Distant Metastatic Disease In Patients Research Articles

SMARCC1 copy number variation is related to metastatic colon cancer: an investigation based on TCGA data*

Abstract Objective There are no well-defined genetic indicators for distant metastatic illness in patients with colon cancer (CC). The discovery of genetic changes linked to metastatic CC might aid in the development of systemic and local therapeutic approaches. Using The Cancer Genome Atlas (TCGA), we examined the relationship between copy number variation (CNV) of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1) and distant metastatic illness in patients with CC. Methods Genetic sequencing data of all relevant CC patients and clinical features were collected from TCGA using R. There were 506 CC patients with CNV and clinical outcome data. The CNV of SMARCC1 was examined for its correlation with distant metastatic disease using the TCGA CC dataset (M1 vs. M0). After adjusting for age, sex, T stage, N stage, adjuvant chemotherapy, microsatellite instability (MSI), and surgical margin status, univariate and multivariate logistic regression analyses were performed. Results SMARCC1 CNV was linked to distant metastatic disease (P = 0.012 and 0.008 in univariate and multivariate analysis, respectively); positive lymph nodes and margin status were also associated with distal metastases (all P < 0.01). MSI, T stage, N stage, adjuvant treatment, sex, race, and MSI were not associated with metastases (all P > 0.05). Conclusion SMARCC1 CNV is associated with distant metastatic disease in patients with CC. In individuals with CC, such genetic profiles might be utilized therapeutically to support optimal systemic treatment options against local treatments for CC, such as radiation therapy, pending additional confirmation.

Whole-Body [18F]FDG-PET/MRI vs. [18F]FDG-PET/CT in Malignant Melanoma.

To assess the diagnostic performance of simultaneous whole-body 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) compared to [18F]FDG PET/x-ray computed tomography (CT) for detection of distant metastatic disease in patients with malignant melanoma. We included patients with malignant melanoma who underwent a single injection [18F]FDG dual-imaging protocol that included whole-body PET/CT and subsequent whole-body PET/MRI for staging or restaging purposes in a prospective setting. Images from both modalities were analyzed by two rater teams for the presence of metastatic lesions. PET/CT-PET/MRI overall agreement as well as region-based accuracies, sensitivities (Se), and specificities (Sp) were computed. Between July 2014 and December 2018, 22 patients were enrolled. Interrater agreement and overall accuracy (consensus reading) were 78.8% (95% CI 71-84.9) and 96.1% (95% CI 92.3-98) for PET/MRI and 78% (70.2-84.3) and 97.4% (95% CI 93.7-98.9) for PET/CT, respectively (P = 0.42). PET/MRI reached a region-based Se of 89.1% (95% CI 79.4-94.5) and a Sp of 100%, whereas PET/CT showed a region-based Se of 92.7% (95% CI 84-96.9) and a Sp of 100% for the detection of metastatic disease in malignant melanoma. Whole-body [18F]FDG-PET/MRI appears to be comparable to [18F]FDG-PET/CT for lesion detection in patients with malignant melanoma.

Abstract 5178: MUC13 is a novel molecular signature, for early detection and metastatic colorectal cancer

