Unfavorable Tumor Characteristics Research Articles

Cryoablation of Primary Breast Cancer in Patients Ineligible for Clinical Trials: A Multiinstitutional Study.

BACKGROUND. Breast cancer cryoablation clinical trials have strict inclusion criteria that exclude patients with potentially treatable disease. OBJECTIVE. The purpose of this study was to evaluate the safety and outcomes of breast cancer cryoablation without surgical excision in patients ineligible for prospective cryoablation clinical trials due to unfavorable patient or tumor characteristics. METHODS. This retrospective study included women who underwent cryoablation of biopsy-proven unifocal primary breast cancer with locally curative intent, without surgical excision, despite being ineligible for (and thus excluded from) cryoablation clinical trials, across seven institutions between January 1, 2000, and August 26, 2021. Adverse events (AEs) were recorded. Cryoablation procedures were classified as technically successful if they were not prematurely terminated and achieved intended treatment parameters and if the first follow-up imaging examination showed no evidence of residual disease. The results of follow-up biopsies were recorded. Ipsilateral breast tumor recurrences (IBTRs) diagnosed during follow-up were identified and classified as true recurrence or new primary disease. A competing-risk model was used to estimate the cumulative incidence of IBTR accounting for death before IBTR as a competing risk. RESULTS. The final study sample included 112 patients (median age, 71 years). A total of seven of 112 (6.3%) patients had a minor AE; no moderate or major AEs occurred. A total of 110 of 112 cryoablation procedures (98.2%) were technically successful. During a median follow-up of 2.0 years, 22 of 110 patients (20.0%) underwent biopsy for suspicious imaging findings in the ipsilateral breast, which yielded benign concordant findings in nine of 22 patients (40.9%) and IBTR in 12 of 22 patients (54.5%). Overall, 12 of 110 patients (10.9%) experienced IBTR, including seven with true recurrence and five with new primary disease; three of 12 patients (25.0%) with IBTR had received earlier adjuvant or neoadjuvant therapy. When death was accounted for as a competing risk, the cumulative incidence of IBTR was 5.3%, 12.2%, and 18.2% at 1, 2, and 3 years, respectively. CONCLUSION. In select individuals with unfavorable patient or tumor characteristics, breast cancer cryoablation provides a safe alternative to surgery and has good outcomes. These findings may be particularly relevant in patients who are also poor surgical candidates. CLINICAL IMPACT. Breast cancer cryoablation can be safely applied in a larger patient populations than those defined by clinical trial inclusion criteria.

The Impact of the Coexpression of MET and ESR Genes on Prognosticators and Clinical Outcomes of Breast Cancer: An Analysis for the METABRIC Dataset

Purpose. Breast cancer is a heterogeneous disease. Exploring new prognostic and therapeutic targets in patients with breast cancer is essential. This study investigated the expression of MET, ESR1, and ESR2 genes and their association with clinicopathologic characteristics and clinical outcomes in patients with breast cancer. Methods. The METABRIC dataset for breast cancer was obtained from the cBioPortal public domain. Gene expression data for MET, ESR1, and ESR2, as well as the putative copy number alterations (CNAs) for MET were retrieved. Results. The MET mRNA expression levels correlated inversely with the expression levels of ESR1 and positively with the expression levels of ESR2 (r = −0.379, p<0.001 and r = 0.066, and p=0.004, respectively). The ESR1 mRNA expression was significantly different among MET CNAs groups p<0.001. Patients with high MET/ESR1 coexpression had favorable clinicopathologic tumor characteristics and prognosticators compared to low MET/ESR1 coexpression in terms of greater age at diagnosis, reduced Nottingham Prognostic Index, lower tumor grade, hormone receptor positivity, HER2-negative status, and luminal subtype p<0.001. In contrast, patients with high MET/ESR2 coexpression had unfavorable tumor features and advanced prognosticators compared to patients with low MET/ESR2 coexpression p<0.001. No significant difference in overall survival was observed based on the MET/ESR coexpression status. However, when data were stratified based on the treatment type (chemotherapy and hormonal therapy), survival was significantly different based on the coexpression status of MET/ESR. Conclusions. Findings from our study add to the growing evidence on the potential crosstalk between MET and estrogen receptors in breast cancer. The expression of the MET/ESR genes could be a novel prognosticator and calls for future studies to evaluate the impact of combinational treatment approaches with MET inhibitors and endocrine drugs in breast cancer.

