Pattern Of Metastatic Spread Research Articles

Inferring cancer type-specific patterns of metastatic spread.

The metastatic spread of a cancer can be reconstructed from DNA sequencing of primary and metastatic tumours, but doing so requires solving a challenging combinatorial optimization problem. This problem often has multiple solutions that cannot be distinguished based on current maximum parsimony principles alone. Current algorithms use ad hoc criteria to select among these solutions, and decide, a priori, what patterns of metastatic spread are more likely, which is itself a key question posed by studies of metastasis seeking to use these tools. Here we introduce Metient, a freely available open-source tool which proposes multiple possible hypotheses of metastatic spread in a cohort of patients and rescores these hypotheses using independent data on genetic distance of metastasizing clones and organotropism. Metient is more accurate and is up to 50x faster than current state-of-the-art. Given a cohort of patients, Metient can calibrate its parsimony criteria, thereby identifying shared patterns of metastatic dissemination in the cohort. Reanalyzing metastasis in 169 patients based on 490 tumors, Metient automatically identifies cancer type-specific trends of metastatic dissemination in melanoma, high-risk neuroblastoma and non-small cell lung cancer. Metient's reconstructions usually agree with semi-manual expert analysis, however, in many patients, Metient identifies more plausible migration histories than experts, and further finds that polyclonal seeding of metastases is more common than previously reported. By removing the need for hard constraints on what patterns of metastatic spread are most likely, Metient introduces a way to further our understanding of cancer type-specific metastatic spread.

Evolving patterns of metastatic spread, treatment, and outcome for patients with oligometastatic colorectal cancer

IntroductionThe assessment and management of oligometastatic colorectal cancer has evolved over the last two decades. We aimed to examine trends in the presentation, management and outcomes of patients presenting with liver-only disease, given recent changed standards for baseline imaging, and evolving definitions of resectability. Patients with lung-only disease can provide a contemporaneous control group. MethodsProspectively maintained data from the multi-site Treatment of Recurrent and Advanced Colorectal Cancer Registry were reviewed over three consecutive periods; 2009–2013, 2014–2018, and 2019–2023. Survival outcomes were determined by Kaplan-Meier method. ResultsOf 4613 patients with metastatic colorectal cancer, median age was 66 years (interquartile range 56–76), and 2356 (51 %) patients had a single metastatic site. Compared to the earlier periods, patients diagnosed in 2019–2023, were younger, had better ECOG scores and were more likely to have three or more metastatic sites. The proportion of patients with liver-only metastases decreased over the three consecutive periods, from 32.0 % (n = 462), to 27.0 % (n = 498) to 25.9 % (n = 33), p < 0.001, however the proportion of liver-only metastases patients undergoing resection increased from 41.5 to 59.3 %, p < 0.001. The incidence and resection rate of lung-only metastases was unchanged over time. ConclusionThe increasing number of metastatic sites and reduced number of patients with liver-only metastases is potentially explained by the increased use of FDG-PET imaging at baseline. The increased proportion of patients with liver-only disease undergoing resection may be explained by advancement in surgical techniques, improvements in systemic therapies and the evolving definition of resectable disease. SynopsisThe pattern and treatment of metastatic colorectal cancer has evolved over the last two decades. This study examines the trends in presentation management and outcomes of patients with metastatic colorectal cancer using a multi-site database.

Atypical Presentation of Metastatic Castrate-resistant Prostate Cancer in a Middle Aged African Male with Good Response to Radioligand Therapy.

Prostate cancer typically follows a characteristic pattern of metastatic spread to the pelvic lymph nodes and bone. Atypical patterns of metastasis are rare but have been documented. In African men, this disease tends to follow a more aggressive course, with the possibility of an atypical site of metastatic spread. We present a case of a 58-year- old African male with metastatic castrate-resistant prostate cancer who presented with both typical and atypical patterns of metastatic disease detected by a fluorine 18 prostate-specific membrane antigen positron emission tomography/computed tomography scan. This patient also had a good response to radioligand therapy.

Racial disparities in GU cancer metastasis: A comprehensive analysis from 2010-2018.

30 Background: Patterns of metastatic spread vary between bladder, kidney, and prostate metastasis. Of these cancers, kidney cancer often spreads to the brain, while prostate cancer is most likely to spread to bone, for example. Sites of metastasis can influence prognosis and in some instances may even direct therapy. The knowledge gap on racial disparities in metastatic patterns merits further investigation. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified bladder, kidney, and prostate cancer patients (2010-2018) in White (W) and Black (B) races. Data on metastasis to the lungs, liver, bones, and brain at diagnosis were extracted. The relative risk (RR) was calculated to compare the metastatic patterns between Black and White patients. P-value, and confidence interval were computed using SPSS 28.0. Results: 3.95% of Black and 1.65% of White patients had metastasis at diagnosis. Black patients had metastasis prevalence of 3.2% lung, 1.8% liver, 4.4% bone, and 0.3% brain. Comparatively, White patients had 1.3%, 0.8%, 3.2%, and 0.3% respectively. For bladder cancer, Black patients had a 60% higher risk for bone and lung metastasis and double the risk for liver metastasis compared to White patients. In kidney cancer, Black patients had a 90% higher brain metastasis risk but 20% lower for bone and lung than White patients. For prostate, Black patients had comparatively heightened risks of bone, lung, and liver metastases by 10%, 20%, and 30%, respectively. Conclusions: Racial disparities are evident in GU cancer metastatic patterns at time of diagnosis. Black patients especially have higher liver metastasis, often associated with poor prognosis. Further studies are vital to unravel biological, socioeconomic, and other contributing factors. [Table: see text]

