Pattern Of Metastatic Spread Research Articles

Biomarker alterations associated with distinct patterns of metastatic spread in colorectal cancer

Metastatic spread is the most important life-threatening feature of colorectal cancer and is supposed to be mainly driven by alterations in different carcinogenic pathways. The present study compared mutation and expression profiles of distinctive biomarkers in colorectal cancer patients with different clinical metastatic patterns. As for a case-control study, patients were matched according to T category, grading and primary tumour site. Overall, 246 patients with either exclusive lung metastasis (N = 82), exclusive liver metastasis (N = 82) or non-metastatic colorectal cancer (N = 82) were identified. Paraffin-embedded specimens were examined for mutations in the RAS and RAF genes and for the expression of β-catenin and CD133. Clinical endpoints were presence or absence of distant metastasis, formation of metastasis in lungs versus the liver and survival. MAPK pathway mutations in either the KRAS, NRAS or BRAF gene were associated with the development of lung metastasis (63.4%) compared to the control group (47.6%; p = 0.04). MAPK pathway alterations plus high β-catenin expression were associated with metastasis to the lungs but not to the liver (28.0% vs. 13.4%; p = 0.02). High CD133 expression correlated with the development of liver metastasis compared to the control group (30.5% vs. 14.6%; p = 0.02). This data indicates that different patterns of distant spread are associated with specific biomarker alterations and may represent different molecular subtypes of colorectal cancer. However, underlying mechanisms of metastasis formation in different anatomic sites remains unclear. Since knowledge of the anticipated site of distant spread would substantially impact clinical management, further research is needed to identify solid biomarkers for different metastatic patterns.

Radiological evaluation of malignant pleural mesothelioma - defining distant metastatic disease

BackgroundMalignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking.MethodsIn this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes.Results67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without.ConclusionsThis report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms.

Improvements in Clinical Outcomes for BRAFV600E -Mutant Metastatic Colorectal Cancer.

Although the last two decades have seen a broad improvement in overall survival, colorectal cancer is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their colorectal cancer. Consequently, many patients present with metastatic colorectal cancer, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of colorectal cancer tumors and are associated with uninhibited cell proliferation, reduced apoptosis, and resistance to standard therapeutic options. In colorectal cancer, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared with tumors with wild-type BRAF Success in treating other BRAFV600E -mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic colorectal cancer. Consequently, combination therapy with inhibitors of BRAF, MEK, and EGFR, which overcomes the innate treatment-resistant characteristics of BRAF V600E-mutant colorectal cancer, is now recommended by treatment guidelines.

Abstract 1109: Integrative analysis of clinical and genomic information identifies predictive markers of metastatic risk

Abstract Despite the fact that the majority of cancer related deaths are due to metastatic disease, existing large-scale cancer sequencing projects such as The Cancer Genome Atlas have so far focused mainly on primary tumors. Moreover, most publicly available datasets in cancer genomics lack information about spatiotemporal patterns of metastatic spread. We have developed new clinical data extraction methods and performed an integrative analysis of clinical and genomic features from 34,836 patients treated at Memorial Sloan Kettering Cancer Center (MSK), stratified into 45 cancer subtypes. Tumors were sequenced with MSK-IMPACT, a targeted next-generation sequencing assay that identifies genomic alterations in 468 genes. Indications of metastatic events, including affected organs and detailed timeline annotations, were extracted from the electronic medical records. This allowed us to distinguish not only sequenced primaries (58%) from sequenced metastases (42%), but also primaries in patients with evidence of metastatic disease (33%) from patients without evidence of metastatic disease (25%) at the time of sequencing. Tumors from patients with evidence of metastatic disease exhibited increased copy-number alterations, measured as fraction of genome altered (FGA) in multiple cancer types, including prostate adenocarcinoma, endometrial endometrioid, HR+/HER2- breast invasive carcinoma and lung adenocarcinoma (all p < 0.001). This supports the existence of a positive correlation between disease burden and chromosomal instability, although this effect is weaker or non-existent in some cancer types, including hepatocellular carcinoma, ovarian serous, and cholangiocarcinoma. We investigated associations between somatic alterations and metastatic organotropisms. For example, among patients with microsatellite stable colorectal cancer, tumors that metastasized exclusively to the peritoneum were enriched in BRAF alterations when compared to patients that never metastasized to that site (21% vs. 6%; p=0.003), while tumors that metastasized exclusively to the lung were enriched in KRAS alterations (69% vs. 41%; p=0.002). By analyzing primary tumors in patients with no evidence of metastatic disease at the time of sequencing, and comparing those that would eventually metastasize with those that would not, we identified predictive markers of metastatic risk. For example, in bladder cancer, tumors with altered TP53 were twice as likely to metastasize (54% vs. 27%; p<0.001), while tumors with FGFR3 alterations exhibited the opposite trend (24% vs. 43%; p<0.001). We present a comprehensive, spatiotemporal map of metastasis that integrates clinical and molecular information and can be used to build personalized risk models of metastatic spread at target-organ resolution based on individual molecular profiles, which can enhance precision medical care and optimize clinical outcomes. Citation Format: Christopher J. Fong, Francisco Sanchez-Vega, Bastien Ngyuen, Anisha Luthra, Subhiksha Nandakumar, Henry Walch, Walid Chatila, Arjun Rajanna, Ahmet Zehir, Michael Berger, Jianjiong Gao, Nikolaus Schultz. Integrative analysis of clinical and genomic information identifies predictive markers of metastatic risk [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 1109.