Abstract PS13-04: Frequent Intra-Tumoral Hypoxia in Pregnancy-Associated Breast Cancer

Abstract Rationale: Breast cancer is the most common malignancy in pregnant women, occurring in approximately 1:3000 pregnancies. Breast cancer diagnosed during pregnancy or after childbirth is also known as Pregnancy-Associated Breast Cancer (PABC). PABC is known for exhibiting several unfavorable prognostic tumor characteristics, such as an advanced tumor stage at diagnosis, high histologic grade and frequent hormone receptor negativity. Most probably, several interplaying mechanisms may promote the tumor progression and adverse clinical outcome of PABC. One of these mechanisms may be the presence of hypoxia, a relative state of low intra-tumoral oxygen levels which is a known marker of adverse outcome in breast cancer. However, the occurrence and prognostic consequences of the presence of intra-tumoral hypoxia in PABC have not been studied yet. Methods: We constructed a cohort with histopathological, clinical, and outcome data of patients diagnosed with breast cancer during pregnancy (PrBC) or within one year after childbirth (PPBC) in the Netherlands between 1988 and 2022. Next, tissue blocks of all patients were collected from the participating Dutch pathology laboratories. Using H&E stained slides of the tumor tissue blocks, we selected suitable donor sites for a tissue micro array (TMA). Slides from these TMAs were stained for three important hypoxia-associated proteins: glucose transporter-1 (Glut-1), carbonic anhydrase IX (CAIX) and hypoxia-inducible factor-1α (HIF-1α). Expression was scored by an expert breast pathologist blinded by clinicopathologic data. Results: For a total of 195 PrBC and PPBC patients, we were able to assess the expression of Glut-1, CAIX and HIF-1α on tumor cells. Patients had a median age of 33 years at diagnosis, whilst a large majority had a Bloom & Richardson grade III tumor (76%) with frequent hormone receptor negativity (50%). Expression of hypoxia-associated proteins was frequent, with 61% of the tumors expressing Glut-1, 30% expressing CAIX and 56% expressing HIF-1α. In total, 153 (78%) of the tumors expressed at least one of the hypoxia-associated proteins. We observed a significantly worse 5-year overall survival for patients with intra-tumoral hypoxia in comparison to patients without intra-tumoral hypoxia (70% vs. 90%, p=0.046). Conclusions: We show that the presence of intra-tumoral hypoxia in PABC is common, with 78% of tumors expressing at least one of the studied hypoxia-associated proteins. Importantly, patients with tumors overexpressing hypoxia-markers have a significantly worse survival. This shows that intra-tumoral hypoxia may be an important underlying carcinogenic mechanism in PABC, and might be a promising novel therapeutic target in this patient group. Citation Format: Carsten Bakhuis, Carmen Van Dooijeweert, Britt Suelmann, Pieter Westenend, Sabine Linn, Elsken Van der Wall, Paul Van Diest. Frequent Intra-Tumoral Hypoxia in Pregnancy-Associated Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-04.

Abstract PS13-01: Worse Prognosis for Breast Cancer in the Second and Third Trimesters and Shortly Postpartum:An Update of the Dutch Pregnancy-Associated Breast Cancer Cohort

Abstract Rationale: Pregnancy-Associated Breast Cancer (PABC), often defined as breast cancer during pregnancy (PrBC) or in the first year postpartum (PPBC), is known for its aggressive histopathology and higher stage at diagnosis. In a previous study of the nationwide Dutch PABC Cohort, we observed an impaired survival for patients diagnosed in the second and third trimester of pregnancy. However, the etiology of these differences, and how this relates to the patients diagnosed with breast cancer in the postpartum period (PPBC) or after an abortion (AABC), remains to be elucidated. While we are exploring the etiologic hypotheses, we updated and expanded our database to compare these specific PABC subgroups. Methods: All pathology reports of invasive breast carcinoma between January 1st 1988 and July 1st 2022 were screened for pregnancy-related keywords to find all patients diagnosed with PrBC, PPBC or AABC within one year after childbirth or an interrupted pregnancy (induced abortion or miscarriage before a gestational age of 24 weeks). A local patient series provided 22 additional cases. Pregnant patients were subdivided by gestational trimester at time of diagnosis. The different PrBC, PPBC and AABC subgroups were compared by histopathology, clinical characteristics and outcome. Results: 787 patients were included, of whom 60% were pregnant during their diagnosis. Median age at diagnosis was 34 years. In line with our previous findings, a large majority (68%) of patients had a Bloom & Richardson (B&R) grade III tumor and 37% of tumors were triple negative. Moreover, over a third of patients presented with lymph node metastases (38%). We observed two distinct groups based on histopathology and prognosis: group A, consisting of three patient groups: (I) patients diagnosed in the first trimester of pregnancy, (II) patients diagnosed between 6-12 months postpartum, and (III) patients diagnosed after an abortion, and group B, consisting of two patient groups, (I) patients diagnosed in the second or third trimester of pregnancy or (II) within 6 months after childbirth. Compared to group A, patients in group B more often had B&R grade III tumors: (73% vs. 60%, p=0.002) and more frequently had triple negative tumors (43% vs. 28% in group A, p< 0,001). Survival was significantly worse for patients in group B (5-year OS 67,3% versus 88.2%, p< 0.001). In a multivariable analysis, corrected for grade, type of surgery and overall stage, these differences upheld with an HR of 1.515 (95% CI 1,012 – 2,268). Conclusions: With this extensive update of our nationwide Dutch PABC cohort, we show that especially PrBC patients diagnosed in the second and third trimesters and PPBC patients within six months after childbirth exhibit unfavorable tumor characteristics, with an associated worse prognosis. This highlights the need for in-depth analyses in these specific groups of PABC patients to elucidate the etiologic mechanisms involved. Citation Format: Carsten Bakhuis, Carmen Van Dooijeweert, Britt Suelmann, Janneke Verloop, Pieter Westenend, Sabine Linn, Paul Van Diest, Elsken Van der Wall. Worse Prognosis for Breast Cancer in the Second and Third Trimesters and Shortly Postpartum:An Update of the Dutch Pregnancy-Associated Breast Cancer Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-01.

