Multiple Metastatic Sites Research Articles

Metastatic sites as predictors in advanced NSCLC treated with PD-1 inhibitors: a systematic review and meta-analysis

ABSTRACT Background Programmed cell death protein 1 (PD-1) inhibitors are the first-line treatment for advanced non-small-cell lung cancer (NSCLC) patients. However, their efficacy in metastatic NSCLC patients remains controversial. Aim of the study The aim of our study was to evaluate the prognosis of advanced metastatic NSCLC patients treated with PD-1 inhibitors, and discuss the predictive effect of metastatic site on the long-term outcome. Methods The Embase, Ovid Medline, Cochrane Central Register of Controlled Trials, and PubMed databases were systematically screened up to February 10, 2020. Twenty-five eligible studies, involving 8,067 patients that assessed the impact of metastatic sites on survival outcome were incorporated in our study. Overall survival (OS) and progression-free survival (PFS) were described as hazard ratio (HR) with 95% confidence interval (CI). Results Among the advanced NSCLC patients, the median proportion of brain, liver, bone, and adrenal gland metastases were 21%, 17%, 35%, and 21%, respectively. Patients with metastases to the brain, liver, and bone had worse OS compared to patients without these metastases when treated with PD-1 inhibitors. Similarly, patients with metastasis to the brain and liver were more likely to progress when treated with PD-1 inhibitors. Besides, patients with multiple metastatic sites had worse PFS compared to patients with one metastatic site, while no significant difference was found in terms of OS. Conclusions Based on the findings of our systematic review and meta-analysis, metastatic sites were independent predictors of the survival outcome for advanced NSCLC patients treated with PD-1 inhibitors.

Promising xenograft animal model recapitulating the features of human pancreatic cancer.

BACKGROUNDMultiple sites of metastasis and desmoplastic reactions in the stroma are key features of human pancreatic cancer (PC). There are currently no simple and reliable animal models that can mimic these features for accurate disease modeling.AIMTo create a new xenograft animal model that can faithfully recapitulate the features of human PC.METHODSInterleukin 2 receptor subunit gamma (IL2RG) gene knockout Syrian hamster was created and characterized. A panel of human PC cell lines were transplanted into IL2RG knockout Syrian hamsters and severe immune-deficient mice subcutaneously or orthotopically. Tumor growth, local invasion, remote organ metastasis, histopathology, and molecular alterations of tumor cells and stroma were compared over time.RESULTSThe Syrian hamster with IL2RG gene knockout (named ZZU001) demonstrated an immune-deficient phenotype and function. ZZU001 hamsters faithfully recapitulated most features of human PC, in particular, they developed metastasis at multiple sites. PC tissues derived from ZZU001 hamsters displayed desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotypes, whereas PC tissues derived from immune-deficient mice did not present such features.CONCLUSIONZZU001 hamsters engrafted with human PC cells are a superior animal model compared to immune-deficient mice. ZZU001 hamsters can be a valuable animal model for better understanding the molecular mechanism of tumorigenesis and metastasis and the evaluation of new drugs targeting human PC.

Metastatic pancreatic adenocarcinomas could be classified into M1a and M1b category by the number of metastatic organs

BackgroundWith the improvement of treatment and prognosis for patients with late malignant diseases, certain malignancies with distant metastasis (M1 category) have been further classified into M1a (single metastatic site) and M1b (multiple metastatic sites) category in the staging system. We aimed to assess the feasibility of sub-classifying metastatic pancreatic adenocarcinoma (mPA) into M1a and M1b category depending on the number of metastatic organs.MethodsPatient records were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2010–2015). Univariable and multivariable analyses were performed using the Cox regression model. Then survival analysis was determined using the Kaplan–Meier method.ResultsA total of 11,885 patients were included in this analysis, including 9425 patients with single metastasis and 2460 patients with multiple metastases. Multivariable analysis showed that gender, age, marital status, grade, surgery, chemotherapy, and radiotherapy were independent prognostic factors for patients with single metastasis; gender, age, marital status, grade, chemotherapy and radiotherapy were independent prognostic factors for patients with multiple metastases. Notably, surgery was an independent prognostic factor for patients with single metastasis (P < 0.001) but not for patients with multiple metastases (P = 0.134). Kaplan–Meier analysis showed that patients with single metastasis (M1a) had better survival outcomes than patients with multiple metastases (M1b) (P < 0.001).ConclusionsPA patients with M1 diseases could be divided into M1a (single metastasis) category and M1b (multiple metastases) category by the number of metastatic organs. The subclassification would facilitate individualized treatment for late PA patients. Surgery was associated with lower mortality in M1a patients but not significantly in M1b patients.