Abstract Objective: Colorectal cancer (CRC) is a leading cause of cancer mortality affecting over a million people every year. Biological markers for early detection and distant metastatic disease in patients with CRC are not well defined. We have identified transmembrane mucin MUC13, which is expressed in normal colon mucosa to be highly expressed in colorectal cancer, but the underlying pathways and the signaling mechanisms involved in CRC pathogenesis are not known. Our studies suggest MUC13 correlation with demographic and clinicopathologic characteristics. Materials and Methods: Retrospective institutional tumor registry was reviewed to identify patients with resected colon adenocarcinoma. Archived FFPE tissue blocks were reviewed by an experienced pathologist. Selected representative tissue blocks were serially sectioned at 4 µm. IHC staining was performed using an in-house MAb for MUC13. Slides were digitally scanned and analyzed qualitatively as well as quantitatively using a modified H-score based on the intensity of expression and percentage of stained cells. MUC13 was correlated with disease stage, aggressiveness and inflammatory markers, indicating poor prognosis in CRC patients. MUC13 splice variants were probed using novel designed probes. MUC13 SNPs were identified using unbiased approach by analyzing dpGAP database. Results: 196 tissues, of which 56.1% were female, 52% were white, and the median age at resection was 70. 38 (19.4%) were stage I, 64 (32.7%) stage II, 84 (42.9%) stage III, and 10 (5.1%) stage IV. 100% of colon adenocarcinoma tissues stained positively for MUC13, including definitive tumor epithelial staining, little-to-no background stromal staining, and mild staining of adjacent normal colon mucosa. Typical colon adenocarcinoma cells exhibited strong apical membranous staining with varying degrees of cytoplasmic staining. Advanced stage tumors were noted to more frequently exhibit basolateral and/or circumferential membranous staining compared to early stage tumors which more frequently displayed apical membrane staining alone. Five MUC13 transcript variants were identified by database analysis. Two of the protein coding MUC13 variants (long and short) showed differential expression in aggressive cell lines and patient tissues. Cyclic turnover between the short and long isoforms were observed during Anoikis resistance, cortisol, alcohol and BAP treatments. SNPs have been associated with increased risk of cancer incidence or fatality. Relevant MUC13 SNPs have been identified through systematic analysis of patient databases (dpGAP database). Verification and correlation of identified SNPs with patient disease stage and prognosis will also be presented. Conclusion: This is the first study to correlate MUC13 expression with disease outcome. Alternative transcripts and single nucleotide polymorphisms gave genetic insight of the role of MUC13 in CRC pathogenesis. Citation Format: Manish K. Tripathi, Chidi Zacheaus, Kyle Doxtater, Zachary Stiles, Fatemeh Keramatnia, Nadeem Zafar, Mahul Amin, Meena Jaggi, Subhash Chauhan. MUC13 is a novel molecular signature, for early detection and metastatic colorectal 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 5178.

Synchronous isolated ipsilateral salivary gland metastasis from a primary breast cancer – A case report

The most common sites of distant metastasis for breast are the lungs, liver, bones and brain. Here we report an extremely rarepresentation of isolated salivary gland metastasis from primary breast cancer, indicating advanced stage of breast disease and signof poor prognosis. The case emphasizes the need for a thorough workup for distant metastatic disease in patients diagnosed withinvasive breast cancer.

Use and Yield of Baseline Imaging and Laboratory Testing in Stage II Breast Cancer.

Despite guideline recommendations, baseline laboratory testing and advanced imaging are widely ordered in clinical practice to stage asymptomatic patients with clinical stage II breast cancer (BC). A retrospective study at two academic centers in Boston, Massachusetts, between 2006 and 2007 explored the use, results, and implications of laboratory tests, tumor markers, and imaging in patients with clinical stage II BC. Among 411 patients, 233 (57%) had liver function testing, 134 (33%) had tumor marker tests, and 237 (58%) had computed tomography (CT) as part of their initial diagnostic workup. Median age was 52 (range, 23-90 years). On multivariable analysis, young age, more advanced stage, and tumor subtype (human epidermal growth receptor-positive [HER2+] and triple-negative breast cancer [TNBC]) were significantly associated with baseline CT. The rate of detection of true metastatic disease with use of baseline staging imaging was 2.1% (95% confidence interval, 0.7%-5%). It was 2.2% (3 of 135) for estrogen receptor/progesterone receptor-positive disease, 1.9% (1 of 54) for HER2+ disease, and 2.1% (1 of 48) for TNBC. At 5 years of follow-up, 46 of 406 patients were diagnosed with metastatic breast cancer. Thirty-four of 46 (73.9%) who developed recurrent disease had imaging at their initial diagnosis, and of these, five had abnormalities on their initial imaging that was correlated with where they developed metastatic disease. In this cohort of women with stage II BC, staging imaging at diagnosis had a low yield in detecting distant metastases (2.1%). The detection rate was not higher with HER2+ disease or TNBC, despite the trend that patients with these subtypes were more likely to undergo imaging. Despite guideline recommendations, asymptomatic patients with stage II breast cancer (BC) often undergo staging imaging with computed tomography, bone scanning, or positron emission tomography. Physicians have often reported that they order imaging despite recommendations because they believe that younger patients or patients with more aggressive BC phenotypes, such as human epidermal receptor 2-positive BC or triple-negative BC, benefit from staging imaging. In this cohort of women younger than those in prior studies, the yield of detecting distant metastatic disease in patients with clinical stage II BC was very low and the detection rate was not higher in the presence of HER2-positive or triple-negative BC.

TNFRSF10C copy number variation is associated with metastatic colorectal cancer.

Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA). Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status. TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13-10.85) P<0.001] and positive lymph nodes [OR 18.83 (95% CI, 8.42-42.09)]; P<0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016). TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease. With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation therapy for rectal adenocarcinoma.

Abstract P1-10-01: Are physicians "choosing wisely" when imaging for distant metastases in women with early stage (1 or 2) breast cancer? A population study

Abstract Background: The probability of detecting radiologically evident distant metastases in asymptomatic patients with early stage (stage 1 and 2) breast cancer (BC) is low. Published guidelines, including the 2012 American Society of Clinical Oncology (ASCO) "Top-5" recommendation for "choosing wisely" in oncology, recommend against imaging in these patients. Imaging is also associated with significant false positive results and the need for additional confirmatory imaging and/or invasive procedures. Despite this evidence-base, imaging continues to be over-utilized. We decided to quantify the rates of staging imaging in women with early breast cancer in Canada’s largest province to determine whether provincial practice patterns are in keeping with the spirit of the guidelines and the 2012 ASCO "Top-5" recommendation. Methods: Provincial registry data available through the Institute for Clinical Evaluative Sciences were used to identify all patients with a first diagnosis of stage 1 and 2 breast cancer who underwent breast cancer surgery. For each patient, all imaging of the most common metastatic sites (i.e. skeleton, thorax and abdomen) was captured from the date of diagnosis up until 3 months after definitive breast cancer surgery. Patients who received neoadjuvant therapy or with a prior history of any invasive malignancy were excluded. Results: Between 2007 and 2012, 27,236 patients with stage 1 and 2 BC were identified. Overall data are shown in the table: StageNo. of patients% having at least one imaging test (total)Total no. of imaging tests (mean per patient imaged)% of patients imaged who required confirmatory imaging (total)No. of confirmatory imaging tests performed (% of total imaging)114,11383% (11,713)40,464 (3.5)55% (6,420)11,202 (28%)213,12394% (12,330)53,729 (4.4)65% (7,983)16,292 (30%) The most common initial (i.e. not confirmatory) imaging modalities of the skeleton, thorax and abdomen, for both groups were, bone scan (19%; 12,799/66,699), chest x-ray (28%; 18,789/66,699) and abdominal ultrasound (20%; 13,387/66,699) respectively. Use of advanced imaging (isotope bone scans, CT, MRI, PET) to look at potential sites of metastasis represented 38% (11,063/29,262) and 46% (17,180/37,437) of initial imaging tests in stage 1 and 2 BC patients respectively. Conclusion: Imaging for distant metastatic disease in patients with stage 1 and 2 BC is commonly performed in Ontario despite multiple guidelines recommending against this. Advanced imaging (isotope bone scans, CT, MRI, PET) is commonly used as the initial imaging modality of choice. Of particular concern is the fact that 60% (14,403/24,043) of BC patients with early stage disease who were imaged required some form of confirmatory imaging. These results show the importance of the recent ASCO "Top-5" recommendation against staging imaging in such patients. The reasons for this disconnect between evidence and practice are not fully understood, but knowledge translation strategies beyond publishing guidelines or recommendations are required if we are to elicit a meaningful and sustained change in physician practice. Citation Format: Demetrios Simos, Christina Catley, Carl vanWalraven, Ian D Graham, Dean Fergusson, Angel Arnaout, Susan Dent, Mark Clemons. Are physicians "choosing wisely" when imaging for distant metastases in women with early stage (1 or 2) breast cancer? A population study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-10-01.

Survival of cervical cancer patients presenting with isolated supraclavicular metastases vs. extra-nodal disease, as assessed by positron-emission tomography (PET) scans

Objectives: Distant metastatic disease in patients with cervical cancer is usually fatal. We aimed to describe progression free (PFS) and overall survival (OS) of women with cervical cancer presenting with supraclavicular lymph node (SCLN) metastases. Specifically, we sought to compare the OS of patients with isolated SCLN metastases to that of patients with both nodal and extra-nodal metastatic disease.