Abstract 2509: Abundant glucocorticoid receptor (GR) expression in human tumors: A tissue microarray study on more more than 18,000 tumors

Abstract The glucocorticoid receptor (GR, or GCR) is a nuclear receptor protein for cortisol and other glucocorticoids and regulates the transcription of thousands of genes involved in metabolism, development, stress, and inflammatory response. In cancer, both an oncogenic and a tumor suppressive function of GR has been proposed. To comprehensively evaluate GR expression in normal and tumorous tissues, a tissue microarray containing 18,570 samples from 147 different tumor types and subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC). GR positivity was found in 76.3% of 14,349 interpretable cancers, including 18.5% with weak, 19.6% with moderate, and 38.3% with strong positivity. GR positivity of at least a fraction of tumors was found in all 147 analyzed tumor types and at least one strongly GR positive tumor was found in 136 tumor types. 77 of our 147 tumor entities showed GR positivity of variable intensity in all analyzed cases. 43 further tumor entities showed GR positivity in 80-99.9% of cases. 21 tumor entities had a GR positivity rate between 50 and 80%, including urothelial carcinoma as well as gastric and esophageal adenocarcinoma. Only 6 tumor types had less than 50% GR positive. These included adenomas (21.7-32.5%), adenocarcinomas (17%) and neuroendocrine carcinomas (45.5%) of the colorectum. Reduced GR staining was significantly associated with adverse histopathological and clinical features in several tumor types. Low GR expression was linked to grade progression in pTa (p<0.0001) and to nodal metastasis in pT2-4 urothelial carcinoma of the urinary bladder (p=0.0051), advanced pT stage (p=0.0006) and estrogen receptor positivity (p=0.0126) in breast carcinomas of no special type (NST), as well as to high grade (p≤0.0076), advanced pT stage (p<0.0001), distant metastasis (p=0.0081), and poor overall survival (p=0.002) in clear cell renal cell carcinoma. GR expression was unrelated to clinic-pathological parameters in gastric, pancreatic, and colorectal adenocarcinoma as well as in serous high-grade carcinoma of the ovary. In summary, our data demonstrate frequent GR expression across all cancer types. Significant associations between reduced GR expression and unfavorable tumor features in some but not all tumor types suggest that the functional importance of GR regulated genes for cancer progression depends on the cell of tumor origin. Citation Format: Christina Tsourlakis, Frederike Wegener, Katharina Möller, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Guido Sauter, Andreas H. Marx, Ronald Simon, Till Krech, Christoph Fraune, Natalia Gorbokon, Maximilian Lennartz, Sarah Minner, Florian Viehweger. Abundant glucocorticoid receptor (GR) expression in human tumors: A tissue microarray study on more more than 18,000 tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2509.

Stromal Type I Collagen in Breast Cancer: Correlation to Prognostic Biomarkers and Prediction of Chemotherapy Response

IntroductionFibrillar collagens accumulate in the breast cancer stroma and appear as poorly defined spiculated masses in mammography imaging. The prognostic value of tissue type I collagen remains elusive in treatment-naïve and chemotherapy-treated breast cancer patients. Here, type I collagen mRNA and protein expression were analysed in 2 large independent breast cancer cohorts. Levels were related to clinicopathological parameters, prognostic biomarkers, and outcome. MethodCOL1A1 mRNA expression was analysed in 2509 patients with breast cancer obtained from the cBioPortal database. Type I collagen protein expression was studied by immunohistochemistry in 1395 women diagnosed with early invasive breast cancer. ResultsLow COL1A1 mRNA and protein levels correlated with poor prognosis features, such as hormone receptor negativity, high histological grade, triple-negative subtype, node positivity, and tumour size. In unadjusted analysis, high stromal type I collagen protein expression was associated with improved overall survival (OS) (HR = 0.78, 95% CI = 0.61-0.99, p = .043) and trended towards improved breast cancer–specific survival (BCSS) (HR = 0.65, 95% CI = 0.42-1.01, P = 0.053), although these findings were lost after adjustment for other clinical variables. In unadjusted analysis, high expression of type I collagen was associated with better OS (HR = 0.70, 95% CI = 0.55-0.90, P = .006) and BCSS (HR = 0.55, 95% CI = 0.34-0.88, P = .014) among patients not receiving chemotherapy. Strikingly, the opposite was observed among patients receiving chemotherapy. There, high expression of type I collagen was instead associated with worse OS (HR = 1.83, 95% CI = 0.65-5.14, P = .25) and BCSS (HR = 1.72, 95% CI = 0.54-5.50, P = .357). ConclusionLow stromal type I collagen mRNA and protein expression are associated with unfavourable tumour characteristics in breast cancer. Stromal type I collagen might predict chemotherapy response.

