Cancer-specific Characteristics Research Articles

Non-Operative Ttreatment of patients with Chondrosarcoma: An analysis of patients who refused cancer-directed surgery or patients contraindicated to surgery.

Chondrosarcomas are the second most common primary bone sarcoma. Due to chondrosarcomas relative resistance to chemotherapy and radiation, surgical treatment has become the mainstay treatment option. The purpose of our study was to understand the proportion of patients in this population who undergo non-operative treatment options secondary to various reasons and analyze the difference in survival as well as patient and cancer specific characteristics between the two groups. We retrospectively reviewed the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with primary chondrosarcoma from 1973 to 2015. We evaluated the patients for both descriptive characteristics as well as cancer specific characteristics. We then performed a propensity matched analysis and other analyses to compare difference in cancer characteristics as well as survival. There were 3048 patients with chondrosarcoma of the bone during our study period of which 188(6.2%) patients did not undergo operative treatment either due to refusal of cancer directed surgery or contraindicated to surgery. A one unit increase in age was significantly associated with increased odds of not undergoing surgery(Odds Ratio 1.04;95% CI, 1.03- 1.05). No statistically significant difference(P = 0.9) in survival was noted between patients with long bone, grade 1 chondrosarcomas regardless of if they did or did not undergo operative treatment. This study provides data to inform the patient on their decisions for or against surgery and may assist the surgeons in counseling patients regarding the surgical treatment of chondrosarcomas. Patients not undergoing operative treatment for chondrosarcomas are at statistically significantly increased risk of mortality.

Platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC)

ObjectivesPembrolizumab +/− chemotherapy is standard therapy for r/m HNSCC. Despite regulatory approval of platinum/5FU/pembrolizumab, a taxane is often substituted for 5FU for convenience and tolerability. We aimed to characterize nationwide use patterns and compare outcomes between platinum/taxane/pembrolizumab vs platinum/5FU/pembrolizumab. MethodsPatients in a US nationwide database with r/m HNSCC treated from 2017 to 2022 with pembrolizumab plus platinum chemotherapy were included. Demographic and cancer-specific characteristics were summarized. Overall survival (OS) was estimated using Kaplan-Meier methodology, and compared between groups using log-rank test and multivariable Cox regression. Time on treatment, number of cycles, receipt of second-line therapy, and toxicities were compared between groups. ResultsOf 438 patients, 320 (73 %) received 5FU and 118 (27 %) received a taxane. Taxane use became more frequent over time and was higher in academic vs community practices (51 % vs 23 %, p < 0.001). OS did not differ between taxane and 5FU groups (mOS 12.2 vs 13.4 months, p = 0.662). On multivariable Cox regression, HR for death associated with taxane vs 5FU was 0.99 (95 %CI 0.71–1.38). Receipt of 2L therapy was numerically higher for 5FU patients (46 %) compared to taxane patients (35 %, p = 0.071). Grade ≥ 3 anemia was more common in taxane patients (33 % vs 20 %, p = 0.003), whereas grade ≥ 3 lymphopenia and thrombocytopenia were numerically higher in 5FU patients. ConclusionIn patients with r/m HNSCC undergoing chemoimmunotherapy, taxane vs 5FU use varies by practice setting and geographical region. Platinum/taxane/pembrolizumab was associated with similar survival as platinum/5FU/pembrolizumab; these results suggest that chemoimmunotherapy with taxane is a reasonable alternative to 5FU.

The frequency of HER2-low breast cancer among BRCA1, BRCA2, and PALB2 mutation carriers.