Liver Tumor Burden in Pancreatic Neuroendocrine Tumors: CT Features and Texture Analysis in the Prediction of Tumor Grade and 18F-FDG Uptake.

Pancreatic neuroendocrine tumors (p-NETs) are a rare group of neoplasms that often present with liver metastases. Histological characteristics, metabolic behavior, and liver tumor burden (LTB) are important prognostic factors. In this study, the usefulness of texture analysis of liver metastases in evaluating the biological aggressiveness of p-NETs was assessed. Fifty-six patients with liver metastases from p-NET were retrospectively enrolled. Qualitative and quantitative CT features of LTB were evaluated. Histogram-derived parameters of liver metastases were calculated and correlated with the tumor grade (G) and 18F-fluorodeoxyglucose (18F-FDG) standardized uptake value (SUV). Arterial relative enhancement was inversely related with G (−0.37, p = 0.006). Different metastatic spread patterns of LTB were not associated with histological grade. Arterialentropy was significantly correlated to G (−0.368, p = 0.038) and to Ki67 percentage (−0.421, p = 0.018). The ROC curve for the Arterialentropy reported an area under the curve (AUC) of 0.736 (95% confidence interval 0.545–0.928, p = 0.035) in the identification of G1–2 tumors. Arterialuniformity values were correlated to G (0.346, p = 0.005) and Ki67 levels (0.383, p = 0.033). Arterialentropy values were directly correlated with the SUV (0.449, p = 0.047) which was inversely correlated with Arterialuniformity (−0.499, p = 0.025). Skewness and kurtosis reported no significant correlations. In conclusion, histogram-derived parameters may predict adverse histological features and metabolic behavior of p-NET liver metastases.

37. Spatiotemporal patterns of metastatic spread and survival from MSK-IMPACT, a large-scale prospective clinical sequencing

37. Spatiotemporal patterns of metastatic spread and survival from MSK-IMPACT, a large-scale prospective clinical sequencing

Efficacy of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) by pattern of metastatic spread: ARCHES post hoc analyses.

5547 Background: ENZA + ADT significantly reduced the risk of radiographic progression or death in men with mHSPC (NCT02677896). Here, we assess how pattern of metastatic spread impacts the efficacy of ENZA + ADT in patients enrolled in ARCHES. Methods: Patients with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT, stratified by disease volume and prior docetaxel treatment. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included time to prostate-specific antigen (PSA) progression, time to first symptomatic skeletal event (SSE), time to castration resistance, and time to initiation of new antineoplastic therapy. Post hoc analyses were performed by pattern of metastatic spread at study entry. Results: Of the overall population with known metastases at screening (n=1146), the largest patient subgroups were those with bone metastases only (n=513) and those with bone and soft-tissue metastases only (n=351); there were fewer M0 patients or patients with soft-tissue metastases only (n=154) and patients with visceral ± bone metastases (n=128). ENZA + ADT reduced the risk of rPFS and other secondary endpoint measures versus PBO + ADT across all subgroups, with greater relative efficacy observed in patients without visceral metastases (Table). Conclusions: ENZA + ADT provides improvements in rPFS and other secondary endpoints versus PBO + ADT in patients with mHSPC regardless of pattern of metastatic spread, particularly in patients without visceral metastases. These results highlight the importance of patient/physician discussion regarding the use of ENZA in the treatment of mHSPC. Clinical trial information: NCT02677896 . [Table: see text]