Effect of Surgery at Primary and Metastatic Sites in Patients With Stage IV Breast Cancer

BackgroundThere is no clear evidence of a survival benefit of resection of the primary tumor, or distant site resection (metastasectomy) in patients with stage IV breast cancer. Patients and MethodsThis retrospective analysis of stage IV breast cancer using the National Cancer Database. To evaluate variables associated with surgery at the primary site, we used univariate analyses followed by multivariate logistic regression. Consequently, we evaluated the impact of lumpectomy, mastectomy or metastasectomy on survival by conducting multivariate Cox regression survival analyses on the following groups: all stage IV patients; a subset of those with only one metastatic site; and another subset with metastasis to multiple distant sites. ResultsA total of 54,871 stage IV breast cancer patients were included in this analysis. Variables associated with the use of surgery at the primary were: age, race, Charlson/Deyo score, insurance and facility type, involved breast quadrant, receptor status, N stage, extent of metastasis, and year of diagnosis. Survival analysis showed that both lumpectomy (median overall survival [OS], 45 months) and mastectomy (median OS, 44 months) were associated with better OS compared to no surgery (median OS, 22 months). The statistical effect was larger in the subgroup with metastasis to one site, but still significant in the subgroup with multiple metastatic sites. Distant site resection also yielded a survival benefit. ConclusionIn patients with metastasis to only one site, metastasectomy was associated with better OS when that site was the liver, lung, or brain.

Abstract 6519: Patient, primary colorectal tumor and liver metastases factors which influence survival after liver metastasectomy and therefore should be considered at the preoperative tumor board

Abstract Aim of the study: Patients with colorectal liver metastases (CRLM) should be considered for liver surgery and this study illuminate important factors to be considered at the preoperative multidisciplinary tumor board. Background: Survival after surgical resection or ablation of colorectal liver metastases is increasingly favorable but only a minority of patients undergo curatively intended treatment. Several studies have shown the importance of assessing resectability by liver surgeons. Which prognostic factors to consider before liver surgery is not fully understood. Methods: The Swedish colorectal cancer registry (SCRCR) and the Swedish registry for liver tumors (SweLiv) were linked to identify radically resected primary colorectal cancer patients during the years 2009-2013 also surgically treated for liver metastases, synchronously or metachronously. CRLM characteristics and treatment strategies as well as primary tumor and patient factors were analyzed for prognostic impact. 5-year age-standardized relative survival (RS) and 5-year excess mortality rate ratio (EMRR) were calculated. Treatment with ablation only for tumors with maximum size of 30 mm was analyzed in a propensity score weighted cox regression. Results: 1325 patients were included in the study cohort, whereof 300 were 75 years or older. 1200 were treated with resection and 125 were treated with ablation only. Age-standardized relative five-year survival after open resection of colorectal liver metastases was 54.8 % (95 % CI: 50.6-58.7) and after ablation 32.4 % (95 % CI: 23.3-41.9). Multivariate analysis identified age ≥75 years, tumor size &amp;gt;20 mm, location in segment 4, 6, 7 or 8, multiple metastatic sites and progress after chemotherapy as important risk factors with more than 25 % higher EMRR. Only when analyzed without segments included in the multivariate model was the number of metastases a significant risk factor. Vascular invasion, lymph node ratio and complications at time of primary tumor resection were also important negative prognostic factors. Ablation of small metastases compared to resection was a significant risk factor (HR 2.25 (95 % CI 1.61-3.15)). Conclusion: Tumor size over 20 mm and location of metastases as well as lymph node status and complications after resection of the primary tumor are important risk factors for survival outcome after liver surgery of CRLM. Progress after preoperative chemotherapy and ablation compared to resection more than doubled the risk of death within 5 years. Citation Format: Peter Scherman, Peter Naredi, Ingvar Syk, Erik Holmberg, Magnus Rizell. Patient, primary colorectal tumor and liver metastases factors which influence survival after liver metastasectomy and therefore should be considered at the preoperative tumor board [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6519.

Abstract 2510: High-depth whole genome sequencing of clinically-annotated high-grade serous ovarian cancers