Comparative transcriptomic analyses reveal activation of the epithelial-mesenchymal transition program in non-metastasizing low grade pseudomyxoma peritonei

Epithelial-mesenchymal transition (EMT), angiogenesis, cell adhesion and extracellular matrix (ECM) interaction are essential for colorectal cancer (CRC) metastasis. Low grade mucinous neoplasia of the appendix (LAMN) and its advanced state low grade pseudomyxoma peritonei (lgPMP) show local aggressiveness with very limited metastatic potential as opposed to CRC. To better understand the underlying processes that foster or impede metastatic spread, we compared LAMN, lgPMP, and CRC with respect to their molecular profile with subsequent pathway analysis.LAMN, lgPMP and (mucinous) CRC cases were subjected to transcriptomic analysis utilizing Poly(A) RNA sequencing. Successfully sequenced cases (LAMN n = 10, 77%, lgPMP n = 13, 100% and CRC n = 8, 100%) were investigated using bioinformatic and statistical tests (differential expression analysis, hierarchical clustering, principal component analysis and gene set enrichment analysis).We identified a gene signature of 28 genes distinguishing LAMN, lgPMP and CRC neoplasias. Ontology analyses revealed that multiple pathways including EMT, ECM interaction and angiogenesis are differentially regulated. Fifty-three significantly differentially regulated gene sets were identified between lgPMP and CRC followed by CRC vs. LAMN (n = 21) and lgPMP vs. LAMN (n = 16). Unexpectedly, a substantial enrichment of the EMT gene set was observed in lgPMP vs. LAMN (FDR=0.011) and CRC (FDR=0.004). Typical EMT markers were significantly upregulated (Vimentin, TWIST1, N-Cadherin) or downregulated (E-Cadherin) in lgPMP. However, MMP1 and MMP3 levels, associated with EMT, ECM and metastasis, were considerably higher in CRC.We show that the different tumor biological behaviour and metastatic spread pattern of midgut malignancies is reflected in a different gene expression profile. We revealed a strong activation of the EMT program in non-metastasizing lgPMP vs. CRC. Hence, although EMT is considered a key step in hematogenous spread, successful EMT does not necessarily lead to hematogenous dissemination. This emphasizes the need for further pathway analyses and forms the basis for mechanistic and therapy-targeting research.

Patterns of metastatic spread and tumor burden in unselected cancer patients using PET imaging: Implications for the oligometastatic spectrum theory

Introduction and backgroundMetastatic disease has been proposed as a continuum, with no clear cut-off between oligometastatic and polymetastatic disease. This study aims to quantify tumor burden and patterns of spread in unselected metastatic cancer patients referred for PET-based staging, response assessment of restaging. Materials and methodsAll oncological fluorodeoxyglucose (FDG-) and prostate-specific membrane antigen (PSMA-) positron emission tomography (PET) scans conducted at a single academic center in 2020 were analyzed. Imaging reports of all patients with metastatic disease were reviewed and assessed. ResultsFor this study, 7,000 PET scans were screened. One third of PET scans (n = 1,754; 33 %) from 1,155 unique patients showed presence of metastatic disease from solid malignancies, of which 601 (52 %) and 554 (48 %) were classified as oligometastatic (maximum 5 metastases) and polymetastatic (>5 metastases), respectively. Lung and pleural cancer, skin cancer, and breast cancer were the most common primary tumor histologies with 132 (23.8 %), 88 (15.9 %), and 72 (13.0 %) cases, respectively. Analysis of the number of distant metastases showed a strong bimodal distribution of the metastatic burden with 26 % of patients having one solitary metastasis and 43 % of patients harboring >10 metastases. Yet, despite 43 % of polymetastatic patients having >10 distant metastases, their pattern of distribution was restricted to one or two organs in about two thirds of patients, and there was no association between the number of distant metastases and the number of involved organs. ConclusionThe majority of metastatic cancer patients are characterized by either a solitary metastasis or a high tumor burden with >10 metastases, the latter was often associated with affecting a limited number of organs. These findings support both the spectrum theory of metastasis and the seed and soil hypothesis and can support in designing the next generation of clinical trials in the field of oligometastatic disease.

Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer.

