Single-nucleus RNAseq uncovers multiple tumor lineages in 5 metastatic sites of a prostate adenocarcinoma rapid-autopsy patient

e13506 Background: The National Cancer Institute has developed a repository of preclinical models [Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov )] including patient derived xenografts (PDXs), organoids (PDOrgs) and in vitro tumor cultures (PDCs) from patients with solid tumor cancer histologies. A subset of these preclinical models is derived from post-mortem collections from rapid autopsies representing the end point in disease progression. Clinical annotations and genomic datasets associated with these models provide a unique opportunity to study tumor evolution, mechanistic insights into the metastatic process, and treatment resistance. Methods: To date, 43 PDXs, 21 PDCs, and 23 PDOrgs using rapid autopsy specimens from 8 primary and 35 metastatic sites of 18 patients have been developed by the Biological Testing Branch (DTP, DCTD, NCI Frederick, MD) for the PDMR. Whole exome (WES) and total transcriptome (RNASeq) data were processed to generate mutation, copy number alteration (CNA) and gene expression data. Multi-model lineage trees were reconstructed based on putative somatic variants for all the models derived from all patients. The fraction of the genome affected by CNA was compared both within and across PDX models. Results: Most of the rapid autopsy PDX models (32/43) are derived from pancreatic adenocarcinoma (PAAD) patients (13/18), with metastatic specimens originating from sites including liver, colon, omentum, and lung. Driver mutations are present in all preclinical model specimens derived from the same patient. For instance, KRAS p.G12D is present in all patient-derived model specimens derived from PAAD patient 521955. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n = 24, mean = 6.39%, sd = 5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n = 19, mean = 16.92%, sd = 10.46%). This indicates presence of tumor heterogeneity between metastatic and primary sites. The lineage tree for models from patient 521955 indicates that one liver metastasis has a unique seeding event compared to the other 4 metastatic sites. Unsupervised clustering analysis on gene expression data also confirms the observed tumor site relationships. Conclusions: Our data demonstrate the potential use of these preclinical models available from the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance.

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Prognostic value of neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS), progression free survival (PFS) and disease control rate (DCR) in patients with metastatic colorectal cancer (mCRC) from the RECOURSE study.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.744 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 744-744 ◽

Cited By ~ 2

Author(s):

Guillem Argiles ◽

Takayuki Yoshino ◽

Atsushi Ohtsu ◽

Robert J. Mayer ◽

Robert Winkler ◽

...

Keyword(s):

Progression Free Survival ◽

Ethnic Origin ◽

Exact Test ◽

Multiple Tumor ◽

Number Of Patients ◽

Immune Response To Cancer ◽

Cox Analysis ◽

Metastatic Sites ◽

Ecog Ps ◽

Tumor Types

744 Background: Elevated neutrophil-to-lymphocyte (NLR) ratios may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types. Trifluridine/tipiracil (FTD/TPI also known as TAS-102) compared with placebo significantly improved OS (median: 7.1 vs.5.3 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) [0.58;0.81], p < 0.0001), PFS, and DCR in the phase 3 RECOURSE study, conducted in patients with refractory mCRC. A post-hoc analysis was conducted to assess correlation between clinical outcomes and baseline NLR (in blood) in RECOURSE. Methods: A retrospective review on 782/800 patients, with available NLR, was performed on OS, PFS, and DCR in two subgroups of patients with low ( < 3) or high (≥ 3) NLR at baseline. Based on literature, the cutoff value of 3 was chosen as the number of patients was similar in each NLR subgroup. Between-group comparison was performed using a stratified Cox’s proportional hazard model for OS and PFS, and Fisher’s Exact test for DCR. Results: The median value of NLR at baseline was similar in each group, FTD/TPI (N = 519): 4.4 ± 6.3, placebo (N = 263): 4.7 ± 6.5. Almost 60% of patients in each group had high NLR. In the low NLR vs. high NLR subgroup, there were differences at baseline for ethnic origin (Asian: 45% vs.29%), ECOG PS 0 (69% vs. 49%), and number of metastatic sites ≥ 3 (32% vs. 46%). The median OS [95 % CI] was statistically significantly higher in the low vs. high NLR subgroup: 8.4 [7.8;9.5] vs. 5.3 [4.7;5.7] months, HR = 0.49, 95% CI [0.41;0.59], p < 0.0001. Irrespective of NLR, all patients benefited from FTD/TPI vs. placebo. The results of PFS and DCR were statistically significantly better in the low NLR vs. high NLR subgroup. The multivariate Cox analysis for OS with the interaction test between treatment groups and NLR showed that NLR is not a predictive factor (p = 0.15). Conclusions: In this retrospectively analyzed mCRC population, NLR was shown to be an independent prognostic factor. Further research is warranted to assess if NLR can be a stratification factor in mCRC clinical trials. Clinical trial information: NCT01607957.