Value of Fluoro-2-Deoxy-D-Glucose-Positron Emission Tomography for Detecting Metastatic Lesions in Head and Neck Cancer

The role of positron emission tomography (PET) scans in the staging of head and neck cancer (HNC) is unclear. The National Comprehensive Cancer Network guidelines do not recommend routine metastatic workup beyond physical examination, chest x-ray, and laboratory tests. The purpose of this report is to examine the accuracy of staging PET scans for detecting distant metastatic disease in patients with HNC. Retrospective review of 182 consecutive newly diagnosed HNC patients who had a staging PET scan at Thomas Jefferson University Hospital between 2003 and 2007. The overall incidence of confirmed distant metastatic disease in this population was 5.0%. About 26 of the staging PET scans had areas suspicious for a metastatic lesion(s). Of total, 23 patients were further evaluated with imaging and/or biopsy, revealing 9 (39%) true positives, and 14 (60%) false positives. Of the 156 negative PET scans, there was 1 false negative and 155 true negatives. Thus, the sensitivity of PET was 90% and specificity was 92%. Positive predictive value was 39% and negative predictive value was 99.4%. No patients with pre-PET clinical stage I or II cancer had confirmed distant metastases. The only statistically significant predictor for metastatic disease was clinical stage IV versus all other stages (P=0.03). Given the marked differences in the treatment of locally advanced/nonmetastatic HNC versus metastatic HNC, we recommend PET for clinical stage IV disease. Although the sensitivity, specificity, and negative predictive value rates were acceptable, the positive predictive value was suboptimal. Patients found to have a PET scan "positive" for metastatic disease require confirmatory imaging or ideally biopsy.

Role of Whole-Body Staging Computed Tomographic Scans for Detecting Distant Metastases in Patients With Bladder Cancer

This study aimed to establish the incidence of distant metastases on whole-body computed tomographic (CT) scans in patients with newly diagnosed bladder cancer and to determine whether there is a significant difference in the incidence of metastases in patients with superficial and muscle invasive cancers. A total of 201 patients who had a proven histological diagnosis of transitional cell carcinoma of the bladder and a whole-body staging CT scan at diagnosis were identified from our MDT database during a 36-month period. Imaging was retrospectively reviewed with view to recording site, if any, of distant metastases. Of 201 patients, 11 (5.5%) were found to have distant metastases on CT. In univariable models, staging was not associated with either age (odds ratio, 0.98; 95% confidence interval, 0.92-1.04; P = 0.4) or sex (Fisher exact test, P = 0.07). Mean (SD) age was 74.1 (10.5) years. There was a significant association between staging and metastasis (odds ratio, 19.9; 95% confidence interval, 3.2-infinity; P = 0.0003). Of the patients, 7% of males had metastases versus 0% of the females. Staging CT scans for assessment of distant metastatic disease in patients with newly diagnosed bladder cancer can be restricted to patients with muscle invasive disease.

Identification of distant metastases with PET‐CT in patients with suspected recurrent head and neck cancer

To investigate the utility of positron-emission tomography/computed tomography (PET-CT) in identifying distant metastatic disease in patients with suspected recurrent head and neck squamous cell cancer (HNSCC). Retrospective analysis. Retrospective analysis of 64 consecutive patients with suspected recurrent HNSCC following definitive treatment who underwent PET-CT imaging were eligible for inclusion. Patients with previous known distant metastatic disease were excluded. The majority of patients (81%) had TNM stage III or IV disease. PET-CT was suspicious for pulmonary malignancy in 14 patients (22%) and indeterminate in 6 patients (9%). Pulmonary metastases or a new lung primary were present in 10 patients (16%): 7 of 14 patients with positive PET-CT scans (50%) and 3 of 50 patients with negative or indeterminate PET-CT scans (6%). Including nonpulmonary sites, the overall incidence of distant disease was 23% (15/64) with 20% (13/64) unsuspected prior to PET-CT. The sensitivity and specificity of PET-CT in predicting distant malignancy was 86% and 84%, respectively, with a positive predictive value of 60% and a negative predictive value of 95%. There was a significant correlation between standardized uptake value (SUV) on PET-CT and positive histology, with a mean SUV of 8.5 (range, 4.7-16.2) in patients with distant metastases compared with a mean SUV of 2.9 (range, 1.9-4.2) in patients with benign pathology (r = 0.87, P < .0001). A significant number of patients with recurrent HNSCC have distant metastases at the time of recurrence. These data suggest that PET-CT improves detection of metastatic disease in the high-risk patient and should be performed as part of the routine evaluation of patients with suspected recurrence prior to salvage surgery.

EUS with or without FNA is a highly effective modality in the evaluation of positive PET scan findings

Background: Positron emission tomography (PET) is commonly employed to detect distant metastatic disease in patients with known or suspected cancer. When the PET demonstrates uptake near the esophagus, stomach, duodenum, or rectum, EUS can be used to evaluate these areas to confirm or exclude malignant disease. The effectiveness of EUS for this indication is not known. The aim of this study was to evaluate the impact of EUS with or without FNA on the clinical management of patients with positive PET scans.