BRAF Expression and Copy Number Alterations Predict Unfavorable Tumor Features and Adverse Outcomes in Patients With Breast Cancer.

Background: The role of BRAF in breast cancer pathogenesis is still unclear. To address this knowledge gap, this study is aimed at evaluating the impact of BRAF gene expression and copy number alterations (CNAs) on clinicopathologic characteristics and survival in patients with breast cancer. Methods: The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset was obtained from the cBioPortal public domain. Tumoral BRAF mRNA expression and CNAs along with demographic and tumor data for patients with breast cancer were retrieved. The association of BRAF expression and CNAs with breast cancer clinicopathologic characteristics was analyzed. The impact of BRAF mRNA expression on the overall survival of patients was assessed using Kaplan-Meier survival analysis. Results: BRAF gene mRNA log intensity expression was positively correlated with tumor size and the Nottingham Prognostic Index (NPI) (p < 0.001). Alternatively, BRAF gene expression was negatively correlated with the age at diagnosis (p = 0.003). The average BRAF mRNA expression was significantly higher in premenopausal patients, patients with high tumor grade, hormone receptor-negative status, and non-luminal tumors compared to postmenopausal patients, patients with low-grade, hormone receptor-positive, and luminal disease. BRAF gain and high-level amplification copy numbers were significantly associated with higher NPI scores and larger tumor sizes compared to neutral copy number status. Survival analysis revealed no discernible differences in overall survival for patients with low and high BRAF mRNA expression. Conclusion: High BRAF mRNA expression as well as the gain and high-level amplification copy numbers were associated with advanced tumor characteristics and unfavorable prognostic factors in breast cancer. BRAF could be an appealing target for the treatment of premenopausal patients with hormone receptor-negative breast cancer.

Clinical value of preoperative serum tumor markers CEA, CA19-9, CA125, and CA15-3 in surgically treated urachal cancer.

Urachal adenocarcinoma (UrAC) is a very rare malignancy with a poor prognosis. The role of preoperative serum tumor markers (STMs) in UrAC is unknown. The aim of this study was to assess the clinical value of elevated STMs including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), cancer antigen 125 (CA125), and cancer antigen 15-3 (CA15-3) in surgically treated UrAC, and to evaluate their prognostic significance. This was a retrospective study of consecutive patients with histopathologically confirmed UrAC who underwent surgical treatment at a single tertiary hospital. Blood levels of CEA, CA19-9, CA125, and CA15-3 were determined before surgery. The proportion of patients with elevated STMs was calculated, as well as the association between elevated STMs and clinicopathological characteristics, recurrence-free survival and disease-specific survival. Of the 50 patients included; CEA, CA 19-9, CA125, and CA15-3 were elevated in 40%, 25%, 26%, and 6% respectively. Elevated CEA was associated with higher pT-stage (odds ratio [OR] 3.3 [95% confidence interval 1.0-11.1], P = 0.003), higher Sheldon stage (OR 6.9 [95% CI 0.8-60.4], P = 0.01), male sex (OR 4.7 [95% CI 1.2-18.3], P = 0.01), and the presence of peritoneal metastases at the time of diagnosis (OR 3.5 [95% CI 0.9-14.2], P = 0.04). Elevated CA19-9 was associated with signet-cell component (OR 1.7 [95% CI 0.9-3.3], P = 0.03) and elevated CA125 was associated with peritoneal metastases at the time of diagnosis (OR 6.0 [95% CI 1.2-30.6], P = 0.04). Elevated STMs before surgery were not associated with recurrence-free survival and/or disease-specific survival. A subset of patients with surgically treated UrAC has elevated STMs preoperatively. CEA was most frequently (40%) elevated and correlated with unfavorable tumor characteristics. However, STM levels did not correlate with prognostic outcomes.

Characteristics of breast cancers detected by screening mammography in Taiwan: a single institute’s experience