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Bladder cancer rapid autopsy: A mechanism for collecting metastatic tumor tissue and establishing xenograft models of metastatic disease.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.478 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 478-478 ◽

Cited By ~ 1

Author(s):

Hung-Ming Lam ◽

Funda Vakar-Lopez ◽

Andrew Caleb Hsieh ◽

Eva Corey ◽

Robert B. Montgomery ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Carcinoma ◽

Checkpoint Inhibitors ◽

Metastatic Tumor ◽

Clinical History ◽

Multiple Tumor ◽

Treatment Information ◽

Metastatic Bladder Cancer ◽

Biological Studies ◽

Rapid Autopsy

478 Background: Patients with metastatic bladder cancer have a poor prognosis with a median survival of only 9-15 months. Understanding the biology of metastatic bladder cancer has been historically difficult due to a paucity of specimens and models that recapitulate human disease. We established a bladder cancer rapid autopsy program to systemically acquire metastases, and build patient-derived xenograft (PDX) and organoid models for biological studies. Methods: Patients with metastatic bladder cancer were consented and a rapid autopsy was performed 2-6 hours after death to allow acquisition of normal and metastasis specimens. Frozen and formalin-fixed and paraffin embedded specimens were collected and pathological evaluation was performed on each specimen. Additionally, tumors were implanted subcutaneously into SCID mice to establish PDXs. Once PDXs were developed, PDXs were dissociated for companion organoid culture. Clinical history and treatment information was documented for each patient. Results: We have performed 10 bladder cancer rapid autopsies to date, and have acquired 105 metastatic and 45 normal specimens. The pathological subtypes of patients include urothelial cell carcinoma (5/10), squamous cell carcinoma (3/10), and plasmacytoid variant of urothelial carcinoma (2/10). The cohort has been treated BCG only (1/10), chemotherapy (3/10), and chemotherapy and immune checkpoint inhibitors (6/10). The leading site of metastasis was the liver (7/10) and lung (7/10), followed by lymph node (5/10), bone (5/10), intestine (4/10), and omentum (2/10). Half (5/10) of the patients had extensive liver metastases that allow acquisition of multiple tumor foci. For the first time, PDX and organoids from two independent metastases (omentum – CoCaB 14.1 and liver –CoCaB 14.2) from the same patient were successfully developed. Conclusions: This bladder cancer rapid autopsy program provides an important volume of metastatic tumor specimens for study. Importantly, the first bladder cancer PDX derived from metastasis has been developed. The availability of metastatic bladder cancer specimens, PDXs, and organoids will allow biological studies of advanced disease.

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Novel temporal and spatial patterns of metastatic colonization from breast cancer rapid-autopsy tumor biopsies

Genome Medicine ◽

10.1186/s13073-021-00989-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Xiaomeng Huang ◽

Yi Qiao ◽

Samuel W. Brady ◽

Rachel E. Factor ◽

Erinn Downs-Kelly ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Critical Role ◽

Metastatic Breast ◽

Clinical Intervention ◽

Metastatic Spread ◽

Tumor Evolution ◽

Metastatic Colonization ◽

Rapid Autopsy ◽

Metastatic Sites

Abstract Background Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult and thus poorly understood. Methods Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole-genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor’s evolution at subclonal resolution. Results The most unique, previously unreported aspect of the tumor’s evolution that we observed in this patient was the presence of “subclone incubators,” defined as metastatic sites where substantial tumor evolution occurs before colonization of additional sites and organs by subclones that initially evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g., abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion, subclones at this site were likely the source of all four subsequent metastatic waves, and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known drivers or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient’s metastases for effective clinical intervention. Conclusions Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites in a patient, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