Even with contemporary treatment strategies, more than 10% of HER2-positive early stage breast cancer patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive breast cancer. A total of 677 HER2-positive stage I-III breast cancer patients from ShortHER trial, Cher-LOB trial, and 2 institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site specific) was evaluated using competing risk analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. Stage III and high HER2DX risk score identified patients at the highest risk of distant relapse as first event (10-year incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared with other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-year incidence 3.8% vs 0.6%, P = .005), basal-like tumors were associated with an increased risk of lung metastases (10-year incidence 11.1% vs 2.6%, P = .001), and luminal tumors developed more frequently bone-only metastases (10-year incidence 5.1% vs 2.0%, P = .042). When added to stage or HER2DX risk score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. The integration of intrinsic molecular subtypes with stage or HER2DX risk score predicts site-specific metastatic risk in HER2-positive breast cancer, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.

Lymphotropic Pattern of Prostate-specific Membrane Antigen–detected Metastases Among Biochemically Recurrent Radical Prostatectomy Patients with Cribriform Disease

BackgroundCribriform morphology portends worse oncologic outcomes, and has unique cellular intrinsic pathway alterations and tumor microenvironments that may impact metastatic spread patterns. ObjectiveTo determine whether the presence of cribriform morphology in prostatectomy specimens of patients with biochemical recurrence after radical prostatectomy (RP) is associated with the presence of metastasis on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and a distinct pattern of spread. Design, setting, and participantsA cross-sectional analysis was conducted of all prostate cancer patients with biochemical recurrence after RP undergoing 18F-DCFPyL-PET/CT between December 2018 and February 2021 at the Princess Margaret Cancer Centre. Outcome measurements and statistical analysisOutcomes were presence of any metastasis in the overall cohort and lymphatic versus bone/visceral metastases among patients with metastatic disease. The associations between the presence of intraductal (IDC) and/or invasive cribriform (ICC) carcinoma on the RP specimen and study outcomes were evaluated using logistic regression analyses. Results and limitationsThe cohort included 176 patients. IDC and ICC were observed in 77 (43.8%) and 80 (45.5%) RP specimens, respectively. The median time from RP to PSMA-PET/CT was 5.0 yr. The median serum prostate-specific antigen level at PSMA-PET/CT was 1.12 ng/ml. Overall, metastasis was observed in 77 patients, of whom 58 were had lymphatic-only metastasis. On a multivariable analysis, presence of IDC on RP was associated with increased odds of overall metastasis (odds ratio [OR]: 2.17; 95% confidence interval [CI]: 1.07–4.45; p = 0.033). Presence of ICC on RP was associated with significantly increased odds of lymphatic versus bone/visceral metastases (OR: 3.13; 95% CI: 1.09–21.7; p = 0.004). ConclusionsPresence of cribriform morphology on RP specimens of patients with biochemical failure after RP is associated with increased odds of PSMA-PET/CT–detected metastases with a lymphatic predominant pattern of spread. These findings have implications for the design and evaluation of post-RP salvage therapies. Patient summaryWe found that microscopic cribriform appearance correlates with disease spread on imaging in prostate cancer patients with recurrence and has a predilection for spread to lymph nodes, as opposed to bone or visceral organs.

Metastatic Invasive Lobular Carcinoma of Bilateral Breasts Presenting with an Abdominal Mass

Background: Breast cancer remains the most frequent malignancy in women, with the two most common histological subtypes of breast cancer being the invasive ductal carcinomas (IDC) and invasive lobular carcinomas (ILC). The most common sites of breast cancer metastases are the liver, lung, pleura, brain and bone. Gastrointestinal, peritoneal, gynaecological and renal metastases are less common, often masquerading as primary malignancies and causing diagnostic confusion, mostly occurring in ILC as compared to IDC. Case Presentation: We report a case of a young woman presenting with an enlarging abdominal mass which was suspicious of a primary abdominal malignancy. Endoscopy and gastric biopsy revealed poorly differentiated carcinoma. On the top-most slices of her abdominal CT, bilateral enhancing breast lesions were detected, suspicious of metastases. Ultrasound and biopsy done for the breast lesions showed bilateral ILCs. Further staining of the gastric biopsy specimen confirmed the final diagnosis of gastric metastases from bilateral breast ILCs rather than a primary gastric tumour with breast metastases. Conclusion: This case highlights how breast cancer metastases to the GI tract may mimic primary GI cancers as well as the importance of breast examination, family history, radiological and pathological examination in detecting the breast origin of advanced carcinomas. Awareness of the different patterns of metastatic spread of ILC and IDC is also important due to the infiltrating nature and non-specific imaging findings of these tumours, requiring a high index of suspicion from the surgeons, oncologists, radiologists and pathologists.