10509 Background: Human epidermal growth factor 2 (HER2) expression in breast cancer (BC) has historically been characterized as negative (0 or 1+ by immunohistochemistry (IHC); 2+ by IHC and not amplified by in-situ hybridization, ISH) or positive (2+ by IHC and amplified by ISH or 3+ by IHC). Recently developed therapies highlight the importance of identifying tumors that are HER2-low (IHC 1+, or 2+ with negative ISH). A minority of BC associated with germline BRCA1, BRCA2( BRCA1/2) or PALB2pathogenic variants (PV) are HER2-positive, but the proportion of BRCA1/2- and PALB2-associated HER2-negative BC that are HER2-low and may benefit from novel HER2-low therapies is unknown.This study aims to retrospectively identify the frequency of HER2-low BC in BRCA1/2 and PALB2 mutation carriers whose cancers were identified as HER2-negative. Methods: We conducted a retrospective chart review of 170 patients diagnosed with HER2-negative BC in the context of a BRCA1/2or PALB2PV at the University of Pennsylvania from 2003 to 2023. Genomic and cancer-specific characteristics including variant classification and receptor status were collected and are descriptively reported. Results: 170 individuals with BRCA1/2 or PALB2 PV developed 190 HER2-negative BC. Forty-seven percent of primary tumors that had been identified as HER2-negative were HER2-low (39% of BRCA1-, 56% of BRCA2-,60% of PALB2-associated BC; see Table). 17 individuals had 17 metastatic site biopsy reports available for review. Of these, 10 (59%) were HER2-low (1 BRCA1-, 8 BRCA2-, and 1 PALB2-associated). 6 of 17 (35%) individuals had discordant HER2 status in primary and metastatic samples; in all cases, the primary tumor was HER2 IHC 0 and the metastatic site was HER2-low. Conclusions: Despite the lower frequency of conventionally HER2-positive BC among individuals with BRCA1/ 2and PALB2PVs, the proportion of these BC that have low HER2 expression is substantial and similar to that of sporadic breast cancer. Discordance in HER2 status between primary and metastatic samples is observed. Individuals with BRCA1/2and PALB2HER2-negative BC may benefit from therapies for HER2-low BC; reevaluation of HER2 status on metastatic samples may identify additional candidates for such therapies. [Table: see text]

Unraveling Immune Heterogeneity across Pan-Cancer and Deep Insights in Lung Adenocarcinoma based on Alternative Splicing.

Alternative splicing (AS) participates in tumor development and tumor microenvironment formation. However, the landscape of immune infiltrating AS events (IIASE) in pan-cancer and mechanisms of AS in lung adenocarcinoma (LUAD) have not been comprehensively characterized. We systematically profiled the IIASE landscape of pan-cancer using data from The Cancer Genome Atlas (TCGA), analyzing both commonalities and specific characteristics among different cancer types. We found that AS events tend to occur specifically in one cancer type rather than in multiple cancer types. AS events were used to classify 512 LUAD samples into two subtypes by unsupervised clustering: aberrant splicing subtype (ABS) and immune infiltrating subtype (IIS). The two subtypes showed significant differences in clinicopathology, prognosis, transcriptomics, genomics and immune microenvironment. We constructed a classification signature comprising 10 genes involved in 14 AS events using Logistic regression. The robustness of the signature was validated in three independent datasets using survival analysis. To explore AS mechanisms in LUAD, we constructed subtype-specific co-expression networks using Pearson correlation analysis. AS event of AKT3 regulated by splicing factor ENOX1 was associated with poor prognosis in LUAD. Overall, we outline AS events associated with immune infiltration in pan-cancer and this study provides insights into AS mechanisms in LUAD patient classification.

Advancing Korean nationwide registry for hepatocellular carcinoma: a systematic sampling approach utilizing the Korea Central Cancer Registry database.

Hepatocellular carcinoma (HCC) presents a substantial public health challenge in South Korea as evidenced by 10,565 new cases annually (incidence rate of 30 per 100,000 individuals), in 2020. Cancer registries play a crucial role in gathering data on incidence, disease attributes, etiology, treatment modalities, outcomes, and informing health policies. The effectiveness of a registry depends on the completeness and accuracy of data. Established in 1999 by the Ministry of Health and Welfare, the Korea Central Cancer Registry (KCCR) is a comprehensive, legally mandated, nationwide registry that captures nearly all incidence and survival data for major cancers, including HCC, in Korea. However, detailed information on cancer staging, specific characteristics, and treatments is lacking. To address this gap, the KCCR, in partnership with the Korean Liver Cancer Association (KLCA), has implemented a systematic approach to collect detailed data on HCC since 2010. This involved random sampling of 10-15% of all new HCC cases diagnosed since 2003. The registry process encompassed four stages: random case selection, meticulous data extraction by trained personnel, expert validation, anonymization of personal data, and data dissemination for research purposes. This random sampling strategy mitigates the biases associated with voluntary reporting and aligns with stringent privacy regulations. This innovative approach positions the KCCR and KLCA as foundations for advancing cancer control and shaping health policies in South Korea.

Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation

BackgroundAs one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma and adenocarcinoma, arising from distinct cells-of-origin. Distinguishing cell-type-specific molecular features from cancer-specific characteristics is challenging.ResultsWe analyze whole-genome bisulfite sequencing data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both methylation level and genomic distribution of PMDs across tumor samples. We identify subtype-specific PMDs that are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie genomic distribution of PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor HNF4A maintains the binding sites that it generates in normal cells, while establishing new binding sites cooperatively with novel partners such as FOSL1 in esophageal adenocarcinoma. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of cell-type-specific PMDs and DMRs identified here in esophageal cancer are actually markers that co-occur in other cancers originating from related cell types.ConclusionsThese findings advance our understanding of DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.

Alteration in molecular properties during establishment and passaging of endometrial carcinoma patient-derived xenografts

Patient-derived xenograft (PDX) tumor models are known to maintain the genomic and phenotypic profiles, including the histopathological structures, of the parental tumors. On the other hand, unique enrichment of single-nucleotide variants or copy number aberrations has been reported in several types of tumors. However, an understanding of endometrial carcinoma PDXs is limited. The purpose of the present study was to clarify the presence or absence of the molecular properties of endometrial carcinomas in PDXs passaged up to eight times. Established PDXs of endometrioid carcinomas maintained their histopathological characteristics, but those of carcinosarcomas predominantly consisted of sarcomatous components when compared to the parental tumors. Alterations in the proportion of cells with positive/negative immunohistochemical staining for estrogen receptor, PTEN, PAX8, and PAX2 were observed, whereas the proportions of cells with AE1/AE3, TP53, ARID1A, PMS2, and MSH6 staining were unchanged. Variants of cancer-associated genes were compared between PDXs and parental tumors. Mutations in POLE and a frameshift deletion in BRCA1 were observed in the parental tumor tissue in each of the six cases, and additional genomic alterations, which were not apparently related to histopathological and immunohistochemical alterations, were found in the PDXs of these cases. The genomic and phenotypic alterations observed between endometrial carcinoma PDXs and parental tumors were partly associated with endometrial cancer-specific characteristics related to cellular differentiation and gene mutations.

The Biological Roles and Molecular Mechanisms of Long Non-Coding RNA MEG3 in the Hallmarks of Cancer.

Long non-coding RNAs (lncRNAs) are critical regulators in various biological processes involved in the hallmarks of cancer. Maternally expressed gene 3 (MEG3) is lncRNA that regulates target genes through transcription, translation, post-translational modification, and epigenetic regulation. MEG3 has been known as a tumor suppressor, and its downregulation could be found in various cancers. Furthermore, clinical studies revealed that impaired MEG3 expression is associated with poor prognosis and drug resistance. MEG3 exerts its tumor suppressive effect by suppressing various cancer hallmarks and preventing cells from acquiring cancer-specific characteristics; as it could suppress tumor cells proliferation, invasion, metastasis, and angiogenesis; it also could promote tumor cell death and regulate tumor cell metabolic reprogramming. Hence, MEG3 is a potential prognostic marker, and overexpressing MEG3 might become a potential antitumor therapeutic strategy. Herein, we summarize recent knowledge regarding the role of MEG3 in regulating tumor hallmarks as well as the underlying molecular mechanisms. Furthermore, we also discuss the clinical importance of MEG3, as well as their potential in tumor prognosis and antitumor therapeutic strategies.

The Role of Electronic Patient-Reported Outcome Measures in Assessing Smoking Status and Cessation for Patients with Lung Cancer.