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Novel temporal and spatial patterns of metastatic colonization from rapid-autopsy tumor biopsies

10.1101/2021.06.03.446803 ◽

2021 ◽

Author(s):

Xiaomeng Huang ◽

Yi Qiao ◽

Samuel W Brady ◽

Rachel E Factor ◽

Erinn Downs-Kelly ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Critical Role ◽

Metastatic Breast ◽

Clinical Intervention ◽

Metastatic Spread ◽

Tumor Evolution ◽

Metastatic Colonization ◽

Rapid Autopsy ◽

Metastatic Sites

Background: Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult, and thus poorly understood. Results: Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor's evolution at subclonal resolution. The most unique, previously not reported aspect of the tumor's evolution we observed in this patient was the presence of "subclone incubators", i.e. already metastatic sites where substantial tumor evolution occurred before colonization of additional sites and organs by subclones that evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g. abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion; subclones at this site were the source of all four subsequent metastatic waves; and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known driver or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient's metastases for effective clinical intervention. Conclusions: Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

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Distinct genomic hallmarks exist between metastatic upper and lower tract urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.371 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 371-371

Author(s):

Brian Winters ◽

Navonil De Sarkar ◽

Sonali Arora ◽

Hamid Bolouri ◽

Funda Vakar-Lopez, MD ◽

...

Keyword(s):

Copy Number ◽

Metastatic Tumor ◽

Single Nucleotide Variants ◽

Chromosomal Structure ◽

Whole Exome ◽

Genomic Landscape ◽

Gene Definition ◽

Rapid Autopsy ◽

Metastatic Sites ◽

Genome Scale

371 Background: Although the genomic landscape of LTUC is well studied, less is known about UTUC, including in the metastatic sites. We compared genomic features of metastatic UTUC and LTUC. Methods: We performed whole exome sequencing on 7 rapid autopsy patients with metastatic UC, with matched primary and metastatic tumor samples (N = 37). Single nucleotide variants (SNV) were identified using Mutect and Strelka. Focused analyses were performed on mutations with known significance in UC as well as mutations predicted to have functional impact using 11 mutation assessors. Genome scale copy number aberrations (CNA) were estimated using Sequenza (normalized for ploidy) to derive gene definition restricted copy number estimation outcomes. Multi-dimensional scaling (MDS) was used to visualize how copy number and mutation-derived genomic distances differed between LTUC and UTUC. Results: Three pts with UTUC (3 primary samples, 13 metastases) and four pts with LTUC (4 primary samples, 17 metastases) were examined. The majority of patients were male (5) and received cisplatin-based therapy (5). We found that SNV burden (mean mutation per megabase) was significantly higher in LTUC vs. UTUC overall (6.6 vs. 3.8, p = 0.001) and when stratified by primaries (6.1 vs. 2.9, p = 0.047); or metastases (6.7 vs. 4.1, p = 0.001). Mutational signature analysis revealed higher proportion of APOBEC signature in all LTUC vs. UTUC tumors. Both inter- and intra-individual genomic distances between primary and metastatic tissues were substantially larger in UTUC than LTUC, suggesting a wider spectrum of mutations at the level of individual nucleotides and chromosomal structure. Interestingly, Gene definition-restricted CNA analysis revealed MDM2 amplification exclusively in UTUC tumors which was associated with shallow p53 deletion. Conclusions: Metastatic UTUC appears to have a lower overall mutational burden but greater genomic variability compared to LTUC. Our relatively small dataset suggests that metastatic UTUC displays a greater spectrum of mutational divergence from LTUC which may partially explain differences in clinical behavior.

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Correlative microscopy in distrubuted (client/server) computing environments: tools for catalyzing the rapid dissemination of information about the cell biology of the human prostate

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100139780 ◽

1995 ◽

Vol 53 ◽

pp. 682-683

Author(s):

A. Hakam ◽

J.T. Gau ◽

M.L. Grove ◽

B.A. Evans ◽

M. Shuman ◽

...

