Low-stage Tumors Research Articles

Risk factors for breast cancer development by tumor characteristics among women with benign breast disease

BackgroundAmong women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown.MethodsUsing a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.ResultsBreast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14–14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21–3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.ConclusionMost tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.

Targeted therapy response in early versus late recurrence of renal cell carcinoma after surgical treatment: A propensity score‐matched study using the Korean Renal Cancer Study Group database

To investigate the clinicopathological features and outcomes of targeted therapy in patients with recurrence of renal cell carcinoma in <5years or ≥5years after the surgical treatment for renal cell carcinoma. Patients with metastatic renal cell carcinoma treated with targeted therapy in a multicenter database were retrospectively characterized according to time from surgery to recurrence. Early recurrence was defined as recurrence within 5years after surgery, and late recurrence was defined as occurring ≥5years after surgery. The propensity scores for recurrence status were calculated, and patients with late recurrence were matched to patients with early recurrence at a 1:3 ratio. The oncological outcomes of targeted therapy in both groups were compared. Among 716 patients, 512 (71.5%) experienced early recurrence and 204 (28.5%) experienced late recurrence. The patients with late recurrence presented with younger age at surgery, lower tumor stages and Fuhrman grade, and fewer sarcomatoid features and lymphovascular invasion (all P<0.005). All differences in clinicopathological characteristics before targeted therapy disappeared after matching. Patients with late recurrence had significantly longer median overall survival (56months vs 36months; P<0.0001) and median first-line progression-free survival (12months vs 8months; P=0.031). The early recurrence status was a significantly worse predictor for overall survival and first-line progression-free survival (hazard ratio 1.30, P=0.007; and hazard ratio 1.76, P<0.001, respectively). Late recurrence might have prognostic value in terms of oncological outcomes in metastatic renal cell carcinoma treated with targeted therapy.

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Intratumoral budding and automated CD8-positive T-cell density in pretreatment biopsies can predict response to neoadjuvant therapy in rectal adenocarcinoma

Tumor budding and CD8-positive (+) T-cells are recognized as prognostic factors in colorectal adenocarcinoma. We assessed CD8+ T-cell density and intratumoral budding in pretreatment rectal cancer biopsies to determine if they are predictive biomarkers for response to neoadjuvant therapy and survival. Pretreatment biopsies of locally advanced rectal adenocarcinoma from 117 patients were evaluated for CD8+ T-cell density using automated quantitative digital image analysis and for intratumoral budding and correlated with clinicopathological variables on postneoadjuvant surgical resection specimens, response to neoadjuvant therapy, and survival. Patients with high CD8+ T-cell density (≥157 per mm2) on biopsy were significantly more likely to exhibit complete/near complete response to neoadjuvant therapy (66% vs. 33%, p = 0.001) and low tumor stage (0 or I) on resection (62% vs. 30%, p = 0.001) compared with patients with low CD8+ T-cell density. High CD8+ T-cell density was an independent predictor of response to neoadjuvant therapy with a 2.63 higher likelihood of complete response (95% CI 1.04–6.65, p = 0.04) and a 3.66 higher likelihood of complete/near complete response (95% CI 1.60–8.38, p = 0.002). The presence of intratumoral budding on biopsy was significantly associated with a reduced likelihood of achieving complete/near complete response to neoadjuvant therapy (odds ratio 0.36, 95% CI 0.13–0.97, p = 0.048). Patients with intratumoral budding on biopsy had a significantly reduced disease-free survival compared with patients without intratumoral budding (5-year survival 39% vs 87%, p < 0.001). In the multivariable model, the presence of intratumoral budding on biopsy was associated with a 3.35-fold increased risk of tumor recurrence (95% CI 1.25–8.99, p = 0.02). In conclusion, CD8+ T-cell density and intratumoral budding in pretreatment biopsies of rectal adenocarcinoma are independent predictive biomarkers of response to neoadjuvant therapy and intratumoral budding associates with patient survival. These biomarkers may be helpful in selecting patients who will respond to neoadjuvant therapy and identifying patients at risk for recurrence.

Negative Correlation Between Circular RNA SMARC5 and MicroRNA 432, and Their Clinical Implications in Bladder Cancer Patients.