The Effect of Intrathoracic Lesion Location on Initial Tyrosine Kinase Inhibitor Response in Advanced Oncogene-Addicted Non-Small Cell Lung Cancer: A Comparison Between RECIST 1.1 and a Novel Method of Response Assessment (MAX)

IntroductionDifferent subtypes of non-small cell lung cancer (NSCLC) are associated with different patterns of metastatic spread. Anatomic location of lesions in the chest may influence patterns of cancer growth and the shrinkage to therapy. Consequently, lesion location could affect apparent response rates per RECIST. We sought to explore this and develop, as needed, treatment response assessments less affected by the location. MethodsCases of advanced oncogene-addicted NSCLC (EGFR, ALK, and ROS1) with pre- and on-therapy imaging during initial targeted therapy were identified. Lesions located in the lung parenchyma, pleural space or intra-thoracic lymph nodes were identified and analyzed separately from each other by RECIST 1.1 (unidimensional measurements) and by a novel MAX methodology (bidimensional measurements) which takes the axis with the greatest absolute percentage change on therapy in each location as the representative measurement. ResultsThree hundred three patients with 446 unidimensional measured lesions were included for RECIST analysis. Two hundred forty nine patients with 386 bidimensional measured lesions were included for MAX analysis, as well as the analysis comparing RECIST and MAX. Intrathoracic location significantly impacted percentage shrinkage and the response rate per RECIST. The response rates for pleural, intra-parenchymal and nodal lesions were 34.1%, 49.6%, and 68.3%, respectively (P = .0002). The MAX methodology both increased the apparent treatment effect and made it consistent between intrathoracic locations. For pleural, parenchymal and nodal lesions, the MAX calculated response rate were 83.7%, 72.2%, and 75.4%, respectively (P-value = .24). ConclusionIntrathoracic lesion location affects RECIST-based treatment effectiveness estimations. The MAX methodology neutralizes location effect when examining impact of treatment and should be explored further.

Molecular alterations across sites of metastasis in patients with renal cell carcinoma (RCC).

287 Background: RCC has a distinct pattern of metastatic spread with common sites of metastasis including the lung, bone, and liver. Less common sites include the brain, adrenal gland, and pancreas. While the pattern of metastatic spread has prognostic significance, the biology driving tropism to specific organ sites has not been fully characterized. We utilized a multi-institutional real-world dataset to examine genomic alterations and transcriptional signatures across the spectrum of metastatic sites in patients with RCC. Methods: RCC tissue specimens derived from the kidney and distant metastatic sites were sequenced utilizing a commercially available Clinical Laboratory Improvement Amendments (CLIA)-certified assay by Caris Life Sciences. Whole exome and transcriptome sequencing was performed. Molecular subgroups were defined according to the IMmotion151 metastatic RCC subtypes, with subgroups determined by a weighted average of gene expression levels. Molecular analysis and PD-L1 expression (SP142) were described by metastasis site. Results: 657 RCC samples from 653 patients underwent molecular profiling. The median age was 62 years (range 14-90) and the majority were male (70.6%). The most common histology was clear cell RCC (n = 509, 77.5%), followed by papillary (n = 63, 9.6%), chromophobe (n = 30, 4.6%), medullary (n = 8, 1.2%), collecting duct (n = 6, 0.9%), and mixed (n = 41, 6.2%). Specimen source included the kidney (n = 340, 51.8%), lung (n = 75, 11.4%), bone (n = 45, 6.8%), lymph nodes (n = 34, 5.2%), liver (n = 28, 4.3%), endocrine glands (adrenal, pancreas, and thyroid; n = 23, 3.5%), brain/CNS (n = 16, 2.4%), and other metastatic sites (n = 96, 14.6%). Compared to kidney, several genes were mutated at higher rates for select metastatic sites, including PBRM1 (59.5% bone, 59.1% endocrine, and 45.9% lung vs 33.8% kidney, p&lt; 0.05) and KDM5C (27.8% endocrine, 29.2% lymph nodes, and 35.3% soft tissue vs 9.3% kidney, p&lt; 0.05). When evaluating metastatic specimens versus kidney specimens, bone metastases had a significantly higher proportion of tumors classified as ‘Angio/stromal’ (n = 19, 42.2%; vs n = 52, 15.4%; p&lt; 0.0001), while liver metastases had a higher proportion of the ‘complement/Ω-oxidation’ subgroup (n = 17, 60.7%; vs n = 48, 14.1%; p&lt; 0.0001). PD-L1 expression in metastatic sites (range 6.8%-21.7%, with exception of 0% in GI; p= 0.09 to 0.99) was not significantly different from the kidney (16.6%). Conclusions: In our contemporary real-world analysis, we demonstrate differential patterns of molecular alterations among sites of metastasis in RCC. Our observations elucidate the biology underlying heterogeneous disease outcomes associated with site of metastasis. Application of predictive signatures by site of metastasis may help inform personalized therapy strategies in advanced RCC. Further studies are warranted to validate our findings.