Abstract P2-16-26: Mixed invasive ductal and lobular carcinoma (IDC/L) behaves similarly to invasive lobular carcinoma (ILC) with regard to neoadjuvant chemotherapy response and metastatic dissemination

Abstract Mixed invasive ductal and lobular carcinoma (Mixed IDC/L) is a rare subtype (3-5%) of invasive breast cancer with elusive pathophysiology. This entity is characterized by a mixed population of both ductal and lobular components within an individual tumor. Few studies have been published to date which compare Mixed IDC/L to invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) from a histopathologic perspective. Available literature on this topic is sparse and has been conflicting with regards to outcomes, and no studies to date describe the response of Mixed IDC/L to neoadjuvant chemotherapy. Patients with ILC have been shown to have lower response rates to neoadjuvant chemotherapy as compared to patients with IDC, which in turn leads to lower rates of successful breast conserving surgery and higher rates of re-excision due to positive margins. We aimed to compare Mixed IDC/L to pure ILC with regards to response to neoadjuvant chemotherapy and the need for repeat surgical intervention. We identified 26 patients with Mixed IDC/L and 113 patients with ILC who received neoadjuvant chemotherapy at our institution between 1990 – 2017. At baseline, the groups had a similar median age, as well as ER H-score, PR H-score, and Ki-67 index. There was no statistical difference in rates of pathologic complete response (pCR) or percent tumor volume reduction post therapy between the two groups. Similarly, the percent of patients that required re-excision was not statistically different. Interestingly, the metastatic pattern was similar between the groups and included sites of dissemination such as the peritoneal cavity and omentum, which are not common sites of metastasis for IDC. These findings suggest that Mixed IDC/L tumors behave similarly to ILC with regard to their response to neoadjuvant chemotherapy and patterns of metastatic spread. These findings support a prominent role for the lobular component in this mixed subtype in driving biology, including response to neoadjuvant therapy and metastatic dissemination. Ongoing efforts are directed towards incorporating data from the IDC cohort, as well as evaluation of changes in histology, ER/PR H-scores, and Ki-67 levels as a result of therapy. These data may imply that Mixed IDC/L tumors may behave clinically more like ILC than IDC, but larger studies are needed to study this rare breast cancer subtype. Citation Format: Azadeh Nasrazadani, Jennifer M Atkinson, Yujia Li, Priscilla F McAuliffe, Rachel C Jankowitz, Leisha A Emens, George C Tseng, Adrian V Lee, Norman Wolmark, Steffi Oesterreich, Peter C Lucas. Mixed invasive ductal and lobular carcinoma (IDC/L) behaves similarly to invasive lobular carcinoma (ILC) with regard to neoadjuvant chemotherapy response and metastatic dissemination [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-26.

Abstract P3-01-12: Breast cancer orbital and periorbital metastases can be bilateral, are associated with invasive lobular histology, and can co-occur with brain metastases