Objective: Our study aimed to evaluate the correlation of circular RNA SMARCA5 (circ-SMARCA5) and microRNA 432 (miR-432) with clinical characteristics and survival in bladder cancer patients. Methods: Preoperative clinicopathologic features and survival data of 156 bladder cancer patients were retrospectively reviewed. A total of 156 cases of tumor tissues, whereas 71 cases out of 156 available adjacent tissues were obtained from the Pathology Department for circ-SMARCA5 and miR-432 detections using real-time quantitative polymerase chain reaction. Results: Circ-SMARCA5 was upregulated but miR-432 was downregulated in tumor tissues compared with adjacent tissues; meanwhile, circ-SMARCA5 expression was negatively correlated with miR-432 in bladder cancer tissues. Circ-SMARCA5 high expression was correlated with larger tumor size, higher tumor stage, and lymph node (LYN) metastasis. However, miR-432 high expression was correlated with single multiplicity, smaller tumor size, lower tumor stage, less LYN metastasis in bladder cancer patients. Regarding survival, circ-SMARCA5 high expression was correlated with shorter disease-free survival (DFS) and overall survival (OS); whereas, miR-432 high expression was correlated with longer DFS and OS in bladder cancer patients. Further multivariate Cox's regression analysis displayed that circ-SMARCA5 high expression was an independent predictive factor for both worse DFS and OS in bladder cancer patients. Conclusion: Circ-SMARCA5 high expression but miR-432 low expression is correlated with advanced tumor features and poor survival of bladder cancer patients, which present as potential prognostic markers in bladder cancer.

Diagnosis of Hydronephrosis or Ureteral Obstruction using Renal Sonography among Patients with Cervical Cancer

Background. Cervical cancer is the second most common malignancy among Filipino women. The recent 2018 FIGO guidelines recommend imaging in cases of grossly invasive disease to determine the presence of hydronephrosis, which would immediately classify the disease as at least stage IIIB. CT and MRI are state-of-the-art modalities that can provide such information; however, these are costly and may not be accessible in areas with limited resources. Sonography is a safe and inexpensive alternative in this regard. Objective. This study aimed to evaluate the diagnostic performance of renal sonography in identifying the presence of ureteral obstruction or hydronephrosis among patients with grossly invasive cervical cancer, with non-enhanced CT as the reference standard. Methods. A blinded, prospective study was conducted among patients diagnosed with grossly invasive cervical cancer from the Philippine General Hospital. Participants underwent same-day evaluation with both renal sonography and non-enhanced CT. The presence of either ureteral obstruction or hydronephrosis secondary to cervical cancer was independently determined. The sensitivity, specificity, positive predictive value, and negative predictive value of renal sonography were calculated, with non-enhanced CT as the reference standard. Results. A total of 127 participants were enrolled. The mean age was 46 years, with a range of 24 to 65 years. The majority had stage IIB (41.7%) and stage IIIB (52.0%) disease. On non-enhanced CT, 46 (36.2%) showed evidence of ureteral obstruction or hydronephrosis, while 81 (63.8%) had negative results. On renal sonography, 46 (36.2%) had positive results, and 81 (63.8%) had negative findings. The sensitivity, specificity, and positive and negative predictive values of sonography were 91.3%, 95.1%, 91.3%, and 95.1%, respectively. Among patients with stage IIIB disease, sonography was shown to have higher sensitivity and specificity of 92.1% and 96.4%, respectively. Meanwhile, among patients with stage IB to IIB disease, its sensitivity and specificity were 87.5% and 94.3%, respectively. Conclusion. Renal sonography has high sensitivity and specificity in the diagnosis of ureteral obstruction or hydronephrosis in patients with grossly invasive cervical cancer. Its sensitivity is higher when used in patients with stage IIIB disease, compared with those having lower-stage tumors.

The association between the histopathological features and microsatellite instability in young patients with urothelial carcinoma of the bladder.

Bladder cancer under the age of 40 is extremely rare. Bladder cancer development involves complex and multi-stage processes, one of which is the DNA damage repair mechanism. In this retrospective study, we aimed to evaluate the histopathological features of bladder urothelial carcinoma seen in patients under 40 years of age and tumor microsatellite instability status using immunohistochemistry. A total of 50 patients under the age of 40 with urothelial bladder carcinoma from two different centers in the same country were included. Expression of the mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 was analyzed by immunohistochemistry. Age at the time of diagnosis ranged from 17 to 40 years old. Most tumors were non-invasive papillary urothelial carcinoma. Two cases had nuclear loss of MSH-6 and PMS-2. We observed that tumor grade, tumor stage, presence of tumor differentiation, and infiltrative growth pattern of the tumor have significant impact on prognosis, but microsatellite instability does not have an effective role in bladder carcinogenesis in young patients. Our results indicate that the presence of microsatellite instability is not related to the low tumor grade and stage in urothelial neoplasms in young patients, suggesting that urothelial carcinoma of the bladder in young patients may represent a genetically stable form of neoplasia.