Metastases to the Pituitary Gland: Histological Patterns of Spread and Review of the Literature

Few studies have focused on histological patterns of metastatic spread to the pituitary gland. We review our experience and that in the literature, 1970-present. Departmental cases, 1998-2021, were assessed for anterior versus posterior gland and/or capsular involvement and cohesive tumor obliterating underlying pituitary architecture versus metastatic cells filling pituitary acini with relative acinar preservation. Eleven autopsy/15 surgical cases, including 2 metastases to pituitary adenomas, were identified. Cohesive/obliterative patterns predominated histologically in both surgical and autopsy cases, but acinar filling by metastatic cells was extensive in 3/26 cases, focal in 5/26, and had resulted in initial erroneous impressions of atypical pituitary adenoma/pituitary carcinoma in 1 case and pituitary adenoma with apoplexy in another, likely due to focusing on necrotic areas in the specimen where the acinar pattern had been broken down and not appreciating nearby areas with acinar filling by metastatic cells. Although most pituitary metastases produce readily identifiable cohesive/obliterative patterns, diagnostic challenges remain with the less frequently seen "acinar filling" pattern. A dichotomy exists between patients with symptomatic pituitary metastases occurring early in the disease course and requiring surgical excision versus patients in whom asymptomatic small pituitary metastases are found incidentally at autopsy, the latter almost invariably in late disease stages, with widely disseminated metastatic disease.

Prediction of Metastatic Patterns in Bladder Cancer: Spatiotemporal Progression and Development of a Novel, Web-based Platform for Clinical Utility

BackgroundBladder cancer (BCa), the sixth commonest cancer in the USA, is highly lethal when metastatic. Spatial and temporal patterns of patient-specific metastatic spread are deemed random and unpredictable. Whether BCa metastatic patterns can be quantified and predicted more accurately is unknown. ObjectiveTo develop a web-based calculator for forecasting metastatic progression in individual BCa patients. Design, setting, and participantsWe used a prospectively collected longitudinal dataset of 3503 BCa patients who underwent a radical cystectomy following diagnosis and were enrolled continuously. We subdivided patients by their pathologic subgroup stages of organ confined (OC), extravesical (EV), and node positive (N+). We illustrated metastatic pathway progression using color-coded, circular, tree ring diagrams. We created a dynamical, data-visualization, web-based platform that displays temporal, spatial, and Markov modeling figures with predictive capability. Outcome measurements and statistical analysisPatients underwent history and physical examination, serum studies, and liver function tests. Surveillance follow-up included computed tomography scans, chest x-rays, and radiographic evaluation of the reservoir and upper tracts, with bone scans performed only if clinically indicated. Outcomes were measured by time to clinical recurrence and overall or progression-free survival. Results and limitationsMetastases developed in 29% of patients (n = 812; median follow-up 15.3 yr), with 5-yr overall survival of 20.2%, compared with 78.6% in those without metastases (n = 1983; median follow-up 10.9 yr). The three commonest sites of spread at the time of first progression were bone (n = 214; 26.4%), pelvis (n = 194; 23.9%), and lung (n = 194; 23.9%). The order and frequency of these sites vary when divided by pathologic subgroup stages of OC (lung [n = 65; 25.1%], urethra [n = 45; 17.4%], and bone [n = 29; 11.2%]), EV (pelvis [n = 63; 33.0%], bone [n = 45; 23.6%], and lung [n = 29; 15.2%]), and N+ (bone [n = 111; 30.7%], retroperitoneum [n = 70; 19.3%], and pelvis [n = 60; 16.6%]). Markov chain modeling indicated a higher probability of spread from bladder to bone (15.5%), pelvis (14.7%), and lung (14.2%). ConclusionsOur web-based calculator allows real-time analyses in the clinic based on individual patient-specific demographic and cancer data elements. For contrasting subgroups, the models indicated differences in Markov transition probabilities. Spatiotemporal patterns of BCa metastasis and sites of spread indicated underlying organotropic mechanisms in the prediction of response. This recognition opens the possibility of organ site–specific therapeutic targeting in the oligometastatic BCa setting. In the precision medicine era, visualization of complex, time-resolved clinical data will enhance management of postoperative metastatic BCa patients. Patient summaryWe developed a web-based calculator to forecast metastatic progression for individual bladder cancer (BCa) patients, based on the clinical and demographic information obtained at diagnosis. This can help in predicting disease status and survival, and improving management in postoperative metastatic BCa patients. Take Home MessageFuture pathways of metastatic progression for individual bladder cancer patients can be determined based on currently available clinical and demographic information obtained at diagnosis. In focused subgroups of patients, these metastatic spread patterns can also portend disease status and survival.

Patterns of Metastatic Disease in Patients with Cancer Derived from Natural Language Processing of Structured CT Radiology Reports over a 10-year Period.