Abstract Breast cancer is responsible for most ophthalmic metastases (OM) to the orbit and periorbit. OM are associated with poor prognosis, as 95% of affected patients subsequently die of breast cancer. Previous studies have demonstrated an increased propensity for invasive lobular carcinoma (ILC) to spread to the eye compared to invasive ductal carcinoma (IDC). ILC is less common than IDC, and it can exhibit an unusual pattern of metastatic spread, including to sites such as the ovaries and GI tract. We herein report our single academic institution experience with OM from breast cancer with respect to anatomical presentation, histology (lobular vs. ductal), treatment and survival. We used the natural language processing platform TIES (Text Information Extraction System) to identify OM caused by primary breast cancer in a database of over 2.3 million patients with electronically stored pathology and radiology reports at the University of Pittsburgh Medical Center. Search terms in TIES were translated into ontologies consisting of the NCI Metathesaurus’ synonyms and abbreviations. The search was thus not reliant on specific words. We then reviewed clinical notes, pathology reports, radiology reports, therapeutic regimens, and outcome data for the cases identified through TIES. Data from the patients identified through TIES was also compared to a large institutional database featuring 1,366 patients with metastatic breast cancer (MBC). Histological slides from 3 patients were analyzed. We identified 28 patients diagnosed with primary breast cancer between 1995 and 2016 and subsequent OM. Median age at diagnosis was 54, with a range of 28 to 77. ER, PR, and HER2neu status from the 28 patients with OM did not differ from other patients with MBC in our institutional database. The relative proportion of patients with ILC was significantly higher in the patient cohort with OM (32.1%) than in the metastatic institutional database (11.3%, p=0.007). Median OS in the OM cohort was 78.4 months; distant metastasis free survival (DMFS) was 34.2 months. These survival times did not differ significantly from those patients in the large institutional metastatic database. DMFS tended to be longer (35.05 months) for patients with ILC compared to IDC (23.34 months), supporting a tendency for late relapse. Additionally, after a diagnosis of first metastasis, median survival of patients with ILC (21.4 months) was significantly shorter than that of patients with IDC (55.2 months) (p=0.03). OM were the second most frequent site of first metastasis in the OM cohort after bony metastases. Median time to first OM was 46.7 months. Of the 9 patients who developed bilateral OM, 4 had ILC, 1 had IDC, 2 had a mixed ILC/IDC, and 2 had an unknown histology. We observed a significant co-occurrence of OM and central nervous system (CNS) metastases (p=0.018). Of 14 patients that developed OM and CNS metastases, only 3 were diagnosed with ILC compared to 9 patients diagnosed with IDC. 57.1% of the patients with OM received radiation therapy to the eye, and 25 patients received at least one line of systemic therapy. The histological analysis revealed an interesting case in which the primary tumor was of a mixed ILC/IDC subtype, while only ILC was present in the OM. To our knowledge, our report of 28 patients is the largest analysis of the histological subtype of breast cancer OM. Through our focus on anatomical presentation, histological subtype, treatment, and survival we provide a broad overview of this rare complication of breast cancer. Our data suggests that OM from breast cancer can often impact both eyes, can be associated with CNS metastases, and are more frequent in patients with ILC than IDC. Citation Format: Martin Blohmer, Li Zhu, Jennifer M Atkinson, Sushil Beriwal, Joshua L. Rodriguez-Lopez, Margaret Rosenzweig, George C Tseng, Peter C Lucas, Adrian V Lee, Steffi Oesterreich, Rachel C Jankowitz. Breast cancer orbital and periorbital metastases can be bilateral, are associated with invasive lobular histology, and can co-occur with brain metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-12.

Radiopharmaceuticals for Treatment of Osteosarcoma.

Although trace amounts of radioactivity are routinely used to detect osteosarcoma, the use of larger therapeutic amounts of radiation is often an unrecognized opportunity to treat metastatic osteosarcoma. This chapter will review a number of approaches to use ionizing radiation in the form of injectable radiopharmaceuticals. Since bone metastases are a common pattern of metastatic spread of cancer in general, a number of bone-seeking radiopharmaceuticals have been developed and FDA approved for treatment of bone metastases. Although osteosarcoma, a bone-forming cancer, would seem ideally suited to be treated with bone seekers, patterns of relapse involving non-ossifying metastases remain a major problem to be overcome. Thus, this review will not only describe experience using a number of bone-seeking radiopharmaceuticals such as 153-samarium-EDTMP, 153-samarium-DOTMP, and 223-radium against osteosarcoma, but also approaches to identify patients who may benefit as well as some means to the improve overall efficacy including combination therapy with routine agents and using nuclear imaging to develop best strategy for use. These include imaging with not only 99mTc-MDP standard bone scans, but also 99mTc-MDP bone scans with SPECT CT, bone-specific sodium fluoride PET-CT (Na18F), and 18FDG-PET-CT. Accurate knowledge of oligometastatic active disease can facilitate more effective use of combination therapy, including radiosensitizers and local control measures, for example, stereotactic body radiotherapy (SBRT) and/or cryoablation to reduce disease burden as well as manage and prevent micrometastatic disease from growing and metastasizing. Finally, a new tumor-specific radiopharmaceutical, CLR 131, may also provide another radiopharmaceutical to treat both osteoblastic and non-ossifying areas of osteosarcoma.

Metastatic behavior and overall survival according to breast cancer subtypes in stage IV inflammatory breast cancer