Abstract Background: Prior molecular characterization efforts for high-grade serous ovarian cancer (HGSOC) were restricted to those who had upfront surgical debulking with variable treatment paradigms. Thus, we sought to examine molecular and cellular differences between clinically defined groups (tumor tissues from patients who had complete gross resection (CGR) versus those who were triaged to neoadjuvant chemotherapy (NACT) and experienced either excellent or poor response. Methods: Tumor biopsies were collected from three patient groups managed under a systematic surgical algorithm: CGR after primary surgery (R0, n=10); poor tumor response to NACT (NACT-PR, n=10); excellent tumor response to NACT (NACT-ER, n=10). Primary and multiple metastatic tumor sites per each patient were obtained pre-treatment and subjected to comprehensive omics analyses including high-pass whole-genome (WGS) and targeted deep DNA sequencing. Results: An average of 71 nonsynonymous somatic mutations from each sample for 75 samples with high-purity tumors (≥75%) by WGS were identified from each sample for the entire cohort. Fourteen ovarian-cancer-associated genes were found mutated in our patient cohort and, as expected, the most frequently mutated gene was TP53 in both primary and metastatic sites in all three groups. TP53 nonsense mutations were exclusively identified in the NACT-ER (36.0%) and NACT-PR groups (15.4%), while in the R0 group most TP53 mutations were missense mutations (62.5%). Nonsense mutations in CSMD3 and PIK3CA were exclusively identified in both primary and metastatic sites in the NACT-PR group. The most frequent copy number variations (CNVs) in the R0 were copy number gain/loss of CSMD3 (67%) and copy number loss of NF1 (54%) and CDK12 (50%) in both primary and metastatic sites. Interestingly, copy number losses of NF1 were significantly lower in the NACT groups (18%, p=0.002), especially in the NACT-PR (8%, p=0.0004), when compared to the R0 group (54%). We also identified significant less observation of chromothripsis-like patterns, and a significantly higher level of strong-binding neoantigens in the R0 than in the NACT groups. Conclusions: Our findings using HGSOC samples obtained from patients treated on a prospective algorithm identified distinct molecular abnormalities, and could have prognostic and therapeutic implications for patients with HGSOC. Citation Format: Sanghoon Lee, Li Zhao, Shannon N. Westin, Nicholas W. Bateman, Amir A. Jazaeri, Nicole D. Fleming, Karen H. Lu, Robert L. Coleman, Gordon B. Mills, Jianhua Zhang, Thomas P. Conrads, George L. Maxwell, P. Andrew Futreal, Anil K. Sood. High-depth whole genome sequencing of clinically-annotated high-grade serous ovarian cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2510.

Impact of patient, primary tumor and metastatic pattern including tumor location on survival in patients undergoing ablation or resection for colorectal liver metastases: A population-based national cohort study

IntroductionSelecting the optimal treatment strategy for patients with colorectal liver metastases (CRLM) aim to improve survival for the total cohort. Following the introduction of laparoscopic resections and ablation, localization may direct choice of method. The aim with this study was to re-evaluate prognostic factors that should be considered at the preoperative multidisciplinary tumor board, based on a national population cohort. Materials and methodsA national cohort with radically operated colorectal cancer in 2009-2013, also treated for CRLM was identified in Swedish national registries. Prognostic factors were identified and evaluated in multivariable analyses. Results1200 patients treated with resection and 125 with ablation only were included in the study cohort. Relative five-year survival was 54.7% (50.9%-58.4%) and 32.0% (22.4%-41.9%), respectively). High age, acute surgery and complications at time of primary tumor resection remained important risk factors at liver surgery, as well as the primary tumor characteristics; vascular invasion and high lymph node ratio. As for metastatic pattern; tumor size, location in segment 4, 6, 7 or 8, multiple metastatic sites and progress after preoperative chemotherapy were significant risk factors. In multivariate analyses, ablation therapy doubled the risk of death within 5 years. This strong negative impact was confirmed in a weighted propensity score analysis (HR = 2.1 (95 % CI 1.5 -3.0)). ConclusionSegmental localization and tumor size were prognostic factors but also patient and primary tumor factors significantly impacted survival after intervention for CRLM. Long-term survival was significantly lower after ablation therapy compared to surgical resection.

Prognostic role of targeted therapy in patients with multiple-site metastases from non-small- cell lung cancer

Aim: To evaluate the prognostic role of EGFR mutations in patients with multi-site metastases from non-small-cell lung cancer (NSCLC). Patients & methods: A total of 215 advanced NSCLC patients with multi-site metastases were included. The overall survival (OS) was the primary end point. Results: EGFR tyrosine kinase inhibitors (TKIs) significantly improved the OS in patients with brain metastases (p = 0.031) and bone metastases (p = 0.048). Meanwhile, it prolonged the OS in patients with lung or adrenal metastases, but not in patients with liver metastases. However, in patients without liver metastases, EGFR TKIs significantly improved the OS (p < 0.001). Conclusion: EGFR TKIs improved the prognosis in NSCLC patients with brain, bone, lung and adrenal metastases, but not in patients with liver metastases.