Background Patterns of metastasis in cancer are increasingly relevant to prognostication and treatment planning but have historically been documented by means of autopsy series. Purpose To show the feasibility of using natural language processing (NLP) to gather accurate data from radiology reports for assessing spatial and temporal patterns of metastatic spread in a large patient cohort. Materials and Methods In this retrospective longitudinal study, consecutive patients who underwent CT from July 2009 to April 2019 and whose CT reports followed a departmental structured template were included. Three radiologists manually curated a sample of 2219 reports for the presence or absence of metastases across 13 organs; these manually curated reports were used to develop three NLP models with an 80%-20% split for training and test sets. A separate random sample of 448 manually curated reports was used for validation. Model performance was measured by accuracy, precision, and recall for each organ. The best-performing NLP model was used to generate a final database of metastatic disease across all patients. For each cancer type, statistical descriptive reports were provided by analyzing the frequencies of metastatic disease at the report and patient levels. Results In 91 665 patients (mean age ± standard deviation, 61 years ± 15; 46 939 women), 387 359 reports were labeled. The best-performing NLP model achieved accuracies from 90% to 99% across all organs. Metastases were most frequently reported in abdominopelvic (23.6% of all reports) and thoracic (17.6%) nodes, followed by lungs (14.7%), liver (13.7%), and bones (9.9%). Metastatic disease tropism is distinct among common cancers, with the most common first site being bones in prostate and breast cancers and liver among pancreatic and colorectal cancers. Conclusion Natural language processing may be applied to cancer patients' CT reports to generate a large database of metastatic phenotypes. Such a database could be combined with genomic studies and used to explore prognostic imaging phenotypes with relevance to treatment planning. © RSNA, 2021 Online supplemental material is available for this article.

Local ablative therapy in oncogenic-driven oligometastatic non-small cell lung cancer: present and ongoing strategies-a narrative review.

Oligometastatic (OM) disease is defined by a low metastatic tumor spread. OM non-small cell lung cancer (NSCLC) treatment aims to improve the patient’s prognosis and quality of life, in an attempt-to-cure objective. Oncogenic-driven metastatic NSCLC accounts for about 20–25% of NSCLCs, with an ever-increasing number of potentially druggable molecular alterations. Due to specific targeted therapy, the care and prognosis of mutated NSCLC is quite different from non-oncogenic-driven NSCLC. However, OM-NSCLC treatment guidelines do not specifically discuss oncogenic-driven OM-NSCLC patients. We conducted a narrative review regarding retrospective and prospective studies published from inception to May 2020 dealing with oncogenic-driven OM-NSCLC in order to: (I) describe the specific patterns of metastatic spread of oncogenic-driven NSCLC (i.e., bone and pleural tropism in EGFR mutated NSCLC and serous and brain metastases in ALK NSCLC); (II) review the low level of current evidence for local ablative therapy (LAT) strategies in patients with oncogenic-driven OM-NSCLC, focusing on the benefit/risk of tyrosine kinase inhibitors (TKI) and LATs combination and (III) present strategies to help to select the best candidate for an attempt-to-cure approach. Finally, the optimal strategy may be to introduce a targeted therapy, then treat all tumor sites with LAT, and finally continue TKI for unknown prolonged duration in an attempt to prolong progression free survival in most patients, improve overall survival for some patients, and potentially lead to a cancer cure for a few patients.

Abstract 2834: Integration of genomic and clinical data from 25,000 patients identifies molecular determinants of metastatic potential and organotropisms

Abstract Although most cancer deaths are due to metastatic spread, we are not able to predict if, when and where a tumor will metastasize. So far, large-scale cancer sequencing efforts have either focused on primary tumors (TCGA), or have characterized the overall genomic landscape of metastases without investigating the interplay between genomic profiles and specific routes of metastatic dissemination. Here, we have investigated associations between genomic alterations and metastatic patterns using a cohort of 25,763 patients treated at Memorial Sloan Kettering with available targeted DNA sequencing data (MSK-IMPACT, 468 genes). Our cohort consists of 15,662 (60%) sequenced primaries and 10,101 (40%) sequenced metastases from 44 different tumor types. A total of 99,220 distant metastatic events were automatically extracted from ICD billing codes from electronic medical records and mapped to a reference set of 21 anatomic locations. Metastases had significantly more copy-number alterations (CNA) (inferred by fraction genome altered, FGA) than primaries in 15/44 tumor types. Metastases also exhibited significantly higher fractions of clonal mutations in 11/44 types and higher rates of whole-genome duplication in 7/44 types. Driver genes that were most often altered at higher frequencies in metastases included TP53, CDKN2A, PTEN and MYC, while most frequently altered oncogenic pathways in metastases included TP53, Cell Cycle and DNA damage repair. Importantly, we found that FGA was positively correlated with metastatic burden (defined as the number of distinct metastatic organs throughout the entire clinical history) in 19/44 tumor types. This trend, which was observed even when restricting the analysis to primary tumors, was most pronounced in prostate, breast and endometrioid adenocarcinoma. In other tumor types, including MSS colorectal and serous ovarian tumors, there was no such trend. These findings suggest that CNA burden can be predictive of metastatic potential in some tumor types. The relationship between TMB and metastatic burden was not straightforward: we observed a positive correlation in six tumor types, and a negative correlation in four tumor types. Finally, we explored associations between somatic alterations and metastatic organotropisms. For example, BRAF mutation was enriched in MSS colorectal cancer patients with brain metastasis (7% vs 12%, qval &amp;lt; .05), AR amplification and PTEN deletion were enriched in prostate cancer patients with bone metastasis (5% vs 21%, qval &amp;lt; .05 and 9% vs 19%, qval &amp;lt; .05) whereas ERG fusion was less frequent in patients with bone metastasis (30% vs 24%, qval &amp;lt; .05). In summary, we present a comprehensive, spatiotemporal map of metastasis that integrates clinical and molecular information and serves as an initial proof of concept that genomic profiling of tumors could be used to predict patterns of metastatic spread. Citation Format: Bastien Nguyen, Christopher Fong, Renzo DiNatale, Anisha Luthra, Subhiksha Nandakumar, Henry Walch, Walid K. Chatila, Arjun Rajanna, David B. Solit Solit, Michael F. Berger, Ahmet Zehir, Jianjiong Gao, Francisco Sanchez-Vega, Nikolaus Schultz. Integration of genomic and clinical data from 25,000 patients identifies molecular determinants of metastatic potential and organotropisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2834.