BackgroundDistant metastatic disease is frequently observed in inflammatory breast cancer (IBC), with a poor prognosis as a consequence. The aim of this study was to analyze the association of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) based breast cancer subtypes in stage IV inflammatory breast cancer (IBC) with preferential site of distant metastases and overall survival (OS).MethodsFor patients with stage IV IBC, diagnosed in the Netherlands between 2005 and 2016, tumors were classified into four breast cancer subtypes: HR+/HER2−, HR+/HER2+, HR−/HER2+, and HR−/HER2−. Patient, tumor, and treatment characteristics and sites of metastases were compared. OS of the subtypes was compared using Kaplan-Meier curves and the log-rank test. Association between subtype and OS was assessed in multivariable models using logistic regression.ResultsIn total, 744 eligible patients were included: 340 (45.7%) tumors were HR+/HER2−, 148 (19.9%) HR−/HER2+, 131 (17.6%) HR+/HER2+, and 125 (16.8%) HR−/HER2−. Bone was the most common metastatic site in all subtypes. A significant predominance of bone metastases was found in HR+/HER2− IBC (71.5%), and liver and lung metastases in the HR−/HER2+ (41.2%) and HR−/HER2− (40.8%) subtypes, respectively. In multivariable analysis, the HR−/HER2− subtype was associated with significantly worse OS as compared to the other subtypes.ConclusionBreast cancer subtypes in stage IV IBC are associated with distinct patterns of metastatic spread and display notable differences in OS. The use of breast cancer subtypes can guide a more patient-tailored staging directed to metastatic site and extend of disease.

Advanced urothelial cancer: a radiology update.

The recent genomic characterization of urothelial carcinoma by the Cancer Genome Atlas Project, made possible by the introduction of high throughput, reduced cost, and sequence analysis, has shed new insights on the biology of advanced disease. In addition, studies on imaging of advanced urothelial carcinoma have widened the knowledge on disease presentation and on pattern of metastatic spread and their correlation with the underlying biology of urothelial carcinoma. The wide range of treatments for advanced urothelial cancer, including combined chemotherapy regimens and immune checkpoint inhibitors, each result in treatment class-specific patterns of response and adverse events. Results of studies point to the need for a reliable biomarker, perhaps with imaging, that predicts prognosis and treatment response to systemic treatment, and can be used to select the most effective treatment while minimizing toxicity. This review of advanced urothelial cancer introduces the latest advances in genetic profiling, the current role of imaging, the radiographic appearance of treatment response and their toxicities, and details potential future areas of imaging research.

Abstract 2736: A molecular and histopathologic map of cancer metastasis

Abstract Metastatic disease is responsible for the vast majority of cancer-related deaths. Patterns of metastatic spread and colonization are, however, not random: routes of metastatic dissemination are cancer-type specific, and different cancer types exhibit varying levels of affinity for specific organs as metastatic target sites. We analyzed a cohort of more than 30,000 patients that were treated at Memorial Sloan Kettering Cancer Center (MSK) and had their tumors sequenced using the clinical MSK-IMPACT test, a targeted next-generation sequencing assay that identifies mutations, copy number changes and structural rearrangements in 468 genes. By querying the electronic medical record, we catalogued all metastatic events in the clinical history of these patients and mapped them to a set of 32 tissue sites. The primary diagnoses spanned 30 different cancer types, which were further stratified into >50 relevant molecular subtypes, based on a combination of molecular and histopathological features. Observed patterns of metastatic dissemination were cancer type specific and, in some cases, exhibited strong differences across molecular subtypes of the same cancer type. For example, HER2+ subtypes of breast cancer exhibited increased rates of brain (34% vs. 18%, p<0.0001) and lung (31% vs. 19%, p=0.006) metastasis when compared to HER2- subtypes. The median number of organs affected by metastatic disease per patient was 4 (range 1-14). The number of affected organs exhibited a strong positive correlation with the overall level of aneuploidy, as measured by the total fraction of genome altered by copy number changes (P<0.0001, Spearman correlation), but not with overall mutational burden. We identified genomic alterations that were significantly enriched in tumors from patients with metastasis to specific organs in a cancer-type dependent manner. For example, 244/556 (44%) of lung adenocarcinoma patients with EGFR amplification or activating mutations presented bone metastasis at some point of their clinical history, as opposed to only 400/1,124 (36%) of EGFR wild type patients (p=0.001, Fisher’s exact test). In the case of HR+/ER- breast adenocarcinoma patients, bone metastases were reported in 22/30 (73%) of patients with NF1 inactivated tumors, as opposed to only 330/745 (44%) of patients with NF1 wild-type (p=0.002, Fisher’s exact test). We present the first pan-cancer study that combines molecular and histopathological features to draw a comprehensive atlas of tumor metastasis. Our results provide novel insights into the biology of metastatic tumors and can have a direct impact on patient management and care by optimizing the use and frequency of specific imaging studies for metastasis surveillance. Citation Format: Francisco Sanchez-Vega, Christopher Fong, Walid Chatila, Philip Jonsson, Alexander V. Penson, Renzo G. DiNatale, Michael F. Berger, Ahmet Zehir, Ed Reznik, Jianjiong Gao, Karuna Ganesh, Barry S. Taylor, Nikolaus Schultz. A molecular and histopathologic map of cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2736.