Keyword(s):

United States ◽

Cell Biology ◽

Tissue Bank ◽

The United States ◽

Prostate Adenocarcinoma ◽

Correlative Microscopy ◽

Client Server ◽

Critical Elements ◽

Transplant Organ

Prostate adenocarcinoma is the most common malignant tumor of men in the United States and is the third leading cause of death in men. Despite attempts at early detection, there will be 244,000 new cases and 44,000 deaths from the disease in the United States in 1995. Therapeutic progress against this disease is hindered by an incomplete understanding of prostate epithelial cell biology, the availability of human tissues for in vitro experimentation, slow dissemination of information between prostate cancer research teams and the increasing pressure to “ stretch” research dollars at the same time staff reductions are occurring.To meet these challenges, we have used the correlative microscopy (CM) and client/server (C/S) computing to increase productivity while decreasing costs. Critical elements of our program are as follows:1) Establishing the Western Pennsylvania Genitourinary (GU) Tissue Bank which includes >100 prostates from patients with prostate adenocarcinoma as well as >20 normal prostates from transplant organ donors.

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Abstract #95: Diabetes Mellitus Remission after Multiple Tumor Resection in Pheochromocytoma

Endocrine Practice ◽

10.1016/s1530-891x(20)46367-0 ◽

2004 ◽

Vol 10 ◽

pp. 33

Author(s):

Simona Fica ◽

Ana Maria Stefanescu ◽

Carmen Barbu ◽

Dana Terzea ◽

M. Coculescu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Tumor Resection ◽

Multiple Tumor

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201Tl Scintigraphy in the Evaluation of Palpable and Nonpalpable Breast Lesions: Correlation with Mammography and Ultrasonography

Nuklearmedizin ◽

10.1055/s-0038-1629848 ◽

1997 ◽

Vol 36 (08) ◽

pp. 282-288 ◽

Cited By ~ 8

Author(s):

T. Atasever ◽

A. Özdemir ◽

I. Öznur ◽

N. I. Karabacak ◽

N. Gökçora ◽

...

Keyword(s):

Final Diagnosis ◽

Lower Sensitivity ◽

Breast Lesions ◽

Breast Cancers ◽

Combined Use ◽

Malignant Breast ◽

Malignant Lesions ◽

Benign Breast Lesions ◽

Palpable Breast ◽

Metastatic Sites

Summary Aim: Our goal was to determine the clinical usefulness of TI-201 to identify breast cancer in patients with suspicious breast lesions on clinical examination, and/or abnormal radiologic (mammography and/or ultrasonography) findings. Methods: TI-201 scintigraphy were performed in sixty-eight patients with 70 breast abnormalities (51 palpable, 19 nonpalpable) and compared with mammography and ultrasonography (US). Early (15 min) and late (3 h) images of the breasts were obtained following the injection of 111 MBq (3 mCi) of TI-201. Visual and semiquantitative interpretation was performed. Results: Final diagnosis confirmed 52 malignant breast lesions and 18 benign conditions. TI-201 visualized 47 of 52 (90%) overall malignant lesions. Thirty-eight of 40 (95%) palpable and 9 of 12 (75%) nonpalpable breast cancers were detected by TI-201 scintigraphy. The smallest mass lesion detected by TI-201 measured 1.5x1.0 cm. Eleven breast lesions were interpreted as indeterminate by mammography and/or sonography. TI-201 scintigraphy excluded malignancy in 7 of 8 (88%) patients with benign breast lesions interpreted as indeterminate. Five of the 18 (28%) benign breast lesions showed TI-201 uptake. None of the fibroadenoma and fibrocystic changes accumulated TI-201. TI-201 scintigraphy, mammography and ultrasonography showed 90%, 92%, 85% overall sensitivity and 72%, 56%, 61% overall specificity respectively. Twenty-one of the 28 (75%) axillary nodal metastatic sites were also detected by TI-201. In malignant and benign lesions, early and late lesion/contralateral normal side (L/N) ratios were 1.58 ± 0.38 (mean ± SD) and 1.48 ± 0.32 (p >0.05), 1.87 ± 0.65 and 1.34 ± 0.20 (p<0.05) respectively. The mean early and late L/N ratios of malignant and benign groups did not show statistical difference (p>0.05). Conclusion: Overall, TI-201 scintigraphy was the most specific of the three methods and yielded favourable results in palpable breast cancers, while it showed lower sensitivity in nonpalpable cancers and axillary metastases. Combined use of TI-201 scintigraphy with mammography and US seems to be useful in difficult cases, such as dense breasts and indeterminate breast lesions.

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