Molecular characteristics and tumorigenicity of ascites-derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer.

Ovarian cancer disseminates primarily intraperitoneally. Detached tumor cell aggregates (spheroids) from the primary tumor are regarded as ‘metastatic units’ that exhibit a low sensitivity to classical chemotherapy, probably due to their unique molecular characteristics. We have analyzed the cellular composition of ascites from OvCa patients, using flow cytometry, and studied their behavior in vitro and in vivo. We conclude that ascites‐derived cultured cells from OvCa patients give rise to two subpopulations: adherent cells and non‐adherent cells. Here, we found that the AD population includes mainly CD90+ cells with highly proliferative rates in vitro but no tumorigenic potential in vivo, whereas the NAD population contains principally tumor cell spheroids (EpCAM+/CD24+) with low proliferative potential in vitro. Enriched tumor cell spheroids from the ascites of high‐grade serous OvCA patients, obtained using cell strainers, were highly tumorigenic in vivo and their metastatic spread pattern precisely resembled the tumor dissemination pattern found in the corresponding patients. Comparative transcriptome analyses from ascites‐derived tumor cell spheroids (n = 10) versus tumor samples from different metastatic sites (n = 30) revealed upregulation of genes involved in chemoresistance (TGM1, HSPAs, MT1s), cell adhesion and cell‐barrier integrity (PKP3, CLDNs, PPL), and the oxidative phosphorylation process. Mitochondrial markers (mass and membrane potential) showed a reduced mitochondrial function in tumoroids from tumor tissue compared with ascites‐derived tumor spheroids in flow cytometry analysis. Interestingly, response to OXPHOS inhibition by metformin and IACS010759 in tumor spheroids correlated with the extent of mitochondrial membrane potential measured by fluorescence‐activated cell sorting. Our data contribute to a better understanding of the biology of ovarian cancer spheroids and identify the OXPHOS pathway as new potential treatment option in advanced ovarian cancer.

Correlation between different levels of HER2 expression in circulating tumor cells (cHER2 ratio) and metastatic behavior in stageIVaggressive breast cancer.

3036 Background: The presence of HER2 expressing (HER2+) circulating tumor cells (CTCs) occurs often in metastatic breast cancer (MBC) patients (pts). We have previously showed that the ratio among CTCs expressing high level of HER2 and the total number of HER2+ CTCs (circulating HER2 ratio, cHer2 ratio) has a prognostic role in MBC patients. Here we further investigate the role of the cHER2 ratio in the process of metastatic spread. Methods: Under IRB-approved study we prospectively analyzed blood samples of patients with MBC enrolled before starting a new line of therapy. Samples were collected from pts treated at Northwestern University (Chicago, IL) between 2016 and 2020. CTCs were enumerated through CellSearch (Menarini Silicon Biosystems, Bologna, Italy) and characterized for HER2 expression using the CellSearch CXC Kit. HER2+ CTCs were divided in 3 different categories (1+,2+,3+) leaning on fluorescence intensity. Pts with &lt;5 CTCs (stage IV indolent) were excluded from the analysis. The cHER2 ratio, defined as the sum of 2+ CTCs and 3+ CTCs divided by the total number of HER2+ CTCs, was used to split the remaining pts in 2 different cohorts: cHER2 ratio high (&gt; 0.75) (cHER2high) and cHER2 ratio low (≤0.75) (cHER2low). The frequency of each metastatic site (i.e. liver, lung, central nervous system, bone, lymph nodes, skin/soft tissue, serosa) and the total number of different sites involved (1-7, ≤2 and &gt;2 sites) were compared among the two sub-populations and analyzed through Fisher exact test. Results: Out of 98 pts enrolled, 77 were classified as cHER2low and 21 as cHER2high. We observed a higher frequency of oligometastatic pts (≤2 sites involved) in the cHER2high cohort (16, 76%), compared to only 29 (37%) in the cHER2low (p&lt;0.005). Moreover, the cHER2 ratio was associated with a tropism toward specific sites of disease spread with higher incidence of liver, lung and lymph nodes metastases in the cHER2low cohort (p&lt;0.05). No other statistical associations were observed in respect of specific organ tropism. The frequency of involvement for each metastatic site among the two cohorts are reported in the table. Conclusions: Measuring CTCs enumeration and HER2 expression we identified two cohorts, cHER2high and cHER2low, associated with distinct patterns of metastatic spread. The cHER2low pts were correlated to multiple sites of metastatic involvement, with particular tropism toward liver, lung and lymph nodes. These results confirm the prognostic role of the cHER2 ratio, suggesting a peculiar biological meaning of the HER2+ 1+ CTCs.[Table: see text]