Background/aimBreast cancer is the most common female malignancy in the world. Nearly ninety percent of screening-detected breast cancers were diagnosed with earlier stages of 0 to II in Taiwan. It’s widely acknowledged that mammography screening of breast cancer can achieve the goal of early diagnosis and treatment in terms of preventive task while neglected interval cancers are associated with unfavorable tumor characteristics and worse outcomes. The purpose of this study was to explore the characteristics of screening-detected breast cancers in Taiwan.Materials and methodsBoth screening and diagnostic mammography examinations with accompanied BI-RADS (breast imaging-reporting and data system) classification were extracted from the health information system and linked to cancer registry in Taiwan. Enrolled population included those attending their first mammography between 2012 and 2016, excluding subjects with previous breast cancer, or with missing or incomplete data. We compared treatment outcomes between breast cancers with either initial screening or diagnostic mammography (control group), and investigated the compositions of breast cancers detected by screening mammography through direct chart reviews.ResultsA total of 84,246 screening and 61,230 diagnostic mammography sessions were performed from 2010 to 2020. More positive results (BI-RADS 0, 3, 4 and 5) were observed for those attending the first diagnostic than the first screening mammography (43.58% versus 16.12%, p < 0.001). Earlier stages (0 and I) distribution (92% versus 81%, p < 0.0001), better survivorship (overall survival: 96.91% versus 92.17%, p = 0.007) and a lower HER2 (human epidermal growth factor receptor II) positive status and lower tumor grade were noted in breast cancers with initial screening rather than diagnostic mammography. Among 26,103 mammography screening invitees between 2012 and 2016, 325 breast cancers were ascertained from cancer registry. Of these, 234 had one, 72 had two and 19 had three episodes of mammography before cancer diagnosis. Extensive chart reviews revealed that women with and without breast symptoms constituted 29.9 and 70.1% of the 325 screening-detected breast cancers, with the latter further divided into false negative results (interval cancer), diagnosed at the first mammography, diagnostic at the secondary or subsequent mammography and those with a delayed biopsy or confirmatory imaging constituted (5.2, 47, 10.5 and 7.4%).ConclusionScreening-detected breast cancers were a mixture of women with and without symptoms, those with a false negative result, true negative results with cancer detected at subsequent mammography and non-adherers. Despite this, efficacy of mammography screening was ascertained in Taiwan from this study. To further enhance earlier detection and decrease false negativity, the impact of repeated mammography, and additional sonography for symptomatic women, compliance following a positive screening mammography should not be overemphasized.

The effect of attendance in the Dutch breast cancer screening program on breast tumor characteristics among migrant women.

In general, migrant women have a lower breast cancer (BC) incidence rate and higher BC mortality than autochthonous women. Further, migrant women show lower participation in the national BC screening program. To further investigate those aspects, we aimed to determine differences in incidence and tumor characteristics between autochthonous and migrant BC patients in Rotterdam, the Netherlands. We selected women diagnosed with BC in Rotterdam during 2012-2015 from the Netherlands Cancer Registry. Incidence rates were calculated by migrant status (i.e., women with or without migration background). Multivariable analyses revealed adjusted odds ratios (OR) and 95% confidence intervals (CI) on the association between migration status and patient and tumor characteristics, additionally stratified by screening attendance (yes/no). In total 1372 autochthonous and 450 migrant BC patients were included for analysis. BC incidence was lower among migrants than among autochthonous women. Overall, migrant women were younger at BC diagnosis (53 vs. 64 years, p<0.001), and had higher risks of positive lymph nodes (OR 1.76, 95% CI 1.33-2.33) and high grade tumors (OR 1.35, 95% CI 1.04-1.75). Especially non-screened migrant women had higher risk of positive nodes (OR 2.73, 95% CI 1.43-5.21). Among the subgroup of screened women, we observed no significant differences between migrant and autochthonous patients. Migrant women have lower BC incidence than autochthonous women, but diagnosis was more often at younger age and with unfavorable tumor characteristics. Attending the screening program strongly reduces the latter. Therefore, promotion of participation in the screening program is recommended.

Prognostic significance of estrogen receptor status in de novo metastatic breast cancer.

e13049 Background: The clinical behaviors of de novo metastatic breast cancer (dnMBC) differ according to hormone receptor (HR) status, but an association between estrogen receptor (ER) expression and clinical outcomes has not been established. Our study aimed to investigate the influence of different ER status on survival outcomes for patients with dnMBC. This study was the Medical Science Research Project of Hebei Province and approved by the Ethics Committee of the Ethics Committee of Cangzhou Clinical College of Integrated Traditional Chinese and Western Medicine of Hebei Medical University (NO. 2017-AF29-058). Methods: Using hospital-based database, we identified patients with dnMBC diagnosed between 2010 and 2017, retrospectively collecting demographic data, tumor characteristics, treatment types and survival data. According to ER status, the patients were divided into ER-negative and ER-positive groups, and the propensity score matching (PSM) was used to balance the mixed bias. Overall survival (OS) was estimated by Kaplan-Meier method and log rank test. Univariable and multivariable analyses were performed using the Cox proportional hazard model to identify statistically significant prognostic factors. Results: A total of 322 patients were included. The median age was 53 (21-82) years, and the median follow-up was 8.5 years. The median OS for the PSM cohort was 29 months (95% confidence interval [CI], 26-35 months), and 5-year OS was 18.9%. OS differed significantly between the two groups (p = 0.0012), with a median OS of 36 months (95% CI, 32-41 months) in ER-positive group and 24 months (95% CI, 19-27 months) in ER-negative group. Multivariate analysis showed that clinical T-stage and initial metastatic sites were independent prognostic factors for survival in patients focused on ER status, with Ki-67 index, endocrine therapy and radiotherapy added to the ER-positive group, while initial and advanced chemotherapy added to the ER-negative group. Conclusions: For patients with dnMBC, there were substantial differences in OS according to ER status. ER-negative subtype is clinically different from ER-positive subtype, showing unfavorable tumor characteristics and poorer OS. We identified several prognostic factors that could guide therapy selection in this patient population. Clinical trial information: 20210957 .