The Intersection between Oral Microbiota, Host Gene Methylation and Patient Outcomes in Head and Neck Squamous Cell Carcinoma.

Simple SummaryRecently, there has been increased recognition of an association between the bacterial microbiome and cancer. In this study, we characterized the non-HPV head and neck squamous cell carcinoma (HNSCC) microbiome. We found a significant enrichment of Fusobacterium, depletion of Streptococcus, and the microbial signatures of twelve bacterial genera distinguishing HNSCC. With increased Fusobacterium—in particular, F. nucleatum—in our HNSCC cohort and its known association with prognosis in colorectal cancers (CRC), we sought to further characterize the association between clinical outcomes and F. nucleatum, and the host interaction with F. nucleatum. We identified a higher abundance of F. nucleatum in non-smokers and an improved survival, in contrast to CRC. An integrative analysis also identified that the enrichment of F. nucleatum was associated with host gene promoter methylation, suggesting that the bacterial mircobiome status may have a potential role as a prognostic biomarker and be involved in the pathogenesis of HNSCC.The role of oral microbiota in head and neck squamous cell carcinoma (HNSCC) is poorly understood. Here we sought to evaluate the association of the bacterial microbiome with host gene methylation and patient outcomes, and to explore its potential as a biomarker for early detection or intervention. Here we performed 16S rRNA gene amplicon sequencing in sixty-eight HNSCC patients across both tissue and oral rinse samples to identify oral bacteria with differential abundance between HNSCC and controls. A subset of thirty-one pairs of HNSCC tumor tissues and the adjacent normal tissues were characterized for host gene methylation profile using bisulfite capture sequencing. We observed significant enrichments of Fusobacterium and Peptostreptococcus in HNSCC tumor tissues when compared to the adjacent normal tissues, and in HNSCC oral rinses when compared to healthy subjects, while ten other bacterial genera were largely depleted. These HNSCC-related bacteria were discriminative for HNSCC and controls with area under the receiver operating curves (AUCs) of 0.84 and 0.86 in tissue and oral rinse samples, respectively. Moreover, Fusobacterium nucleatum abundance in HNSCC cases was strongly associated with non-smokers, lower tumor stage, lower rate of recurrence, and improved disease-specific survival. An integrative analysis identified that enrichment of F. nucleatum was associated with host gene promoter methylation, including hypermethylation of tumor suppressor genes LXN and SMARCA2, for which gene expressions were downregulated in the HNSCC cohort from The Cancer Genome Atlas. In conclusion, we identified a taxonomically defined microbial consortium associated with HNSCC that may have clinical potential regarding biomarkers for early detection or intervention. Host–microbe interactions between F. nucleatum enrichment and clinical outcomes or host gene methylation imply a potential role of F. nucleatum as a pro-inflammatory driver in initiating HNSCC without traditional risk factors, which warrants further investigation for the underlying mechanisms.

Association between air cadmium exposure and prostate cancer aggressiveness at diagnosis

Background: There is conflicting evidence of an association between cadmium exposure and prostate cancer (PC) mortality in the general population. Since most PCs are indolent, low grade and low stage tumors may mask associations. We assessed associations between ambient exposure to air cadmium and PC aggressiveness at diagnosis in the US.Methods: We collected outcome data from the 2010 – 2014 Surveillance, Epidemiology, and End Results (SEER). Aggressiveness at diagnosis was defined as stage categorized as either metastatic or localized and Gleason grade as high or low. The 2011 National Air Toxics Assessment database provided county-level air cadmium concentrations. Odds Ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression comparing the 80th to 20th percentile of cadmium exposure and adjusted for age at diagnosis, sociodemographic status, smoking prevalence and overall air quality at the county-level and were stratified by race and degree of urbanization defined by Rural-Urban Continuum Codes (RUCC).Results: The study cohort consisted of 230,540 cases from 493 counties. Overall, higher air cadmium exposure was associated with an increased likelihood of metastatic PC compared to localized PC (OR 1.02, CI 1.01–1.03) and higher Gleason grade at diagnosis (OR 1.01, CI 1.00–1.02). The strongest associations were observed in nonmetropolitan areas with urban populations of 20,000 to 250,000 (RUCC2 counties): (OR 1.26, CI 1.14–1.39) for metastatic vs. localized PC, and (OR 1.36, CI 1.25–1.49) for high vs. low grade cases.Discussion: The strongest associations between air cadmium exposure and tumor aggressiveness were found among nonmetropolitan counties, where 40 million Americans reside. Research is necessary to identify air cadmium pollution sources in these communities and to rule out additional confounding factors. Air cadmium exposure in the general population may be a more important factor in prostate cancer and its progression than previously recognized.