LBA-5 ANCHOR CRC: a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer

BRAFV600E mutations are identified in 8-15% of metastatic colorectal cancer (mCRC) patients and confer a poor prognosis. In patients with BRAFV600E-mutant mCRC, the combination of encorafenib (ENCO) + cetuximab (CETUX) ± binimetinib (BINI) in second- and third-line therapy has demonstrated improved outcomes compared to standard therapies (BEACON CRC study). The ANCHOR CRC study was designed to investigate the triplet combination (ENCO + BINI + CETUX) in the first line setting of this population. ANCHOR CRC is an open-label, single arm, two-stage design, phase 2 study in patients with BRAFV600E-mutant mCRC who did not receive any prior systemic therapy for metastatic disease. Patients received ENCO 300 mg orally QD + BINI 45 mg orally BID and CETUX IV weekly (250mg/m2 after a first dose of 400mg/m2) for the first 28 weeks and then once every two weeks (500mg/m2). The primary endpoint was confirmed Objective Response Rate (cORR) based on local review; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Analysis for Stage 1 was performed after the first 40 evaluable patients with a centrally confirmed BRAFV600E mutation had completed four post-baseline tumor assessments or discontinued. At least 12 responses in Stage 1 were needed to initiate Stage 2 and to enroll 50 additional patients to complete the recruitment with a total of 90 patients in the study. Stage 1 analysis results are presented here. Forty-one BRAFV600E-mutant mCRC patients with a median age of 67 years old (61% of the patients were ≥ 65 years old) were enrolled in Stage 1 and received the triplet combination as first line metastatic treatment. At study entry, 56% of patients presented with ECOG PS 1, 78% had metastases to at least 2 organs and 51% had peritoneal metastasis. Forty patients were evaluable for efficacy (BRAFV600E mutation was not centrally confirmed for one patient). The investigator assessed cORR was 50% (95% confidence interval [CI], 33.8-66.2) with 85% of patients having a decrease in tumor size. The investigator measured median PFS was 4.9 months (95% CI, 4.4-8.1). Adverse events were consistent with those observed in prior studies with this triplet combination. Grade 3 or higher adverse events were seen in 68% of patients, the most common being: diarrhea (15%), acute kidney injury (12%) and anemia (12%). The ANCHOR CRC study is the first prospective study using a BRAF inhibitor-based therapy in first line BRAFV600E-mutant mCRC. Despite the high risk features of the population enrolled in Stage 1, including high proportion of patients ≥ 65 years old and advanced stage at diagnosis (multiple metastatic sites with frequent peritoneal carcinomatosis), most patients had tumor regression. The safety profile was acceptable and toxicities remained manageable. The Stage 1 analysis exceeded the minimal number of confirmed responses and proceeded to enroll 54 additional patients in Stage 2 to complete the study recruitment.

Distribution of Neck Metastases and Survival in Patients with Breast Carcinoma

Purpose: Neck metastases in breast carcinoma are relatively rare and patients show poor survival rates. A controversy exists over whether neck metastases can be treated as distant or loco-regional metastases. The literature concerning the distribution of metastases in the neck is lacking, as well as data about whether metastases in the higher neck regions cause poorer survival than those in the supraclavicular fossa. Methods: Ultrasound investigation with fine-needle biopsy was performed on 41 breast cancer and confirmed neck metastases patients in a 6-year period. We analysed the distribution of neck metastases and patient survival rates using Kaplan-Meier survival curves and Cox regression. Results: The median survival time from the diagnosis of primary disease to that of neck metastases was 21 months. The presence of metastases in sites other than the neck significantly worsened survival, but multiple metastatic sites did not make it significantly worse. The number of nodes and presence of conglomerates did not considerably affect survival. Conclusion: Neck metastases in breast carcinoma can be found not only in the supraclavicular fossa, but elsewhere in the neck as well. Survival of patients with metastases in higher neck regions was shorter, but not very much so. Survival of patients with metastases limited just to the neck was substantially better, therefore early detection and aggressive treatment that could include neck dissection should be considered.

Abstract 39: Real-time spatial and temporal monitoring on tumor subclonal evolution