Elevated serum uric acid is associated with the risk of advanced staging and vascular involvement in patients with hepatoblastoma: a 14-year retrospective study.

Uric acid is the end product of the purine metabolism pathway, and has been linked to cancer risks and prognosis, but its relationship with hepatoblastoma (HB) remains unclear. This study aims to investigate the association between serum uric acid (SUA) and the advanced tumor staging and unfavorable extra-parenchymal tumor characteristics in patients with HB. This study enrolled pediatric patients from Xinhua Hospital between 2007 to 2021.A total of 101 participants with newly diagnosed HB were recruited in the study. PRETreatment EXTent of disease (PRETEXT)/PostTreatment Extent of disease (POSTTEXT) staging were evaluated at diagnosis and following neoadjuvant chemotherapy (NAC). Adjusted smoothing spline plots, subgroup analysis and multivariate logistic regression analysis were conducted to estimate the association of different levels of SUA with the advanced tumor staging and present annotation factors. In accordance with SUA tertiles, those patients with higher pretreatment SUA levels showed increased percentages of PRETEXT group IV, vessel involvement and multifocality of tumors. After fully adjustment with the confounding factors, SUA was positively associated with advanced PRETEXT stage IV (OR: 1.72, 95%CI 1.15-2.57, p=0.0080), as well as vascular invasion (OR: 1.29, 95%CI 1.01-1.64, p=0.0396). Compared with the lowest SUA concentration tertile, the highest tertile were independently associated with vessel involvement of tumor in all of the adjusted models. Following NAC, SUA levels were significantly reduced in response to the downstaging of tumors. SUA remained positively associated with advanced POSTTEXT staging and vessel involvement in adjusted models. Patients with highest tertile of posttreatment SUA showed worse 5-year EFS and OS. Elevated SUA were associated with an increased occurrence of advanced PRETEXT/POSTTEXT staging and unfavorable vessel involvement at diagnosis and following NAC in patients with HB. High posttreatment SUA reflected poor tumor responses to NAC. This study linked SUA, a non-invasive laboratory test, with tumor staging and risk prediction for HB.

Abstract 2212: Prevalence of PGP9.5 expression in human cancers: A TMA study of 14,900 tumors from 148 tumor types

Abstract The ubiquitin C-terminal hydrolase L1 (UCH-L1), also termed protein gene product 9.5 (PGP9.5) is an important component of the ubiquitination/deubiquitination system and plays a role in the posttranslational modification of proteins including protein degradation, relocation and change of function. Altered PGP9.5 expression has been suggested to play a role for resistance to chemotherapy, metastasis, and patient prognosis in several tumor entities. To comprehensively determine PGP9.5 expression in normal and neoplastic tissues, a tissue microarray containing 14,913 samples from 148 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. PGP9.5 immunostaining was found in 2,667 of 11,062 analyzed tumors and considered weak in 9.8%, moderate in 5.8% and strong in 8.5% of tumors. 113 of 148 tumor categories showed at least one positive case, and 90 of these tumor categories contained at least one case with strong PGP9.5 staining. PGP9.5 positivity was most seen in various types of neuronal and neuroendocrine neoplasms (71.1-100%), germ cell neoplasms of the testis (82.1%), and in mesotheliomas (74%). PGP9 positivity was seen in 14.2% of 606 clear cell and in 45.4% of 255 papillary renal cell carcinomas (RCC). In clear cell RCC, strong PGP9.5 staining was associated with high ISUP grade (p&amp;lt;0.0001), pT stage (p=0.0012), nodal (p=0.038) and distant metastasis (p&amp;lt;0.0001) as well as with a shortened overall, tumor specific and recurrence free survival (p&amp;lt;0.0001 each). In papillary RCC, strong PGP9.5 staining was significantly associated with high ISUP grade (p=0.009), advanced UICC stage (p=0.015), and shortened recurrence free survival (p&amp;lt;0.0001). In urothelial carcinoma of the urinary bladder, high PGP9.5 expression was associated with muscle-invasion (p&amp;lt;0.0001) but PGP9.5 immunostaining was unrelated to prognosis in pT2-4 carcinomas. In a joint analysis of 527 squamous cell carcinomas from 11 different sites of origin, PGP9.5 positivity was associated with high tumor grade (p=0.0021). PGP9.5 immunostaining was unrelated to pT and pN status in 207 serous high-grade and 82 endometrioid ovarian carcinoma, in 221 endometrioid endometrium cancer as well as in 292 papillary and in 89 follicular thyroid carcinomas. In ductal adenocarcinomas of the pancreas and in 356 gastric adenocarcinomas, PGP9.5 staining was unrelated to grade, pT and pN stage. Our data provide an overview on prevalence of PGP9.5 expression in cancer. PGP9.5 expression occurs commonly in many different tumor entities. PGP9.5 overexpression is strikingly linked to patient outcome in some tumor entities (i.e. clear cell RCC) but appears to be unrelated to unfavorable tumor characteristics in various other important tumor entities (i.e. gastric, pancreatic, ovarian cancer). Citation Format: Sekander Scherzai, Maximilian Lennartz, Frank Jacobsen, Florian Viehweger, David Dum, Anne Menz, Ria Uhlig, Andrea Hinsch, Doris Hoeflmayer, Christoph Fraune, Christian Bernreuther, Patrick Lebok, Soeren Weidemann, Guido Sauter, Till Sebastian Clauditz, Till Krech, Andreas H Marx, Ronald Simon, Stefan Steurer, Eike Burandt, Natalia Gorbokon, Sarah Minner. Prevalence of PGP9.5 expression in human cancers: A TMA study of 14,900 tumors from 148 tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2212.