Smoking cessation following lung cancer diagnosis is recommended to improve patient outcomes. Electronic Patient Reported Outcome Measures (ePROMs) may be useful for identifying and facilitating cessation support in patients that continue to smoke after a cancer diagnosis. The primary aim was to investigate the level of agreement between clinician-reported and self-reported patient smoking status during the first visit to a cancer centre (I). Secondary aims included investigating differences between cancer-specific characteristics between never smokers and current/ex-smokers (IIA), and the self-reported frequency of smoking cessation after diagnosis of lung cancer (IIB). Retrospective single-centre study carried out at a tertiary cancer centre in the UK. Lung cancer patients that completed at least one ePROM questionnaire within 6weeks of their first visit to the cancer centre (baseline), between February 2019 and February 2020, were included in the study. All ePROM questionnaires included a question regarding smoking status to allow comparison with the clinician records. Patients were offered these electronic questionnaires at each subsequent visit to the hospital. Of 195 patients included, 24 (12.3%) demonstrated discordance between clinician-reported and self-reported smoking status at the baseline assessment. Clinician-reported 'current smokers' were more likely to be discordant with self-reported smoking status, compared with clinician-reported 'ex-smokers' and 'never smokers' (P = 0.017). Never smokers were more likely to have adenocarcinoma (P < 0.005), present with stage IV cancer (P = 0.023) and receive treatment with palliative intention (P = 0.042), compared with current and ex-smokers. Of those that were reported by clinicians as being current smokers, 9/38 (23.7%) were self-reported ex-smokers. A sub-group of 137 patients completed at least one additional ePROM questionnaire after the baseline and were included in the smoking cessation analysis. Thirty-eight patients were clinician-reported as 'current smokers' at baseline. Of these, 9 subsequently stopped smoking, 17 continued and 3 had short periods of cessation, identified through self-reporting. In most cases, there is concordance between clinician- and self-reported smoking status. A small area of discordance was identified where clinicians reported some patients as 'current smokers', whilst patients self-reported having stopped. The causes for this were not explored and require further investigation. This study supports the use of ePROMs as a helpful tool to assess smoking status, and it can be used to identify patients for smoking cessation referral.

CTCFL regulates the PI3K-Akt pathway and it is a target for personalized ovarian cancer therapy

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy due to the lack of reliable biomarkers, effective treatment, and chemoresistance. Improving the diagnosis and the development of targeted therapies is still needed. The molecular pathomechanisms driving HGSC progression are not fully understood though crucial for effective diagnosis and identification of novel targeted therapy options. The oncogene CTCFL (BORIS), the paralog of CTCF, is a transcriptional factor highly expressed in ovarian cancer (but in rarely any other tissue in females) with cancer-specific characteristics and therapeutic potential. In this work, we seek to understand the regulatory functions of CTCFL to unravel new target genes with clinical relevance. We used in vitro models to evaluate the transcriptional changes due to the presence of CTCFL, followed by a selection of gene candidates using de novo network enrichment analysis. The resulting mechanistic candidates were further assessed regarding their prognostic potential and druggability. We show that CTCFL-driven genes are involved in cytoplasmic membrane functions; in particular, the PI3K-Akt initiators EGFR1 and VEGFA, as well as ITGB3 and ITGB6 are potential drug targets. Finally, we identified the CTCFL targets ACTBL2, MALT1 and PCDH7 as mechanistic biomarkers to predict survival in HGSC. Finally, we elucidated the value of CTCFL in combination with its targets as a prognostic marker profile for HGSC progression and as putative drug targets.

Factors Associated with Discontinuation of Active Surveillance among Men with Low-Risk Prostate Cancer: A Population-Based Study.