Abstract Many types of cancer are found to exhibit a high level of intrasample genetic heterogeneity, as a result of the microevolution process. As genomic aberrations accumulate within tumor cells, a subset of the cells may gain a selective advantage and form an outgrowth within the tumor. When chemotherapeutic agents are administered to the patient, these tumor subclones may respond differently to the treatment and may eventually cause relapse. Identifying resistant subclones, and their genotypes, after each chemotherapy would yield valuable insights into how the tumor population reacted to the previously administered chemo-agent, and how the treatment plan should be adjusted based on the genetic features of surviving subclones. Similarly, understanding the relationships between the primary and metastatic tumor cell populations would provide knowledge about the mechanisms driving, and potentially preventing, metastasis. Our method (SubcloneSeeker) is able to reconstruct subclone structures jointly across all samples (temporal or spatial), using somatic variants jointly clustered with their Cell Prevalence (CP), to infer a unified evolutionary structure. When more than one structure is able to explain the observed somatic variants and their CP values, we can compute a consensus structure that captures the most important features (i.e., which subclones and the corresponding genomic aberrations are responsible for the resistance of a certain chemotherapy drug), as well as suggest a panel of variants to be profiled with single-cell assay in order to reduce computational ambiguity. We applied this method to several datasets, including a breast cancer patient who had received three regimens of chemotherapy and had tumor samples taken at 4 consecutive time points. Our analysis revealed that the tumor population reacted to these treatment in two distinct patterns: 1) although a significant reduction in tumor burden was observed, most of the major subclones survived and expanded again after treatment, indicating that the treatment was effective, but terminated prematurely; 2) a single subclone with extra mutations (e.g., FBXL19, a tumor suppressor by inhibiting E-cadherin downregulation) survived the treatment and became the founding clone for the tumor population post-treatment, and the extra mutations were fixed at very high CP (~100%), indicating that these extra mutations are most likely to be causative for chemoresistance. We also applied our method to breast cancer patient rapid-autopsy datasets with 28 tumor samples. Our method was able to map out subclone evolution across multiple metastatic sites and highlight variants unique to each evolutionary lineage. In conclusion, our method is able to elucidate the dynamics of tumorigenesis, drug response, and metastasis by reconstructing unified subclone evolutionary structures, allowing more informed decisions to be made in adjusting treatment plans in real time and potentially facilitating personalized cancer medicine. Citation Format: Gabor Marth, Yi Qiao, Dillon Lee, Xiaomeng Huang. Real-time spatial and temporal monitoring on tumor subclonal evolution [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 39.

Comparative Treatment Patterns and Outcomes of Fulvestrant versus Everolimus Plus Exemestane for Postmenopausal Metastatic Breast Cancer Resistant to Aromatase Inhibitors in Real-World Experience.

BackgroundFulvestrant (FUL) and the combination of everolimus and exemestane (EVE-EXE) were the options to treat hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) patients who were refractory to aromatase inhibitors (AIs). The practical knowledge of treatment patterns and outcomes between the two regimens is essential for improving treatment decisions.MethodsHR+/HER2− MBC patients, who were refractory to AI, were treated with FUL or EVE-EXE from June 2013 to June 2016 were included. Treatment patterns, progression-free survival (PFS), overall survival (OS), and toxicity were reported. Propensity score matching (PSM) was used to minimize potential confounders.ResultsA total of 168 patients were enrolled. Of 168 patients, 124 patients were treated with FUL and 44 patients received EVE-EXE. Patients who were treated with EVE-EXE were younger, more likely to have visceral, liver, multiple sites of metastases, and had received more prior chemotherapy. After adjusting for propensity score matching (PSM), no significant difference in PFS was found between two groups (P=0.419). However, in the subgroup of multiple metastatic sites, the median PFS was significantly improved in the EVE-EXE arm compared with FUL arm (6.1 vs 3.2 months, respectively, P=0.012). More patients in EVE-EXE arm discontinued treatment due to adverse events than in the FUL arm.ConclusionA substantial difference in treatment patterns was observed between the two arms. Clinical outcomes were comparable after PSM.Clinicaltrials.gov IdentifierNCT03695341 (May 14, 2018).

Abstract IA14: Liquid biopsies for tracking molecular resistance in cancer

Abstract Cell-free circulating tumor DNA (ctDNA) can be found in the bloodstream of cancer patients and is increasingly being explored as an important biomarker to monitor adaptive changes to cancer therapies. Cell-free DNA fragments from multiple lesions mix together in the peripheral blood; hence, ctDNA contains a wide representation of the genomes from multiple metastatic sites. For this reason, genome-wide analysis of ctDNA has the potential to provide an unprecedented insight into changes in the genomic landscape that occur during the development of disease and in response to cancer therapies. To date, the use of ctDNA to monitor the tumor landscape has been limited to tracking genomic evolution. However, it is now clear that cancers can also adapt to therapeutic pressure by significantly altering their transcriptome. Currently we have a limited understanding of how “nongenomic” transcriptional adaptation leads to clonal dominance or the evasion of cancer therapies. Here I will provide an overview of the use of ctDNA-based approaches to track both genomic evolution and transcriptional changes in real time to improve our understanding of the mechanisms leading to molecular resistance in cancer. Citation Format: Sarah-Jane Dawson. Liquid biopsies for tracking molecular resistance in cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA14.