Role of AMPK/mTOR-independent autophagy in clear cell renal cell carcinoma

We examined the status and role of autophagy, a process of lysosomal recycling of cellular material, in clear cell renal cell carcinoma (ccRCC). Paired samples of tumor and adjacent non-malignant...

Low PTEN expression and overexpression of phosphorylated AktSer473 and AktThr308 are associated with poor overall survival in upper tract urothelial carcinoma.

The PI3K/Akt signaling pathway serves an essential role in various cellular processes, including cell growth, survival, cell motility, angiogenesis and cell metabolism. Loss of PTEN expression and hyperactivation of Akt can result in tumorigenesis. Previous studies observed expression of the Akt protein and absence of the PTEN protein in bladder cancer and non-small cell lung carcinoma tissues. The aim of the present study was to evaluate the expression status and prognostic value of PTEN and the PI3K/Akt signaling pathway in Taiwanese patients with upper tract urothelial carcinoma (UTUC). Archival formalin-fixed, paraffin-embedded (FFPE) tissues from 65 UTUC cases were stained via immunohistochemistry for PTEN, phosphorylated (p)Akt serine (Ser)473 and pAkt threonine (Thr)308. The expression levels of each protein were significantly correlated with clinicopathological parameters. PTEN, pAktSer473 and pAktThr308 protein expression levels were higher in adjacent normal tissues compared with those in tumor tissues. Cytoplasmic PTEN protein expression levels were lower in high-stage tumors compared with those in low-stage tumors, and nuclear and cytoplasmic pAktThr308 protein expression levels were higher in high-grade tumors compared with those in low-grade tumors. Univariate analysis showed that high pathological tumor stage (pT2-4) [P=0.01; hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.34–8.60], metastatic status (P=0.003; HR=3.55, 95% CI, 1.55–8.11), low cytoplasmic PTEN protein expression levels (P=0.016; HR=3.14; 95% CI, 1.24–7.95) and high cytoplasmic pAktSer473 protein expression levels (P=0.019, HR=2.71, 95% CI, 1.18–6.21) were predictive of poor overall survival. However, only metastatic status (P=0.031; HR=2.73; 95% CI, 1.10–6.78), low cytoplasmic PTEN protein expression levels (P=0.017; HR=3.29; 95% CI, 1.24–8.73) and high cytoplasmic pAktSer473 protein expression levels (P=0.027; HR=2.64; 95% CI, 1.12–6.23) remained significant in the multivariate analysis. Kaplan-Meier survival analysis showed that high T stage, metastasis, low expression levels of cytoplasmic PTEN protein and high expression levels of cytoplasmic pAktSer473 protein were significantly associated with poor survival (P=0.006, 0.001, 0.011 and 0.014, respectively). Co-expression of PTENlow/pAktSer473/high and pAktThr308/high phenotypes was associated with a less favorable overall survival (P=0.001). Overall, the present findings demonstrated that low expression levels of PTEN and high expression levels of pAktSer473 and pAktThr308 were predictors for poor overall survival in patients with UTUC.