Evaluation of Clear Cell, Papillary, and Chromophobe Renal Cell Carcinoma Metastasis Sites and Association With Survival

There exists considerable biological and clinical variability between histologic variants of metastatic renal cell carcinoma (mRCC). Data reporting on patterns of metastasis in histologic variants of mRCC are sparse. To characterize sites of metastasis and their association with survival across the 3 most common histologic variants of mRCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). In this multicenter, international cohort study, the International mRCC Database Consortium (IMDC) database was used to identify consecutive patients starting systemic therapy for mRCC between 2002 and 2019. Patients with mixed histologic subtype were excluded. Statistical analysis was performed from February to June 2020. Data regarding histologic subtype and sites of metastatic involvement at the time of first systemic therapy initiation were collected. The primary outcomes were prevalence of metastatic site involvement and overall survival (OS) from time of systemic therapy initiation. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. A total of 10 105 patients were eligible for analysis. Median (interquartile range) age at diagnosis was 60 (53-67) years, 7310 (72.4%) were men and 8526 (84.5%) underwent nephrectomy. Of these, 9252 (92%) had ccRCC, 667 (7%) had pRCC, and 186 (2%) had chrRCC. The median number of sites of metastasis was 2 (range, 0-7). In ccRCC, the most common sites of metastasis were lung (70%; 6189 of 8804 patients [448 missing]), lymph nodes (45%; 3874 of 8655 patients [597 missing]), bone (32%; 2847 of 8817 patients [435 missing]), liver (18%; 1560 of 8804 [448 missing]), and adrenal gland (10%; 678 of 6673 patients [2579 missing]). Sites of metastasis varied between subtypes. Lung, adrenal, brain, and pancreatic metastases were more frequent in ccRCC, lymph node involvement was more common in pRCC, and liver metastases were more frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (95% CI, 13.7-18.8 months) for the pleura and 50 months (95% CI, 41.1-55.5 months) for the pancreas. Compared with ccRCC, patients with pRCC tended to have lower OS, regardless of metastatic site. Sites of metastatic involvement differ according to histologic subtype in mRCC and are associated with OS. These data highlight the clinical and biological variability between histologic subtypes of mRCC. Patterns of metastatic spread may reflect differences in underlying disease biology. Further work to investigate differences in immune, molecular, and genetic profiles between metastatic sites and histologic subtypes is encouraged.

Cervical lymph node metastasis in squamous cell carcinoma of the buccal mucosa: a retrospective study on pattern of involvement and clinical analysis.

Background The study was performed with an aim to map the pattern of metastasis of squamous cell carcinomas of buccal mucosa to various cervical lymph node levels and analyze its correlation with primary tumor size and histo-pathological grading. Material and Methods 254 patients with squamous cell carcinoma of the buccal mucosa treated with surgery first approach were analyzed retrospectively. The tumor size was noted from pre-operative CT Scans and were divided into early and advanced tumors. The resected specimen was studied to note the histo-pathological grading of the squamous cell carcinoma and the metastatic deposits at various lymph node levels. Results Out of 254 patients (149 females, 105 males), 145 patients showed histo-pathologically proven metastatic deposits in one or more lymph nodes out of which there were 56 patients showing occult metastasis. 78/145 patients showed metastatic involvement of level IB and/or IA lymph nodes, 31 showed involvement of level II and/or I lymph nodes, 27 showed involvement of level III with or without involvement of level I and II and 9 showed metastasis to level IV and V lymph nodes with or without level I, II or III lymph nodes. Cervical lymph node metastasis had statistically significant association with tumor size with advanced tumors showing worse pattern of metastatic spread beyond level I and II lymph nodes. As the degree of differentiation of squamous cell carcinoma reduced, they were more prone for cervical metastasis with moderately and poorly differentiated squamous cell carcinoma showing higher involvement of level III, IV and V lymph nodes. Conclusions The majority of buccal mucosa cases showed metastasis to level I, II and III lymph nodes out of which level IB and/or IA was most frequently involved. Metastasis to level IV and V lymph nodes was rare and was seen especially in patients with advanced primary tumor and poor histo-pathologic differentiation. Key words:Oral squamous cell carcinoma (OSCC), cervical lymph node metastasis, histologic differentiation, locally advanced disease.