Abstract A17: Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies

Abstract Comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) provides an opportunity to noninvasively monitor a patient’s tumor burden via liquid biopsy. Liquid biopsies can assess a patient’s mutational landscape through time and provide information on treatment response and relapse. It has become increasingly common to have paired genomic data analysis between liquid and tissue biopsies from the same patient. However, the impact of clinical, temporal, and biologic factors on percentage of positive agreement (PPA) of variant detection between these biopsies is unclear. For our study, we leveraged two databases containing CGP data from paired liquid and tissue biopsy specimens tested by Foundation Medicine (FMI): the FMI database (&amp;gt;1700 paired samples) and the Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). The CGDB is a subset of the FMI database linked with the Flatiron Health nationwide de-identified EHR-derived database, which includes demographic, treatment, and clinical outcomes information (&amp;gt;500 paired samples). We report pan-solid tumor and per-indication prevalence and PPA for variants commonly assayed in both liquid and tissue tests. We found that PPA depended on the tumor DNA concentration in plasma and tissue biopsies, as well as the amount of time between tests. We also investigated the effect of treatments administered in the time between liquid and tissue tests on the detected variants and observed some well-described resistance alterations at a higher frequency in liquid samples, including a higher prevalence of ESR1 point mutations in breast cancer, more EGFR T790M alterations in lung cancer, and frequent KRAS Q61H alterations in colorectal cancer. Liquid biopsies can also contain DNA shed from multiple metastatic sites. We observed evidence of this in the form of polyclonal resistance alterations, which may also account for differences in PPA over time. Our findings indicate that while PPA is generally high between samples, it may be influenced by factors such as intervening therapies, resistance, therapy efficacy, and polyclonality of liquid samples. Citation Format: Zoe June F. Assaf, Smruthy Sivakumar, Dexter X. Jin, Sophia L. Maund, Svetlana Lyalina, Guneet Walia, Ethan S. Sokol, Sally E. Trabucco. Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A17.

Patterns of metastases of prostatic ductal adenocarcinoma.

The current study was conducted to investigate the patterns of metastases in men with metastatic prostatic ductal adenocarcinoma (DAC) and recurrence patterns after therapy. All patients with a new diagnosis of DAC with de novo metastases and those with localized disease who developed metastases after treatment and were treated at the study institution from January 2005 to November 2018 were included. All patient and tumor characteristics and outcome data were collected. A total of 164 patients (37.7%) had metastatic DAC, including 112 with de novo metastases and 52 who developed metastases after treatment. Men with de novo metastases were found to have a significantly higher median prostate-specific antigen level and International Society of Urological Pathology grade but a lower cT3 and/or T4 classification compared with those with metastases that developed after treatment (all P<.05). Approximately 87% of men with de novo metastases progressed despite multiple systemic therapies, 37.6% required intervention for the palliation of symptoms, and 10.1% responded to systemic therapy and underwent treatment of the primary tumor. Men with de novo metastatic DAC and those who developed metastases after treatment had multiple metastatic sites (including bone and viscera), with higher rates of lung metastases noted in the posttreatment group (23.2% vs 44.2%; P=.01). A total of 45 patients who were treated with curative intent developed metastases at a median of 22months (range, 0.9-74.8months) after treatment, at low prostate-specific antigen levels (median, 4.4ng/mL [interquartile range, 1.7-11.1ng/mL]). The current study described the metastatic patterns of DAC in both patients with de novo metastatic disease and those who later progress to metastases. Men receiving treatment for DAC with curative intent require stringent long-term follow-up with imaging modalities, including chest imaging given the predilection toward lung metastases noted among these patients.

Prognostic markers for overall survival and outcome to LuPSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer.