S0140 A Retrospective Analysis of Tumor Budding, Staging, Invasion, and Immune Response in Patients Diagnosed With Non-Hereditary Young Onset Colorectal Cancer

INTRODUCTION: Tumor budding is an adverse prognostic factor in colorectal cancer, has been studied extensively in patients with somatic, microsatellite stable variants, and is found in 20–40% of such cases. However, the presence and significance of this histopathologic phenomenon in young patients diagnosed with non-hereditary colon cancer is to be determined. In this study, our aim was to ascertain presence of tumor budding in young patients diagnosed with non-hereditary cancer and investigate correlations of this prognostic feature with other prognostic factors such as staging, invasion, and immune response trends. METHODS: In this retrospective observational study, we selected young patients (18–50 years old) with histopathologic diagnosis of non-hereditary colorectal adenocarcinoma at Carilion Clinic, Roanoke, from 2002 to 2017 and followed through 2011–2019. Patients with inflammatory bowel disease and those with predisposing genetic syndromes were excluded. Patient demographics, polyps’ features, cancer features, colonoscopy reports, and mortality were obtained from electronic medical record. Two pathologists reviewed pathology slides to minimize inter-pathologist variability in histologic diagnosis. The cumulative risk of mortality among patients with different pathologic features were estimated using Kaplan Meier curves. RESULTS: One hundred and thirty nine patients (mean age, 41.6 ± 6.9 years) with non-hereditary colorectal cancer were identified. One hundred and four of these cases displayed tumor budding on histology (74.8%). Tumor budding was significantly correlated with lymphovascular and perineural invasion (P < 0.01 for both). Tumor budding grade was also significantly correlated with high cancer stage (P < 0.01), with intratumoral lymphocyte and neutrophil presence (P < 0.01) and the presence of tumor deposits (P < 0.01). Lastly, the occurrence of a Crohn-like response, a histologic indicator for an immune reaction to the colon cancer, was noted to be significantly higher in neoplasms affected by higher grade tumor budding (P < 0.01). CONCLUSION: Tumor budding was found in the majority (74.8%) of young non-hereditary colorectal cancer patients, suggesting that this phenomenon is much more prevalent in this subpopulation than in the somatic, microsatellite stable colorectal cancer group. Tumor budding was also significantly correlated with low and high tumor stages as well as lymphovascular and perineural invasion in young patients with non-hereditary colon cancer.Table 1.: Table summarizing tumor budding correlations with staging, invasion, and immune response trends

Comparison of the eighth edition of the TNM and Brigham Women's Hospital staging systems for cutaneous squamous cell carcinoma of the head and neck: a six-year review.

This study was undertaken with the aim to compare the T stages in a series of cutaneous squamous cell carcinoma (cSCC) patients using both the eighth edition of the Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours (TNM8) and Brigham and Women's Hospital (BWH) staging systems. This would allow comparison of the two to determine suitability with regards to T stage and the effect on local recurrence and nodal disease. This was a six-year retrospective cohort study of patients with primary invasive cSCC of the head and neck who were diagnosed and treated at Western Sussex Hospitals Trust in the United Kingdom between 2007 and 2012. The TNM8 and BWH staging systems were applied to these primary cSCCs. A total of 695 invasive cSCCs treated in 604 patients over six years were identified. Most patients were male (76%), with a mean (range) age of 81 (50-103) years. The most common location for local recurrence was the scalp (n=26, 58%). Regional metastasis occurred most commonly in the parotid gland (n=20, 63%). All tumours were classified using both staging systems. Specifically, 432 tumours remained in the same T stage (61%), and 192 were downstaged (27%) and 71 upstaged using the BWH (10%). The median (SD) follow-up time was 23 (28) months (range 1-123). The BWH alternative staging system overlapped with the TNM8 in high-stage and low-stage tumour assignment. The highest percentage of local recurrence and regional metastasis occurred in T2b tumours.

Abstract 3854: Prevalence and prognostic role of FoxP3regulatory T lymphocytes in cancer: A tissue microarray study on &amp;gt;20,000 cancers