The purpose of this study was to describe the uptake, discontinuation and variation of active surveillance (AS) by provider and patient level characteristics. This observational, population-based study used linked administrative databases and pathology reports to identify all men diagnosed with Gleason score ≤6 prostate cancer (PC) between January 1, 2008 and December 31, 2014 in Ontario, Canada. The Cochran-Armitage test was used for AS trend over time. Treatment-free survival was estimated using cumulative incidence function. Factors associated with discontinuation of AS were evaluated using Cox proportional hazard models. Active surveillance was the initial management strategy for 8,541 cases (51%). Use of AS significantly increased from 38% in 2008 to 69% in 2014 (p=0.001). Men on AS were significantly older (64 years, SD 8.0) than those on initial treatment (62 years, SD 7.7; p=0.001). After a median followup of 48 months, 4,337 (51%) patients had discontinued AS. Treatment-free survival for AS patients at 1, 3, and 5 years were 85%, 58% and 52%, respectively. Median time to definitive treatment after initial AS was 16 months (IQR 11-25 months). Factors associated with AS discontinuation were younger age at diagnosis, year of diagnosis, higher comorbidities, treatment at academic center, treatment by physician and institution in the highest volume tertile, and adverse cancer-specific characteristics (higher prostate specific antigen [PSA], higher number of positive cores and higher percentage of core involvement at diagnosis). Although the uptake of AS significantly increased over time, there has been a relatively high rate of discontinuation over 5 years. Factors associated with transition to definitive treatment were younger age, care provided by higher volume physicians and institutions, higher PSA and greater PC volume at diagnosis. These results may help guide policy making, developing quality indicators, and developing targeted continued education for physician and patients embarking on AS to establish realistic expectations.

A population-based survey of patients’ experiences with teleconsultations in cancer care in Denmark during the COVID-19 pandemic

Background During the COVID-19 pandemic, teleconsultations (TC) have been increasingly used in cancer care as an alternative to outpatient visits. We aimed to examine patient-related and cancer-specific characteristics associated with experiences with TC among patients with cancer during the COVID-19 pandemic. Material and methods This population-based survey included patients with breast, lung, gastrointestinal, urological, and gynaecological cancers with appointments in the outpatient clinics, Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Denmark in March and April 2020. Age- and sex-adjusted logistic regression analyses were used to study associations of sociodemographics, cancer and general health, anxiety, and health literacy with patients’ experiences of TC in regards to being comfortable with TC, confident that the doctor could provide information or assess symptoms/side effects and the perceived outcome of TC. Results Of the 2119 patients with cancer receiving the electronic survey, 1160 (55%) participated. Two thirds of patients (68%) had consultations with a doctor changed to TC. Being male, aged 65–79 years, and having TC for test results were statistically significantly associated with more comfort, confidence, and perceived better outcome of TC. Having breast cancer, anxiety, low health literacy, or TC for a follow-up consultation were statistically significantly associated with less positive experiences with TC. Living alone, short education, disability pension, and comorbidity were statistically significantly associated with anxiety and low health literacy. Conclusions Most patients reported positive experiences with TC, but in particular patients with anxiety and low health literacy, who were also the patients with fewest socioeconomic and health resources, felt less comfortable and confident with and were more likely to perceive the outcome negatively from this form of consultation. TC may be suitable for increasing integration into standard cancer care but it should be carefully planned to meet patients’ different information needs in order not to increase social inequality in cancer.

Prognostic and predictive value of ALDH1, SOX2 and SSEA-4 in bladder cancer

Transurethral resection of bladder tumor (TUR-BT) and radical cystectomy (RC) are standard treatment options for bladder cancer (BC). Neoadjuvant chemotherapy (NAC) prior to RC improves outcome of some patients but currently there are no valid biomarkers to identify patients who benefit from NAC. Presence of cancer stem cells (CSC) has been associated with poor outcome and resistance to chemotherapy in various cancers. Here we studied the expression of stem cell markers ALDH1, SOX2 and SSEA-4 with immunohistochemistry in tissue microarray material consisting of 195 BC patients treated with RC and 74 patients treated with TUR-BT followed by NAC and RC. Post-operative follow-up data of up to 22 years was used. Negative to weak cytoplasmic SOX2 staining was associated with lymphovascular invasion and non-organ confined disease. It was also associated with shortened cancer-specific survival, but the finding was not statistically significant. Contrary to previous reports, none of the other tested biomarkers were associated with cancer-specific mortality or clinicopathological characteristics. Neither were they associated with response to NAC. Despite the promising results of previously published studies, our results suggest that CSC markers ALDH1, SOX2 and SSEA-4 have little if any prognostic or predictive value in BC treated with RC.