5548 Background: The aim of this international multicenter retrospective analysis was to identify prognostic markers for the clinical outcome in late-stage mCRPC patients treated with 177Lutetium-prostate-specific membrane antigen (LuPSMA) radionuclide treatment. Methods: Patients with progressive mCRPC treated with LuPSMA at six centers in Germany, USA, and Australia were considered for inclusion. Eligible patients had 24 predefined, pretherapeutic covariates (demographics, prior mCRPC treatments, and PSMA PET/CT derived parameters) and survival data available. Endpoints included overall survival (OS) and PSA progression-free survival (PSA-PFS). Covariates were tested using univariate and mulitvariate proportional hazards regression Cox models. Results: 267/414 (64%) patients met inclusion criteria and were analyzed. 113 patients participated in clinical trials (ACTRN12615000912583, NCT03042312), while 154 were enrolled in compassionate-access programs. After a median follow-up of 22.5 months, median OS was 13.0 months (95%CI 11.6-14.4); 83% of the patients died. Median PSA-PFS was 4.0 months (95%CI 3.2-4.7). In the multivariate analysis, factors associated with shorter OS were: shorter time since diagnosis of prostate cancer (HR=2.04; p=0.002), lower number of prior systemic therapies (≤3; HR=1.56; p=0.006), prior exposure to chemotherapy (HR=1.42; p=0.05), lower hemoglobin levels (HR=1.13; p=0.002), higher number of lesions (≥20: HR=1.53; p=0.009), multiple sites of metastases (bone/LN only vs. bone + LN; HR=1.39; p=0.03) and visceral involvement (M1c) (HR=1.45; p=0.01). Factors associated with longer PSA-PFS were: longer time since diagnosis of prostate cancer (HR=0.44; p&lt;0.001), higher hemoglobin levels (HR=0.32; p=0.03), presence of pelvic lymph nodes (LN) metastasis (N1) (HR=0.68; p=0.01), no distant lymph node metastases (M1a) (HR=0.66; p=0.01), no skeleton involvement (HR=0.44; p=0.01), no visceral metastases (M1c) (HR=0.51; p&lt;0.001), higher PSMA-positive tumor volume (HR=0.87; p=0.04), and higher SUVmean (HR=0.94; p=0.002). Conclusions: This retrospective analysis identified prognostic factors for survival and treatment response to LuPSMA. Along with the conventional risk factors in mCRPC, PSMA PET/CT can be a useful tool for stratifying patients and guide patient’s selection for LuPSMA radionuclide treatment.

International retrospective cohort study of locoregional and systemic therapy in oligometastatic breast cancer (OLIGO-BC1).

1025 Background: Systemic therapy is the standard care in metastatic breast cancer (BC). However, retrospective studies demonstrated survival benefits of locoregional and systemic (combination) therapy in oligometastatic BC. To clarify it, the Federation of Asian Clinical Oncology conducted an international retrospective cohort study (OLIGO-BC1) (UMIN No.000030047). Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered. “Oligometastases” is defined as low volume metastatic disease with limited number and size of metastatic lesions up to five and not necessarily in the same organ by the ABC guidelines. Overall survival (OS) from the diagnosis of oligometastases was the primary endpoint and compared between combination and systemic therapy using a log-rank test. Assuming the 5-year OS of 50% and 40%, respectively, 698 patients were required to achieve 80% power to detect the superiority of combination therapy, at a two-sided significance level. A multivariable Cox regression model with stratification by country was performed to estimate hazard ratio (HR) for therapy and other risk factors. Results: While 1,262 cases had been registered from February 2018 to May 2019, 1,200 remained for analysis after exclusion of unavailable cases. Among them, 573, 529 and 98 cases were registered from China, Japan and Korea, respectively. Luminal BC was recorded in 526 cases (44%), luminal-HER2 BC in 189 (16%), HER2 BC in 154 (13%), triple-negative BC in 166 (14%) and others in 165 (13%). One oligometastatic BC was found in 578 cases, 2 in 289, 3 in 154, 4 in 102 and 5 in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Combination therapy was performed in 595 cases and systemic therapy in 404. At median follow-up of 4.9 years, 5-year OS was 59.6% and 41.9%, respectively (p &lt; 0.01). An adjusted HR was 0.61 (95% CI: 0.51, 0.74). Type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval were significantly favorable prognostic factors. Discussions: Oligometastatic BC under some conditions seems to be curable. Taken together with recent molecular targeted therapy, locoregional therapy will be advantageous to conquer it. Conclusions: Combination therapy is a promising strategy for patients with oligometastatic BC.

Surgery at primary and metastatic sites for stage IV breast cancer (BC): A National Cancer Database (NCDB) analysis.