Tumor characteristics, therapy, and prognosis in young breast cancer patients ≤ 35years.

Young breast cancer patients aged 35years and younger are a small group of women who tend to present at high-risk form of the disease. More analysis of the data on tumor characteristics, treatment, and survival is necessary to help improving treatment and outcome. In this retrospective study, we compared the clinical and tumor characteristics, the treatments, and the survival of 257 women aged ≤ 35years, with 6566 women aged 50-69years. We used a registry-based data of patients with invasive, non-metastatic breast cancer diagnosed between 2000 and 2015. Young women showed lower rate of hormone receptor (HR) positivity. Their tumors were more often HER2-positive, which showed lower rate of differentiation and higher rate of Ki-67 expression compared to their older counterparts. Women aged 35years and younger were more likely to undergo neoadjuvant therapy and mastectomy. Endocrine therapy was underrepresented in young patients. 5-Year disease-free survival (DFS) was significantly lower in the younger patient group (81.7% vs. 91.3%, p < 0.001), while 5-year overall survival (OS) was not impaired (91.4% vs. 91.1%, p = 0.847). The unfavorable disease-free survival in the group of younger patients might be explained by their unfavorable tumor characteristics. The surgical treatment appears to be more aggressive in young breast cancer patients and is more frequently combined with chemotherapy and immunotherapy, either in a neoadjuvant or in an adjuvant setting.

Clinical, pathological and long-term oncologic outcomes of papillary type I vs. type II renal cell carcinoma.

Despite papillary renal cell carcinoma (pRCC) subtype represents the second most common histological renal tumor, controversial findings have been shown regarding its prognosis. Thus, we investigated the natural history of patients harbouring pRCC, focusing on its clinicopathological characteristics and long-term oncologic outcomes among pRCC subtypes. We identified 447 patients treated with either partial (PN) or radical nephrectomy (RN) for pRCC at a single tertiary centre, between 1994 and 2019. First, we explored differences in baseline and clinicopathological characteristics. Second, Kaplan-Meier plots investigated progression-free survival (PFS) and cancer-specific survival (CSS) differences among pRCC subtypes. Third, multivariable Cox-regression analyses (MVA) were used to assess predictors of clinical progression (CP) and cancer-specific mortality (CSM). Overall, 120 (27%) patients had symptoms at time of diagnosis. 263 (58.8%) vs. 184 (41.2%) patients underwent PN vs. RN. At histopathological evaluation, 243 (54.4%) harboured pRCC type I vs. 204 (45.6%) type II. pRCC type II more frequently showed higher tumor grade, tumor necrosis or lymphovascular invasion (all P<0.001). After a median follow-up of 51 months, 2.5% and 11% of patients had local relapse and CP, respectively. Kaplan-Meier plots revealed 93 vs. 83% 5-year PFS (P<0.001) and 96 vs. 89% 5-year CSS (P=0.01) for non-metastatic pRCC type I vs. II, respectively. At MVA, pRCC type II predicted higher risk of CP (Hazard ratio [HR]: 3.03, 95%CI 1.42-6.44; P=0.01), as well as of CSM (HR: 2.60, 95%CI 1.05-6.29; P=0.02), relative to pRCC type I. PRCC type II harbour more unfavorable tumor characteristics, such as higher tumor grade, more frequent tumor necrosis or lymphvascular invasion, which translates into worse long-term oncologic outcomes, compared with pRCC type I. Thus, patients harbouring pRCC type II may benefit from stricter follow-up, as well as earlier risk-based adjuvant therapies, based on potential worse oncologic outcomes in this patient population.

The Effect of Tumor Characteristics and Location on the Extent of Lymph Node Metastases of Head and Neck Cutaneous Squamous Cell Carcinoma.