Genetics of rectal cancer and novel therapies: primer for radiologists.

Rectal cancer accounts for one-third of newly diagnosed colorectal cancer cases. Given its anatomical location and risk for local recurrence, a multidisciplinary treatment program including surgery, radiation therapy, and chemotherapy has demonstrated improved outcomes in localized disease. Genetic analysis has become part of the standard approach for management of advanced disease and new trials are considering tailored therapies for locally advanced disease. This review describes molecular subsets of colorectal cancer; implications for clinical management, including patterns of metastatic spread and response to therapies; and emerging matched therapies. During the last decade, significant biological differences have been noted based on colorectal cancer primary location and here we focus on rectal cancers and relevant markers for this disease. As more treatment for localized rectal cancer is shifted to the neoadjuvant setting and more targeted regimens are developed for metastatic disease, radiologists will increasingly see patients defined by molecular subsets and their awareness of the genetics of rectal cancer will help further refine our understanding of this disease.

Surface-enhanced Resonance Raman Scattering Nanoprobe Ratiometry for Detecting Microscopic Ovarian Cancer via Folate Receptor Targeting.

Ovarian cancer represents the deadliest gynecologic malignancy. Most patients present at an advanced stage (FIGO stage III or IV), when local metastatic spread has already occurred. However, ovarian cancer has a unique pattern of metastatic spread, in that tumor implants are initially contained within the peritoneal cavity. This feature could enable, in principle, the complete resection of tumor implants with curative intent. Many of these metastatic lesions are microscopic, making them hard to identify and treat. Neutralizing such micrometastases is believed to be a major goal towards eliminating tumor recurrence and achieving long-term survival. Raman imaging with surface enhanced resonance Raman scattering nanoprobes can be used to delineate microscopic tumors with high sensitivity, due to their bright and bioorthogonal spectral signatures. Here, we describe the synthesis of two 'flavors' of such nanoprobes: an antibody-functionalized one that targets the folate receptor - overexpressed in many ovarian cancers - and a non-targeted control nanoprobe, withdistinct spectra. The nanoprobes are co-administered intraperitoneally to mouse models of metastatic human ovarian adenocarcinoma. All animal studies were approved by the Institutional Animal Care and Use Committee of Memorial Sloan Kettering Cancer Center. The peritoneal cavity of the animals is surgically exposed, washed, and scanned with a Raman microphotospectrometer. Subsequently, the Raman signatures of the two nanoprobes are decoupled using a Classical Least Squares fitting algorithm, and their respective scores divided to provide a ratiometric signal of folate-targeted over untargeted probes. In this way, microscopic metastases are visualized with high specificity. The main benefit of this approach is that the local application into the peritoneal cavity - which can be done conveniently during the surgical procedure - can tag tumors without subjecting the patient to systemic nanoparticle exposure. False positive signals stemming from non-specific binding of the nanoprobes onto visceral surfaces can be eliminated by following a ratiometric approach where targeted and non-targeted nanoprobes with distinct Raman signatures are applied as a mixture. The procedure is currently still limited by the lack of a commercial wide-field Raman imaging camera system, which once available will allow for the application of this technique in the operating theater.

Paget's "Seed and Soil" Theory of Cancer Metastasis: An Idea Whose Time has Come.

The concept that the pattern of metastatic spread of cancer is not random and that cancer cells exhibit preferences when metastasizing to organs, dates back to 1889 when Steven Paget published his "seed and soil" hypothesis. He proposed that the spread of tumor cells is governed by interaction and cooperation between the cancer cells (seed) and the host organ (soil). Extensive studies during the last several decades have provided a better understanding of the process of metastatic spread of cancer and several stages such as intravasation, extravasation, tumor latency, and development of micrometastasis and macrometastasis have been defined. Furthermore, recent studies have shown that the target organs may be prepared for metastatic deposits by the development of premetastatic niches. This specialized microenvironment is involved in promoting tumor cell homing, colonization, and subsequent growth at the target organ. The premetastatic niche consists of accumulation of aberrant immune cells and extracellular matrix proteins in target organs. The primary tumor plays a key role in the development of premetastatic niches by producing tumor-derived soluble factors which mobilize bone marrow-derived hematopoietic cells to the premetastatic niche. Exosomes-derived from the primary tumor also contribute to cancer-favorable microenvironment in the premetastatic niches. These changes prime the initially healthy organ microenvironment and render it amenable for subsequent metastatic cell colonization.