1099 Background: There is no clear evidence of a survival benefit of primary tumor resection in patients with stage IV breast cancer (BC). This large study evaluated factors associated with undergoing primary tumor resection, and whether resection at the primary site, or distant site resection (metastasectomy), was associated with better overall survival (OS). Methods: This retrospective analysis of stage IV BC cases used the 2004-2016 National Cancer Database (NCDB) population. To evaluate variables associated with primary tumor resection, we used univariate analyses (chi-squared and Wilcoxon rank-sum test), followed by multivariate logistic regression. Consequently, we conducted multivariate Cox regression survival analyses on the following groups: 1) all stage IV BC patients; 2) a subset of those with only 1 site of metastasis; and 3) another subset with metastasis to &gt; 1 distant site. Results: A total of 54,871 stage IV BC patients were included in this analysis. From this, we analyzed a subset with only 1 distant site involved (n = 30,480) and another subset with multiple secondary sites (n = 17,344). In total, 15,661 patients underwent surgery at the primary site: 11,451 (73.1%) were non-Hispanic white; 2479 (15.8%) were non-Hispanic black; 981 (6.3%) were Hispanic and 484 (3.1%) were Asian. Variables associated with undergoing resection of the primary tumor were: age, race, Charlson/Deyo score, insurance and facility type, involved breast quadrant, receptor status, N-staging, extent of metastasis and year of diagnosis. Survival analysis of all stage IV patients showed that both lumpectomy (HR 0.59, 95% CI: 0.57-0.62, p &lt; 0.0001) and mastectomy (HR 0.62, 95% CI: 0.60-0.64, p &lt; 0.0001) were associated with better OS when compared to no surgery. The statistical effect was larger in the subgroup with metastasis to 1 site, but still significant in the subgroup with multiple metastatic sites. Distant site resection also yielded a survival benefit compared to no metastasectomy across all 3 groups. In the subgroup with metastasis to only 1 site, metastasectomy was associated with better OS when the metastatic site was liver (HR 0.60, 95% CI: 0.43-0.82, p = 0.0018), lung (HR 0.47, 95% CI: 0.37-0.61, p &lt; 0.0001), and brain (HR 0.70, 95% CI: 0.55-0.88, p = 0.0022). Conclusions: Across all 3 patient subgroups, primary tumor resection (lumpectomy or mastectomy) and metastasectomy were associated with improved OS. Additional stratified analysis in the subgroup with only 1 metastatic site showed benefit of metastasectomy when that site was the lung, liver or brain.

Long-term survival rates in cancer patients achieved with metronomic chemotherapy (cyclophosphamide and methotrexate).

e15519 Background: Metronomic therapy (MT) is one of the most promising advances in cancer treatment strategy focused on both tumor cells and their microenvironment, specifically anti-angiogenic, immune and metabolic regulation. The treatment modality is a durable cytostatic drugs exposure with less toxicity. We investigated the efficacy of MT in point of prolonged duration of response (more than 6 months) in pts with the advanced resistant tumors. Methods: A total of 678 pts have been enrolled in the study and have been treated MT cyclophosphamide 50 mg (qd, PO) and methotrexate 2.5 mg (BID, PO) twice per week dosing schedule until progression. 508 pts (75%) had disease progression during first 6 months. Long-term efficacy (more than 6 months) was assessed in 170 pts (25%). The study population characteristics were female 122 (72%) vs male 48 (28%). Among the enrolled pts median age was 70 years (range from 37 to 91 years). ECOG status ranged from 0 to 4 (median - 1). The majority of pts received MT as a 2nd and 3rd line (57%) of the therapy (range from 1 to 11): 1-2 – 106 (62%), 3-4 - 52 (31%), 5 and more - 12 (7%). The distribution of pts by diagnosis is presented in the table 1. The majority of MT pts were represented by advanced clinical stage III-IV (97,6%): I - 1 (0,5%), II - 3 (2%), III - 7 (4%), IV - 159 (93,5%). MT commonly used in early-stages cancer in elderly patients with multiple comorbidities contraindicated to standard treatment. Most pts had two or multiple metastatic sites. Results: The ongoing long-term effect for MT indication was from 6 to 46 months. The main group consisted of the breast and colorectal cancer, 27% and 15%, respectively. The median time to progression was 9 months (16 months in CR was achieved (0,4%), 11 months and 9 months with a partial response (3,4%) and stable disease (21,2%), respectively). 12 (1,7%) pts are on ongoing long-term follow up more than 24 months. MT was well-tolerated. Drug related adverse events were described upon the study: hematological (10,2%, Gr 3-4 – 3,5%) vs non-hematological (6,6%, Gr 3-4 1,7%) toxicity. Conclusions: MT schedule demonstrated effectiveness in patients with advanced resistant tumors. The median duration of the effectiveness doesn’t depend on the line of therapy, tumor localization and objective response. The role of possible predictive markers of clinical benefit is question of further trials. [Table: see text]

Post-mortem tissue donation programs as platforms to accelerate cancer research.

Given recent advances in the treatment of cancer, patients are surviving longer but frequently develop treatment‐resistant and inoperable metastases. Biomedical research has advanced to the stage where in‐depth study of these lesions is feasible, with the goal of further refining our understanding of metastatic dissemination, therapeutic resistance and inoperable tumors. However, there is a lack of tissue specimens derived from multiple metastatic sites within the same patient that would permit the study of these processes. Furthermore, patients with rapidly progressing or metastatic disease are rarely candidates for surgery, making those most in need of innovation and discovery extremely difficult to study. For this reason, post‐mortem tissue donation programs are an approach that is quickly gaining traction in the cancer research community. Herein, we discuss what post‐mortem tissue donation entails, attitudes towards these procedures, and highlight important studies already utilizing these resources. In addition, we propose future directions for use of this tissue that can directly improve clinical management of advanced cancer patients.