Abstract Regulatory FoxP3+ lymphocytes function as suppressors of T-cell activity. The clinical impact of high FoxP3+ cell density in cancers is not fully understood, as some studies have linked high FoxP3+ cell density to good prognosis and others to poor prognosis in tumor cohorts with associated clinical data. While some data suggest that these variable data are due to biological differences between tumor entities, it is also possible that methodological differences have caused these discrepancies. This study was undertaken to analyze the density of FoxP3+ cells in various different cancer types by employing standardized methods. Tissue microarrays and large sections made from &amp;gt;20,000 prostate, breast, colorectal, ovarian, pancreatic, bladder and stomach cancers were analyzed together with various normal and inflamed tissues by conventional brightfield FoxP3 immunohistochemistry. Samples were also analyzed by fluorescent multiplex immunohistochemistry to assess the fraction of Ki67+ FoxP3+ cells. Our results indeed suggested a variable role of FoxP3+ cells in different tumor types. High FoxP3+ density was linked to high Gleason grade (p=0.0003) and early biochemical recurrence (p&amp;lt;0.0001) in 16923 prostate cancers, but to low tumor stage (p=0.027) and prolonged survival (p=0.0029) in 1341 breast cancers, and to low tumor stage (p&amp;lt;0.0001) in 744 colorectal cancers. No significant associations were found to tumor phenotype in 549 ovarian, 574 pancreatic, 549 bladder and 346 stomach cancers. Multiplex fluorescence IHC analysis of FoxP3 and Ki67 revealed comparable fractions of proliferating FoxP3+ cells in healthy tissues (average 12.3%, range 5.8-18.5%) and inflammatory conditions (average 7.6%, range 2.6-17.2%). Interestingly, the rate of Ki67+FoxP3+ cells was markedly higher in 36 bladder cancers (average 14.2%, range 0-49.3%) suggesting active expansion of FOXP3+ cells in cancer. Our data demonstrate an inverse prognostic impact of the FoxP3+ cell density in prostate and breast cancers. The increased proliferation rate of immune-regulatory FoxP3+ cells in some bladder cancer is interesting in the light of the variable response of these tumors to immune checkpoint inhibitors. Citation Format: Tim Mandelkow, Elena Bady, Niclas Blessin, Claudia Hube-Magg, Ronald Simon, Guido Sauter, Christoph Fraune, Maximilian Lennartz, Katharin Möller, Sören Weidemann, Andreas Luebke, Doris Höflmayer. Prevalence and prognostic role of FoxP3regulatory T lymphocytes in cancer: A tissue microarray study on &amp;gt;20,000 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 3854.

Abstract 6405: Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting Notch signaling

Abstract Ciclopirox (CPX) is a FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in solid and hematologic malignancies. It's clinical utility as an anticancer agent, however, is limited by poor oral bioavailability, gastrointestinal toxicity, and poor water solubility. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), is rapidly and completely metabolized to CPX, the active metabolite, which subsequently undergoes renal elimination resulting in urine concentrations of CPX that exceed in vitro IC50's several-fold. We characterized the activity of CPX-POM and its major metabolites in vitro utilizing authenticated human T24, HT-1376, and UM-UC-3 high-grade urothelial cancer cell lines. CPX inhibited cell proliferation, clonogenicity, and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling, which was partially rescued by ectopic expression of the intracellular domain of Notch1. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin1 and Nicastrin, which are essential for Notch activation. Interrogation of The Cancer Genome Atlas (TCGA) database demonstrated that both proteins were upregulated in bladder tumor tissue, and that higher levels of Presenilin1 and Nicastrin were significantly associated with lower overall survival in muscle invasive bladder cancer (MIBC) patients. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model in two separate studies. Intraperitoneal (IP) administration of CPX-POM once daily for four weeks at doses ranging from 25 to 200 mg/kg significantly decreased bladder weight and resulted in a migration to lower stage tumors in CPX-POM treated animals compared to untreated animals. This was coupled with a reduction in proliferation index, as well as reductions in Presenilin1 and Hey1 expression in bladder tumor tissues in CPX-POM treated animals. A similar anti-tumor response was observed following once daily versus three times weekly IP CPX-POM in this chemical carcinogen mouse model of bladder cancer. The safety, dose tolerance, pharmacokinetics and pharmacodynamics of intravenous (IV) CPX-POM were characterized in a US multi-center, First-in-Human, Phase 1, open-label, dose escalation study (NCT03348514). Eight cohorts of 19 patients received IV CPX-POM doses ranging from 30 to 1200 mg/m2 for as many as six 21-day treatment cycles. Adequate systemic and urinary tract CPX exposures were achieved at the maximum tolerated dose of 900 mg/m2 with evidence of Notch inhibition. An expansion cohort study in 12 cisplatin-ineligible MIBC patients receiving two treatment cycles of CPX-POM prior to radical cystectomy (RC) is underway. Evidence of pharmacologic activity is being characterized in bladder tumor tissues obtained at RC. Citation Format: Scott James Weir, Prasad Dandawate, Prabhu Ramamoorthy, Parthasarathy Ranjarajan, Robyn Wood, Amanda Brinker, Benjamin Woolbright, Mehmet Tanol, Tammy Ham, William McCulloch, Michael Dalton, Michael J. Baltezor, Roy A. Jensen, John A. Taylor, Shrikant Anant. Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting Notch signaling [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 6405.