The Current Evidence for Factors that Influence Treatment Decision Making in Localized Kidney Cancer: A Mixed Methods Systematic Review.

With a growing number of treatment options for localized kidney cancer, patients and health care professionals have both the opportunity and the burden of selecting the most suitable management option. This mixed method systematic review aims to understand the barriers and facilitators of the treatment decision making process in localized kidney cancer. We searched PubMed®, Embase® and Cochrane Central databases between January 1, 2004 and April 23, 2020 using the Joanna Briggs Manual for Evidence Synthesis and the Preferred Reporting Items for Systematic Review and Meta-analysis statement. We identified 553 unique citations; of these, 511 were excluded resulting in 42 articles included for synthesis. The Purpose, Respondents, Explanation, Findings and Significance and the Strengthening the Reporting of Observational Studies in Epidemiology checklist was applied. The key themes describing barriers and facilitators to treatment decision making were identified and categorized into 3 domains: 1) kidney cancer specific characteristics, 2) decision maker related criteria and 3) contextual factors. The main facilitators identified within these domains were size at diagnosis, age, comorbidities, body mass index, gender, nephrometry scoring systems, biopsy, socioeconomic status, family history of cancer, year of diagnosis, geographic region and practice pattern. The key barriers were race, gender, patient anxiety, low confidence in diagnostic and treatment options, cost of procedure, and practice patterns. Future interventions designed to improve the decision making process for localized kidney cancer should consider these barriers and facilitators to ensure a better patient experience.

PCN327 THE IMPORTANCE OF MEASURING HEALTH-RELATED QUALITY OF LIFE IN ROUTINE CANCER CARE FOR OLDER PATIENTS WITH BLADDER CANCER

Health-related quality of life (HRQoL) outcome can be used to monitor health and well-being and is one of the important outcomes that may predict overall survival (OS) in cancer patients. This study examined the association of OS and HRQoL measured before (T0), after cancer diagnosis (T1), and HRQoL changes from T0 to T1 (T1-T0) in patients diagnosed with bladder cancer (BC). This longitudinal retrospective cohort study used the 1998-2013 Surveillance, Epidemiology and End Results (SEER) database linked with Medicare Health Outcomes Survey (MHOS). HRQoL was measured using the SF-36 (1998-2005)/Veterans Rand-12 (2006 onwards) and reported as physical (PCS), mental (MCS) component scores, and 8 domain scores. Adjusted hazard ratios (aHRs [95%CI]) were estimated using multivariable logistic regression models, adjusting for demographics, comorbidities, and cancer specific characteristics. 438 BC patients aged ≥65 years who had HRQoL data at both T0 and T1 were identified. Among those, 220 (50.2%) died and 218 (49.8%) remained alive (censored). Compared to deceased patients, the censored patients were younger (75.3±6.0 vs. 77.2±6.8 years; p<0.01), had longer OS (90.4±39.9 vs. 67.9±42.0 months; p<0.001), had a lower-stage tumor at diagnosis (p<0.001), and had non-invasive tumors (p<0.01). Risk of death was negatively associated with increased PCS at T0 and T1 (aHRT0=0.984 [0.970-0.998] and aHRT1=0.976 [0.962-0.990], respectively). At T1, 6 out of 8 domain scores were also significantly associated with OS. However, PCST1-T0 and MCS at T0, T1, and T1-T0 were not associated with risk of death. We found that PCS was significantly associated with OS in older BC patients in our sample, which implies that older BC patients with better physical health are more likely to survive longer. Therefore, if HRQoL is measured in a routine cancer care, clinicians will be able to intervene early in order to improve or maintain patient’s physical health.

