

Identification of tumor imaging features associated with metastatic pattern may allow better understanding of cancer dissemination. Here, we investigated how primary tumor 18F-fluorodeoxyglucose (FDG) avidity influences the first site of breast cancer metastasis.Subjects were 264 patients with advanced breast cancer who underwent positron emission tomography/computed tomography at diagnosis and had metastasis at presentation (n = 193) or metastatic relapse after surgery (n = 71). Primary tumor FDG avidity (maximum SUV [SUVmax] ≥10.1) was compared with histology and first metastatic sites.The most common site of first metastasis was the bone, occurring in 62.7% of patients with metastasis at presentation and 38.0% of those with metastatic relapse. First metastasis to lung occurred in 30.1% and 35.2%, and to liver in 25.4% and 15.2% of respective groups. In patients with metastasis at presentation, primary tumors were FDG avid in 98/193 cases, and this was associated with more frequent first metastasis to lung (37.8% vs 22.1%; P = 0.018). In patients with metastasis relapse, primary tumors were FDG avid in 31/71 cases, and this was associated with more frequent first metastasis to lung (48.4% vs 25.0%; P = 0.041) and liver (29.0% vs 5.0%; P = 0.008). In patients with metastasis relapse, primary tumors that were FDG avid but hormone receptor negative had more first metastasis to lung (57.9% vs 26.9%; P = 0.016).FDG-avid primary breast tumors have favored first spread to the lung and liver, which suggests that tumor cells with heightened glycolytic activity better colonize these organs.

Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer.

Leptomeningeal metastasis (LM) is an uncommon presentation of relapse in breast cancer, which is associated with poor clinical outcomes and poor prognosis. Notably, LM most commonly occurs in breast cancer. The aim of the present review was to investigate the occurrence of LM as the primary presentation of relapse following remission in breast cancer patients and to determine whether specific histological subtypes are predisposed to meningeal metastases. In addition, the present review evaluated whether patients presenting with LM as the primary site of relapse exhibit differences in survival when compared with patients exhibiting metastasis to other sites. Cross-sectional studies have demonstrated that LM is commonly associated with other sites of distant metastasis including lung, liver and bone metastases. The histological breast cancer subtype most commonly associated with LM was invasive lobular carcinoma, while triple-negative breast cancer patients appear to be predisposed to the development of LM when considering the overall prevalence of histological breast cancer subtypes. At present, data regarding LM as the primary site of relapse are limited due to its rarity as the first site of metastasis in breast cancer. Case-controlled studies are required to investigate the incidence of LM as the primary site of recurrence in breast cancer patients as this would enable treatment standardization and identification of prognostic factors for improved survival.

PET Measurement of Renal Glomerular Filtration Rate: Is There a Role in Nuclear Medicine?

1495 Objectives The site of metastasis, which occurs through compatibilities between cancer cell and distant organ, is highly relevant to the clinical course and outcome of patients. Identification of primary tumor-specific features that affect metastatic pattern may improve our understanding of the mechanisms for cancer dissemination. We thus investigated how primary breast cancer FDG avidity and hormone receptor status influence the site of metastasis. Methods Subjects were 264 patients with advanced breast cancer who underwent FDG PET/CT at diagnosis and had metastatic disease at presentation (n = 193) or had metastatic relapse during follow-up after curative resection (n = 71). Distant metastatic sites included lung, liver, brain, bone, lymph node (L/N) and pleura or peritoneum. Primary tumors were categorized as FDG avid if SUVmax exceeded 10.0. Tumors with estrogen and progesterone receptor expression were categorized as hormone positive. Results In patients with metastasis at presentation, the bone was the most common site of first metastasis (63.7%) followed by lung (30.1%) and liver (25.4%). In this group, patients with FDG-avid primary tumor had significantly greater frequency of lung metastasis (37.8% vs. 22.1%; P = 0.018), while those with hormone positive primary tumor had significantly greater frequency of metastasis to the bone (68.7% vs. 53.9%; P = 0.036) and less to LNs (13.0% vs. 26.9%; P = 0.015). In patients with metastatic relapse, the bone, lung, and LN were the site of first metastasis in similar frequencies (35 to 38%). In this group, patients with FDG-avid primary tumor had significantly greater frequency of metastasis to the lung (48.4% vs. 25.0%; P = 0.041) and liver (29.0% vs. 5.0%; P = 0.008), while those with hormone positive primary tumor had significantly greater frequency of bone metastasis (55.6% vs.27.3%; P = 0.017). Furthermore, in patients with metastasis at presentation, lung metastasis was substantially increased when primary tumors were FDG avid and hormone receptor-negative (57.9%) compared to the remaining subjects (26.9%). Conclusions Primary tumor FDG avidity, as well as hormone status, significantly influences the site of breast cancer metastasis. This may represent greater aggressiveness of breast cancer cells with heightened glycolytic activity that are more apt for survival in more harsh conditions such as the lung and liver, compared to the bone.