Endometrial Carcinomas with Intestinal-Type Metaplasia/Differentiation: Does Mismatch Repair System Defects Matter? Case Report and Systematic Review of the Literature.

Background: Intestinal metaplasia/differentiation in primary endometrial carcinomas is an uncommon phenomenon, with only few cases described. Material and Methods: We performed a systematic review of endometrial carcinomas with intestinal metaplasia/differentiation interrogating the electronic databases Pubmed, Web of Science, and Scopus, and we reported an additional case arising in a 49-year-old woman. Results: We identified only eight patients diagnosed with endometrial carcinomas exhibiting intestinal metaplasia/differentiation, and additionally our case. Endometrial carcinomas with intestinal-type features can present in pure or mixed forms in association with usual-type endometrioid carcinomas; in mixed forms, the two neoplastic components may derive from a common neoplastic progenitor, as evidenced by the concomitant loss of MSH2 and MSH6 protein expression in our case. Disease recurrences occur in a significant fraction of the cases, including patients diagnosed in low-stage disease. Conclusions: Endometrial carcinomas with intestinal metaplasia/differentiation are rare and they may represent a more aggressive tumor variant, thus requiring a proper treatment despite the low-tumor stage. The ProMise classification should be performed also in these unusual tumors, since they can be associated with mismatch repair system defects.

Radiomic Texture and Shape Descriptors of the Rectal Environment on Post-Chemoradiation T2-Weighted MRI are Associated with Pathologic Tumor Stage Regression in Rectal Cancers: A Retrospective, Multi-Institution Study.

(1) Background: The relatively poor expert restaging accuracy of MRI in rectal cancer after neoadjuvant chemoradiation may be due to the difficulties in visual assessment of residual tumor on post-treatment MRI. In order to capture underlying tissue alterations and morphologic changes in rectal structures occurring due to the treatment, we hypothesized that radiomics texture and shape descriptors of the rectal environment (e.g., wall, lumen) on post-chemoradiation T2-weighted (T2w) MRI may be associated with tumor regression after neoadjuvant chemoradiation therapy (nCRT). (2) Methods: A total of 94 rectal cancer patients were retrospectively identified from three collaborating institutions, for whom a 1.5 or 3T T2w MRI was available after nCRT and prior to surgical resection. The rectal wall and the lumen were annotated by an expert radiologist on all MRIs, based on which 191 texture descriptors and 198 shape descriptors were extracted for each patient. (3) Results: Top-ranked features associated with pathologic tumor-stage regression were identified via cross-validation on a discovery set (n = 52, 1 institution) and evaluated via discriminant analysis in hold-out validation (n = 42, 2 institutions). The best performing features for distinguishing low (ypT0-2) and high (ypT3–4) pathologic tumor stages after nCRT comprised directional gradient texture expression and morphologic shape differences in the entire rectal wall and lumen. Not only were these radiomic features found to be resilient to variations in magnetic field strength and expert segmentations, a quadratic discriminant model combining them yielded consistent performance across multiple institutions (hold-out AUC of 0.73). (4) Conclusions: Radiomic texture and shape descriptors of the rectal wall from post-treatment T2w MRIs may be associated with low and high pathologic tumor stage after neoadjuvant chemoradiation therapy and generalized across variations between scanners and institutions.