Abstract P4-09-09: Characteristics of stage 1 to 3 breast cancer patients with amplification of centromere of chromosome 17

Abstract Background: Amplification of the centromeric region of chromosome 17 (CEP17) as measured by In Situ Hybridization (ISH) of the CEP17 probe is used clinically as part of the ISH assay for HER2 status determination in breast cancer. The value of amplification of CEP17 beyond its use in the HER2 ISH test and characteristics of cases bearing CEP17 amplification, have not been fully explored. Methods: A retrospective review of charts of patients with stage 1 to 3 breast cancer that had a dual probe HER2/ CEP17 FISH test in our cancer center during an eight-year period was performed. Data on demographic, and cancer-specific characteristics of the included patients were extracted. The group of patients with an amplified CEP17 defined as mean copy number ≥3 per nucleus was compared with the group without amplification. Results: Two hundred and two patients were included in the analysis. Amplification of CEP17 was observed in 36 patients (17.8%). All patients in the amplified group had a concomitant amplification of HER2 (mean copy number ≥3 per nucleus). In the CEP17 non-amplified group 78 of 166 patients (47%) had an amplified HER2 status. More patients in the amplified group had a clinical HER2+ status according to the 3-protein classifier (33.3% versus 11.5% in the non-amplified group) and less patients in the amplified group had a clinical ER+/ HER2- status (63.9% versus 81.8% in the non-amplified group, x2 p=0.0003). Other significant differences between the amplified and CEP17 non-amplified groups were observed in their lymph node (LN) status (55.6% of patients in the amplified group versus 36.8% in the non-amplified group were lymph node positive, p= 0.04) and in the nuclear heterogeneity component of grade (90.9% of patients in the amplified group were nuclear grade 3 versus 66.9% in the non-amplified group, p= 0.02). There were no statistically significant differences between the groups in overall stage, grade, menopause status or histology. Conclusion: Patients with amplification of CEP17 had a co-amplified HER2 and were more commonly HER2+, LN positive and grade 3 in the nuclear component of grade. Citation Format: Ioannis Voutsadakis, Vanessa Davies. Characteristics of stage 1 to 3 breast cancer patients with amplification of centromere of chromosome 17 [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 P4-09-09.

Amplification of Chromosome 17 Centromere (CEP17) in Breast Cancer Patients with a Result of HER2 2± by Immunohistochemistry

Background: Amplification of the centromeric region of chromosome 17 (CEP17) as measured by In Situ Hybridization (ISH) of the CEP17 probe is used clinically as part of the ISH assay for HER2 status determination in breast cancer. The value of amplification of CEP17 beyond its use in the HER2 ISH test has not been fully explored.Methods: A retrospective review of patients with breast cancer that had a dual probe HER2/CEP17 FISH test during an eight-year period was performed. Data on demographic and cancer-specific characteristics of the included patients were extracted. The group of patients with an amplified CEP17 defined as mean copy number of ≥3 per nucleus was compared with the group without amplification.Results: Two hundred and twelve patients were eligible and included in the analysis. Amplification of CEP17 was observed in 39 patients (18.4%). All patients in the amplified group had a concomitant amplification of HER2 (mean copy number ≥3 per nucleus). In the CEP17 non-amplified group 82 of 172 patients (47.7%) had an amplified HER2 status. More patients in the amplified group had a clinical HER2+ status according to the 3-protein classifier (30.8% versus 12.3% in the non-amplified group) and fewer patients in the amplified group had a clinical ER+/HER2- status (66.7% versus 81.3% in the non-amplified group, x2 p = .01). Other significant differences between the amplified and CEP17 non-amplified groups were observed in their lymph node (LN) status (56.4% of patients in the amplified group versus 38.8% in the non-amplified group were lymph node positive, p = .04) and in the nuclear heterogeneity component of grade (91.2% of patients in the amplified group were nuclear grade 3 versus 67.1% in the non-amplified group, p = .005). There were no statistically significant differences between the groups in overall stage, grade, menopause status or histology. Recurrence Free Survival (RFS) was shorter in stage I to III patients with an amplified CEP17 compared with the non-amplified group.Conclusion: Patients with amplification of CEP17 had a co-amplified HER2 and were more commonly HER2+, LN positive and grade 3 in the nuclear component of grade.