Prognosis and predictors of site of first metastasis after definitive radiation therapy for non-small cell lung cancer

Background and purpose Evidence suggests that distinct biologic phenomenon produce different patterns of distant metastatic (DM) failures. We attempted to identify prognostically poor sites of first DM and to define factors predictive of their development. Methods and materials A total of 1074 patients treated with ≥60 Gy definitive radiation for initially non-metastatic non-small cell lung cancer (NSCLC) were analyzed. Uni- and multivariate Cox regression was utilized to associate clinical factors with DM site, and metastatic site with overall survival (OS). To account for competing events, multivariate Fine and Gray regression was utilized to identify treatment and disease factors predictive of site-specific metastases. Results Sites of first DM associated with worse survival were liver (median OS: 5 months after DM) and bone (median OS: 6.7 months after DM). Multivariate regression identified non-squamous histology to be associated with first DM within the liver (HR = 2.04, 95% CI 1.16–3.60, p = 0.01), while delay between diagnosis and RT (third vs. first tertile: HR = 2.3, 95% CI 1.26–4.21, p = 0.007) in addition to advanced stage (stage III vs. II/I: HR = 2.37, 95% CI 1.11–5.06, p = 0.03) were associated with first DM within bone. Conclusions Liver and bone as site of first DM is associated with worse prognosis and are predicted by different disease and treatment factors.

A novel gene expression signature for bone metastasis in breast carcinomas.

Metastatic cancer remains the leading cause of death for patients with breast cancer. To understand the mechanisms underlying the development of distant metastases to specific sites is therefore important and of potential clinical value. From 157 primary breast tumours of the patients with known metastatic disease, gene expression profiling data were generated and correlated to metastatic behaviour including site-specific metastasis, metastasis pattern and survival outcomes. We analysed gene expression signatures specifically associated with the development of bone metastases. As a validation cohort, we used a published dataset of 376 breast carcinomas for which gene expression data and site-specific metastasis information were available. 80.5 % of luminal-type tumours developed bone metastasis as opposed to 41.7 % of basal and 55.6 % of HER2-like tumours. A novel 15-gene signature identified 82.4 % of the tumours with bone metastasis, 85.2 % of the tumours which had bone metastasis as first site of metastasis and 100 % of the ones with bone metastasis only (p 9.99e−09), in the training set. In the independent dataset, 81.2 % of the positive tested tumours had known metastatic disease to the bone (p 4.28e−10). This 15-gene signature showed much better correlation with the development of bone metastases than previously identified signatures and was predictive in both ER-positive as well as in ER-negative tumours. Multivariate analyses revealed that together with the molecular subtype, our 15-gene expression signature was significantly correlated to bone metastasis status (p <0.001, 95 % CI 3.86–48.02 in the training set; p 0.001, 95 % CI 1.54–5.00 in the independent set). The 15 genes, APOPEC3B, ATL2, BBS1, C6orf61, C6orf167, MMS22L, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PH-4, PGD5, SFT2D2 and STEAP3, encoded mainly membrane-bound molecules with molecular function of protein binding. The expression levels of the up-regulated genes (NAT1, BBS1 and PH-4) were also found to be correlated to epithelial to mesenchymal transition status of the tumour. We have identified a novel 15-gene expression signature associated with the development of bone metastases in breast cancer patients. This bone metastasis signature is the first to be identified using a supervised classification approach in a large series of patients and will help forward research in this area towards clinical applications.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-016-3741-z) contains supplementary material, which is available to authorized users.