Clinical significance of p27 Kip1 expression in advanced ovarian cancer

BackgroundOvarian cancer is the most common gynecological malignancy. In patients with advanced ovarian cancer, some biological parameters have prognostic implementations. P27kip1 is an inhibitor of a cycline-dependent kinase, its loss, can contribute to tumor progression.ObjectiveThis study aimed to examine the importance of P27KIP1 protein in predicting the prognosis and response to neoadjuvant chemotherapy in patients with advanced ovarian epithelial cancer and to compare the outcomes of immunohistochemistry with Quantitative Real-time PCR.Patients and methodsWe have studied P27KIP1expression by both immunohistochemistry and Quantitative Real-time PCR from 88 patients with advanced ovarian carcinomas undergone radical debulking surgery and received Paclitaxel followed by Cisplatin every 3 weeks for a total of 6 cycles. We also studied their association with both chemotherapy response and patient survival.ResultsNuclear expression of p27KIP1 protein was intense in 86 normal ovarian tissues and 42 of 88 carcinomas. The P27kip1mRNA expression level by qRT-PCR was very low in ovarian cancer tissues relative to its adjacent normal tissues. The results were statistically significant by both methods of determination. p27KIP1 expression was significantly related to good prognostic parameters as low stage tumors, differentiated tumors, absence of ascites, residual disease < 2 cm, and response to chemotherapy but not with histopathological type in case of determination by immunohistochemistry. Comparison of P27kip1 by both immunohistochemistry and qRT-PCR with different prognostic parameters revealed no significant difference between both methods in the assessment of these parameters. In 4 years of follow-up, 20.5% of patients were alive without evidence of disease. 6.8% were alive with disease. The disease-related four -year survival rate for the whole group was 28.2%. In multivariate analysis, residual disease, histological type, tumor differentiation, ascites was of independent prognostic significance.ConclusionIn ovarian cancer, patients with loss of p27KIP1 expression are at a greater likelihood of disease progression, p27KIP1 may be used as a molecular marker to predict response to chemotherapy and prognosis. Both immunohistochemistry and qRT-PCR have equal reliability in the determination of p27 KIP1.

Surgery for Gastric Remnant Cancer Results in Similar Overall Survival Rates Compared with Primary Gastric Cancer: A Propensity Score-Matched Analysis

BackgroundThe purpose of this study was to investigate clinical features, prognostic factors, and overall survival (OS) in surgical patients with gastric remnant cancer (GRC).MethodsA retrospective analysis of patients with gastrectomy for pT1–4 gastric cancer between October 1972 and February 2014 at our institution was performed. Clinical characteristics were compared between patients with GRC and those with primary gastric cancer (PGC). Multivariable Cox regression analysis was performed to determine the prognostic factors for OS in patients with GRC. A propensity score-matched cohort was used to investigate OS between the GRC and PGC groups.ResultsOf a baseline cohort of 1440 patients, 95 patients with GRC were identified. Patients with GRC underwent more multivisceral resections (p < 0.001) than patients with PGC despite lower tumor stages (p = 0.018); however, R0 resection rates were not significantly different (p = 0.211). The postoperative overall (p = 0.032) and major surgical (p = 0.021) complication rates and the 30-day (p = 0.003) and in-hospital (p = 0.008) mortality rates were higher in patients with GRC. In multivariable analysis, the only prognostic factors for worse OS in GRC were higher tumor stage (p < 0.001) and the occurrence of postoperative complications (p < 0.001). OS between propensity score-matched GRC and PGC groups was not significantly different (p = 0.772).ConclusionsGRC required more invasive surgery than PGC; however, the feasibility of R0 resection was similar. The prognostic factors of GRC were similar to those of PGC, and OS was not significantly different between both groups. Patients with GRC benefit from extensive surgery when performed with low morbidity and mortality.

Signet Ring Cell Gastric Carcinoma: Clinical Epidemiology and Outcomes in a Predominantly Latino County Hospital Population.

Gastric signet ring cell carcinoma (GSRC) is a rare but increasingly prevalent tumor histotype whose clinical features and natural history are poorly understood, particularly in the USA and minorities. To examine the occurrence, clinico-demographic characteristics, oncologic features, treatment, and outcomes of GSRC in a predominantly minority county hospital setting and benchmark them against data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. We queried biopsy-proven GSRC cases at a Los Angeles County hospital, from 2004 to 2017. Clinical characteristics, treatment, and survival data were collected and compared to SEER data. We identified 63 patients with GSRC. Compared to SEER, our cohort was significantly younger (52.6 vs. 63.5years, p < 0.01), Hispanic/Latino predominant (81% vs. 20%, p < 0.01), had higher overall stage (86% vs. 69% with stage III/IV, p < 0.01), and more frequent node involvement (89% vs. 49%, p < 0.01). Lower tumor stage, Helicobacter pylori positivity, and surgical intervention were associated with significantly longer median survival (all p < 0.05), which was similar in our study compared to SEER (median 12.6 vs. 9.0months, p = 0.26). Patients with GSRC within the Los Angeles County population have different clinical characteristics compared to what has been reported in SEER. Our cohort was younger, and despite having more advanced disease, did not have shorter survival. Further study is needed to better identify protective and risk factors in this population and improve understanding of the etiopathogenesis and natural history of this malignancy.