The biological implications of Yin Yang 1 in the hallmarks of cancer.

Tumorigenesis is a multistep process characterized by the acquisition of genetic and epigenetic alterations. During the course of malignancy development, tumor cells acquire several features that allow them to survive and adapt to the stress-related conditions of the tumor microenvironment. These properties, which are known as hallmarks of cancer, include uncontrolled cell proliferation, metabolic reprogramming, tumor angiogenesis, metastasis, and immune system evasion. Zinc-finger protein Yin Yang 1 (YY1) regulates numerous genes involved in cell death, cell cycle, cellular metabolism, and inflammatory response. YY1 is highly expressed in many cancers, whereby it is associated with cell proliferation, survival, and metabolic reprogramming. Furthermore, recent studies also have demonstrated the important role of YY1-related non-coding RNAs in acquiring cancer-specific characteristics. Therefore, these YY1-related non-coding RNAs are also crucial for YY1-mediated tumorigenesis. Herein, we summarize recent progress with respect to YY1 and its biological implications in the context of hallmarks of cancer.

Prognostic factors for rural endometrial cancer patients in a population-based cohort

BackgroundEndometrial cancer is the second most common cancer among female cancer survivors in the US and is increasing in incidence. Rural endometrial cancer patients experience lower survival rates but the reasons for the lower survival are not known. The aim of this study is to examine whether prognostic factors are different for rural and urban patients in a population-based cohort.MethodsEndometrial cancer patients diagnosed 1997-2012 were identified through the Utah Cancer Registry and Utah Population Database. The address at cancer diagnosis was used to classify patients in rural or urban residences. Demographic and cancer-specific characteristics were examined as prognostic factors for both all-cause and endometrial cancer-specific mortality using Cox proportional hazards models.ResultsThere were 2,994 endometrial cancer patients and 14.1% of these patients lived in rural areas at diagnosis. Rural endometrial cancer patients were older at cancer diagnosis and did not appear to be different in terms of obesity or overweight at cancer diagnosis. There were no differences for treatment or stage at diagnosis although rural patients had higher proportions of higher grade. Age at diagnosis, poverty, education, and histology were significant prognostic factors for all-cause death. Rural patients with more advanced stages of cancer had significantly increased risks of all-cause and endometrial cancer-specific death than urban patients. Rural endometrial cancer patients diagnosed at advanced stage had a 17-fold increase in the risk of all-cause death compared to an 8-fold increase in death for urban patients.ConclusionsRural endometrial cancer patients in Utah were older at diagnosis, had higher grade and higher comorbidities. While urban and rural endometrial cancer patients shared many prognostic factors, the risk of mortality is greater among rural patients with advanced stage endometrial cancer. Future studies should examine where patients are receiving treatment and how that impacts their survival and how to reduce the mortality rates of high risk patients.

Network analysis of aging acceleration reveals systematic properties of 11 types of cancers.

Cancers are known to be associated with accelerated aging, but to date, there has been a paucity of systematic and in‐depth studies of the correlation between aging and cancer. DNA methylation (DNAm) profiles can be used as aging markers and utilized to construct aging predictors. In this study, we downloaded 333 paired samples of DNAm, expression and mutation profiles encompassing 11 types of tissues from The Cancer Genome Atlas public access portal. The DNAm aging scores were calculated using the Support Vector Machine regression model. The DNAm aging scores of cancers revealed significant aging acceleration compared to adjacent normal tissues. Aging acceleration‐associated mutation modules and expression modules were identified in 11 types of cancers. In addition, we constructed bipartite networks of mutations and expression, and the differential expression modules related to aging‐associated mutations were selected in 11 types of cancers using the expression quantitative trait locus method. The results of enrichment analyses also identified common functions across cancers and cancer‐specific characteristics of aging acceleration. The aging acceleration interaction network across cancers suggested a core status of thyroid carcinoma and neck squamous cell carcinoma in the aging process. In summary, we have identified correlations between aging and cancers and revealed insights into the biological functions of the modules in aging and cancers.