Lobular Breast Cancer and Abdominal Metastasis: What Is The Correct Diagnostic Management?

Invasive lobular breast cancer represents the second most prevalent histological type of breast cancer after invasive ductal cancer (IDC) and its incidence has been constantly growing in the last few years. This trend is largely related to the use of MR as a radiological diagnostic method of second level. We have analyzed our institutional case and the use FDG CT/PET in this case. FDG CT/PET demonstrates lower SUV and less accuracy both in primary as well as in metastastic ILC compared to IDC. Moreover, the patterns of metastatic spread differ between ILC and IDC. We think that for this type of cancer could be use CT-PET with a particular metabolite: 1 [18F]-Fluoroestradiol (18F-FES-PET). 18F-FES-PET has the potential to assess heterogeneity in ER expression that are expressed in lobular breast cancer.

Clinical landscape of cancer metastases.

Population‐based data on metastatic patterns are lacking because cancer registries seldom record metastases. This study uses a novel population‐based approach to identify metastases and describes metastatic pathways from 14 common primary cancers to 12 specific metastatic sites. A total of 179 581 patients with metastatic cancer were identified from the Swedish Cancer Registry and metastatic sites were identified using the Cause of Death Register and the National Patient Register. Patterns of metastatic spread were described across age and sex. In men, colorectal cancer was the main source of lung, peritoneal, and liver metastases. Lung cancer was the main origin of pleural and nervous system metastases. Prostate cancer dominated bone metastases but had minor contribution to other metastatic sites. Among women, breast cancer was the dominant origin of most metastatic sites, with the exception of peritoneum which was ruled by metastases from the ovary. As other exceptions, for nervous system metastases, lung cancer was the origin of metastases somewhat more frequently than breast cancer and for liver metastases, colorectal cancer was the main origin instead of breast cancer. The present achievement was to implement the first nationwide description of clinical landscape of cancer metastases, with an aim to serve as a reliable source for clinicians and researchers.

Abstract A57: Adoptive T cell therapy for ovarian cancer: Application of a surgically relevant model

Abstract Ovarian cancer is the most lethal gynecologic cancer, with more than 20,000 new diagnoses and 15,000 cancer-related deaths annually. Current standard therapy for advanced ovarian cancer incorporates upfront surgical cytoreduction followed by cytotoxic chemotherapy. But even with advances in surgical technique, chemotherapeutics and targeted delivery methods, the overall five-year survival rate remains ~50%, highlighting the need for novel treatment strategies. We have focused our efforts on immunotherapy by adoptive transfer of engineered T cells that can target proteins uniquely overexpressed in ovarian cancer. Recent work has identified mesothelin (MSLN) as a potential target, as this protein is overexpressed in malignant ovarian tissue, promotes the oncogenic phenotype, and has limited expression in healthy cells. Preclinical studies have demonstrated that mouse and human T cells engineered to express T cell receptors (TCR) with high-affinity for MSLN kill respectively murine and human ovarian tumor cells in vitro. Furthermore, in vivo studies in mice treating metastatic disease developing after intraperitoneal introduction of mouse ID8 ovarian cancer cells have demonstrated that engineered, adoptively transferred T cells preferentially accumulate in ID8 ovarian cancers, reduce tumor burden and prolong survival. However, our results also revealed that the tumor microenvironment (TME) can limit the persistence and killing capacity of engineered T cells. Immunosuppressive cells, inhibitory ligands that reduce T cell function, and cell death-inducing ligands are abundant within ID8 tumors, and cellular and molecular analyses of human ovarian cancer specimens showed that human T cell therapy will face similar TME-mediated obstacles. The ovarian cancer TME is also a nutrient- and oxygen-deprived milieu, and the adaptive metabolic responses required for survival by infiltrating T cells have protean effects on T cell function. Thus, strategies that modulate T cell responses to inhibitory signals, including metabolic pathways, have the potential to influence activity in the TME, and to enhance T cell function and improve anti-tumor efficacy. Ongoing studies exploring strategies to overcome elements common to the human and murine TME, including both direct modulation of the microenvironment and engineering of T cells to overcome critical components of immune evasion by solid tumors and to promote T cell survival and function, will be discussed. Building upon this work, we have been developing a novel model that more directly reflects the clinical setting requiring intervention. Following orthotopic injection of ID8 ovarian cancer cells directly beneath the ovarian bursa, tumorigenesis occurs initially within the ovary/fallopian tube microenvironment, and is followed by development of small volume metastatic disease. This orthotopic model, which results in formation of intraperitoneal metastatic implants originating from the ovary, replicates the development and patterns of metastatic spread of human ovarian cancer. Following intervention with primary surgical cytoreduction that includes hysterectomy and bilateral salpingo-oophorectomy, mice are being treated by adoptive transfer of antigen-specific T cells to target minimal residual disease in the peritoneal cavity, which models the clinical situation of patients requiring treatment after optimal surgical cytoreduction. Ongoing studies will be discussed that have been designed to modulate the function and persistence of transferred, MSLN-specific T cells and assess the impact on in vivo tumor development and survival in this clinically relevant model of ovarian cancer treatment. Citation Format: Christopher B. Morse, Kristin G. Anderson, Breanna M. Bates, Edison Y. Chiu, Nicolas M. Garcia, Philip D. Greenberg. Adoptive T cell therapy for ovarian cancer: Application of a surgically relevant model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A57.