Identification of Distant Metastases With Positron–Emission Tomography‐Computed Tomography in Patients With Previously Untreated Head and Neck Cancer

To investigate the utility of positron-emission tomography-computed tomography (PET-CT) in identifying distant metastatic disease in patients with previously untreated head and neck squamous cell cancer (HNSCC) prior to definitive treatment. Retrospective analysis of 27 consecutive patients with previously untreated HNSCC who underwent PET-CT imaging in addition to chest radiography (CXR) as part of their metastatic workup. The majority of patients (89%) had TNM stage III or IV disease. PET-CT was suspicious for pulmonary malignancy in four (15%) patients and indeterminate in one (4%) patient. CXR was suspicious for pulmonary malignancy in two (7%) patients. Pulmonary metastases or a new lung primary was present in 3 (11%) patients: 3 of 4 (75%) patients with positive PET-CT scans and 0 of 23 (0%) patients with negative or indeterminate PET-CT scans compared with 2 of 2 (100%) patients with positive CXR and 1 of 25 (4%) patients with negative CXR. The sensitivity and specificity of PET-CT in predicting pulmonary malignancy was 100% and 96%, respectively, with a positive predictive value of 75% and a negative predictive value of 100%. The sensitivity and specificity of CXR in predicting pulmonary malignancy was 67% and 100%, respectively, with a positive predictive value of 100% and a negative predictive value of 96%. Including nonpulmonary sites, the overall incidence of distant metastatic disease was 19% (5/27) with 11% (3/27) unsuspected prior to PET-CT. PET-CT improves detection of metastatic disease in the high-risk patient and should be performed as part of the routine pretreatment evaluation of patients with advanced stage HNSCC.

EUS with Or Without FNA Is a Highly Effective Modality in Evaluation of Positive PET Scan Findings

Background: Positron emission tomography (PET) is commonly employed to detect distant metastatic disease in patients with known or suspected cancer. When the PET demonstrates uptake near the esophagus, stomach, duodenum, or rectum, EUS can be used to evaluate these areas to confirm or exclude malignant disease. The effectiveness of EUS for this indication is not known. The aim of this study was to evaluate the impact of EUS with or without FNA on the clinical management of patients with positive PET scans.

Iodine 131 thyroid ablation in female children and adolescents: Long-term risk of infertility and birth defects

The use of radioactive iodine, or iodine 131 (131I), for remnant thyroid ablation and the treatment of cervical and distant metastatic disease in patients with thyroid cancer is well accepted. 131I concentrates in the bladder, and irradiation to the ovaries has been theorized to increase the risk of infertility and birth defects in subsequent offspring. We conducted a retrospective review of the charts of 154 children and adolescents treated at our institution for thyroid cancer between 1951 and 1991. Review of these charts identified 68 females diagnosed with thyroid cancer, < or = 20 years of age, who received 131I as part of their therapy at our institution. Charts were reviewed and patients recontacted, and initial tumor, date of diagnosis, and 131I administration, including doses, were recorded. Complete pregnancy histories including current health status of the children were also recorded. Twenty-two patients who never attempted pregnancy were excluded from analysis. Eleven patients could not be contacted and were considered lost to follow-up and thus excluded from the study. In the remaining 35 patients, mean age at 131I administration was 18.3 years (range 14.1-20.8), mean follow-up, 16.8 years (range 5.6-39.8), and mean 131I dose, 148.53 mCi (range 77.2-250). Three patients were diagnosed infertile after extensive workup (8.6%). The remaining 32 patients had 69 pregnancies resulting in 60 term and four premature deliveries. There were two elective abortions for nonmedical reasons and three spontaneous abortions. Only two children were conceived within 1 year of 131I therapy. Both were born with birth defects that proved fatal within 8 months. No other children were born with birth defects. One other child born with an estimated gestational age of 27 weeks died due to complications related to his prematurity. No anomalies were noted at autopsy. Of the 61 children alive for follow-up, no major health problems were identified other than asthma in two children. 131I, used in doses up to 250 mCi, is not associated with any long-term risk of infertility. The risks of infertility or birth defects are not different from those of the general population. Because the two children with birth defects were born to mothers treated either during pregnancy or 6 months before conception, it might be wise to suggest avoiding pregnancy for up to 1 year after 131I treatment.