Abstract 2961: First metastasis NGS analysis reveals new targets for personalized treatment in advanced breast cancer

Abstract Background Genomic profile of breast cancer (BC) metastases (M) may differ from that of the primary tumor (PT). Based on a multicenter prospective study (ESOPE, NCT 01956552) including 130 patients with biopsies of the first metastatic site, we report here the results of a matched, comparative PT/M targeted next generation sequencing (NGS) mutational analysis. Methods 117 paired PT/M FFPE samples obtained before any treatment for either early or advanced BC were available for analysis. Targeted sequencing was done using Illumina Hiseq2500 technology with a custom made 91 BC associated genes panel. Sequence data were aligned to the human reference genome (hg19) using Bowtie2 algorithm. High mapping quality and at least 70% coverage were achieved for 69 paired PT/M. Median depth was 723 and 98 % of targets achieved 100X depth. SNVs and indels were called using GATK. We defined the pathogenicity of variants using several public databases. We only retained confirmed pathogenic variant and variant of unknown pathogenicity observed at a frequency lower than 0,1% in population and reported at least once in cbioportal/tumorportal. Results Patient characteristics are representative of patients with first line metastatic BC (Comte et al, ASCO 2016#550). In 69 paired PT/M we retained 256 somatic variants (188 shared, 28 only in PT and 40 only in M) distributed in 47 genes and including 62 indels and 194 SNV. There were 128 distinct variants (33 indels and 95 SNV) classified pathogenic for 98 and of unknown pathogenicity for 30 of them. TP53, PIK3CA, CDH1, GATA3, MAP3K1, BRCA2, ERBB2, ESR1, NF1, PTEN, ARID1A, BRCA1 and EGFR are genes with the more frequently PT/M shared variants (mutated at least in 2 patients). Private mutations are seen mostly in NF1, PIK3CA, MAP3K1, NCOR1, TSC1 genes for PT and in TP53, LAMA2, PIK3CA, ESR1, NF1, MAP2K4 genes for M. ESR1 D538G mutation was detected for 3 PT/M pairs and 1 M. Beyond highly shared PIK3CA and TP53 variants, overall crude PT/M discordance rate was 42%. PT/M shared variants could be considered for targeted treatment in 48% patients. For 13% patients, sequencing M revealed at least one additional druggable target in PIK3CA, ALK, PTEN, SF3B1, NOTCH4, KDR, TSC2, POLE, ESR1 and CDKN2A genes. Examination of M private variants to find a site-specific pattern of metastatic spread suggested enrichment in MAPK (p=0.02) and PI3K (p<0.0001) pathways mutations in liver M (n=30) when compared to other sites. Interestingly, all variants detected in bone M (n=8) were shared with PT. Conclusion In this prospective multicenter study, the targeted mutational analysis showed that most metastatic samples at first relapse share majority of variants with their matched PT. Sequencing M showed additional druggable mutations in 13% of patients. Liver M had more variants in MAPK and PI3K pathways compared to other metastatic sites whereas bone M did not show a specific mutational pattern. Citation Format: celine callens, anais boulai, virginie bernard, sylvain baulande, patricia legoix-ne, anne salomon, walid chemlali, vanessa benhamo, etienne brain, mario campone, thomas bachelot, sylvie giachetti, jacques bonneterre, francois-clement bidard, vincent servois, aurelie comte, frederique berger, ivan bieche, brigitte sigal, paul cottu. First metastasis NGS analysis reveals new targets for personalized treatment in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2961.