BackgroundThe extent of a neck dissection for patients with metastasis of cutaneous squamous cell carcinoma of the head and neck (HNcSCC) is still subject to debate and clear guidelines are lacking. Tumor characteristics like size, differentiation and tumor location are known risk factors for lymph node metastasis (LNM). There is some evidence that, depending on tumor location, LNM follows a specific pattern. This study aims to identify which tumor characteristics can predict the pattern and extent of LNM.MethodIn this cohort study 80 patients were included, who underwent a primary neck dissection for LNM of HNcSCC between 2003 and 2018 at the University Medical Center Groningen, the Netherlands. Retrospective data was collected for primary tumor characteristics and LNM and included surgical and follow-up data. Influence of tumor characteristics on the extent of LNM was analyzed using non-parametric tests. Logistic regression analysis were used to identify a metastasis pattern based on the primary tumor location.ResultsOnly primary tumor location was associated with the pattern of LNM. HNcSCC of the ear metastasized to level II (OR = 2.6) and the parotid gland (OR = 3.6). Cutaneous lip carcinoma metastasized to ipsilateral and contralateral level I (OR = 5.3). Posterior scalp tumors showed a metastasis pattern to level II (OR = 5.6); level III (OR = 11.2), level IV (OR = 4.7) and the parotid gland (OR = 10.8). Ear canal tumors showed a low risk of LNM for all levels. The extent of LNM was not related to age or any tumor characteristics i.e. tumor diameter, infiltration depth, differentiation grade, perineural growth and vascular invasion.ConclusionPrimary tumor location determines the LNM pattern. Whereas known unfavorable tumor characteristics did not relate to the extent of LNM. Location guided limited neck dissection combined with parotidectomy will treat most patients adequately.

Abstract No. 262 Recurrence of breast cancer post-cryoablation in candidates previously excluded from clinical trials

Prior breast cryoablation studies have shown promising results for cryoablation for selected low-risk early-stage breast cancer, but many non-surgical candidates are excluded from these clinical trials due to unfavorable patient and tumor characteristics. This study aims to assess ipsilateral breast tumor recurrence (IBTR) after ultrasound (US)-guided percutaneous cryoablation in these suboptimal cryoablation candidates.

Limited impact of COVID-19-related diagnostic delay on cutaneous melanoma and squamous cell carcinoma tumour characteristics: a nationwide pathology registry analysis.

BackgroundThe COVID‐19 pandemic reduced the number of skin cancer diagnoses, potentially causing a progression to unfavourable tumour stages.ObjectivesTo identify the impact of delayed diagnostics on primary invasive melanoma and cutaneous squamous cell carcinoma (cSCC) by comparing tumour (pT) stage, Breslow thickness and invasion depth from before to after the first and second lockdown periods.MethodsIn this population‐based cohort study, histopathology reports registered between 1 January 2018 and 22 July 2021 were obtained from the nationwide histopathology registry in the Netherlands. The Breslow thickness of melanomas, invasion depth of cSCCs, and pT stage for both tumour types were compared across five time periods: (i) pre‐COVID, (ii) first lockdown, (iii) between first and second lockdowns, (iv) second lockdown and (v) after second lockdown. Breslow thickness was compared using an independent t‐test. pT‐stage groups were compared using a χ2‐test. Outcomes were corrected for multiple testing using the false discovery rate.ResultsIn total, 20 434 primary invasive melanomas and 68 832 cSCCs were included in this study. The mean primary melanoma Breslow thickness of the prepandemic era (period i) and the following time periods (ii–v) showed no significant difference. A small shift was found towards unfavourable pT stages during the first lockdown compared with the pre‐COVID period: pT1 52·3% vs. 58·6%, pT2 18·9% vs. 17·8%, pT3 13·2% vs. 11·0%, pT4 9·1% vs. 7·3% (P = 0·001). No relevant changes were seen in subsequent periods. No significant change in pT stage distribution was observed between the pre‐COVID (i) and COVID‐affected periods (ii–v) for cSCCs.ConclusionsTo date, the diagnostic delay caused by COVID‐19 has not resulted in relatively more unfavourable primary tumour characteristics of melanoma or cSCC. Follow‐up studies in the coming years are needed to identify a potential impact on staging distribution and survival in the long term.

Association of pSTAT3, pSyk with c-Myc, p53, BCL2 proteins expression and survival of patients with diffuse large B-cell lymphoma

Background . Diffuse large B cell lymphoma (DLBCL) is one of the most common non-Hodgkin’s lymphomas. The effectiveness of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) therapy was observed in about 60 % of patients, in 20–30 % of cases DLBCL is characterized by a refractory course. Standard clinical prognostic criteria do not accurately determine the prognosis of the disease. In this regard, the problem of developing additional predictors of DLBCL course remains relevant today and is directly related to the molecular pathogenesis of the disease. The objective : to determine the relationship of pSTAT3, pSyk with c-Myc, p53, BCL2 oncoproteins expression and survival of DLBCL patients. Materials and methods . Biopsy specimens of lymph nodes and other organs and tissues obtained from 100 patients with newly diagnosed DLBCL were used for the study. All patients received standard first-line immunochemotherapy according to the R-CHOP regimen. Determination of the relative amount of tumor cells expressing pSTAT3, pSyk was carried out using immunohistochemical and morphometric methods. The threshold value of proteins expression was calculated using the ROC analysis: for pSTAT3 it was 68 % of positive tumor cells, for pSyk – 28 %. The relationship of pSTAT3, pSyk with c-Myc, p53, BCL2 expression was determined using the Pearson χ2 test. Overall (OS) and progression-free (PFS) survival were calculated using the Kaplan–Meier method (log-rank test). Results . The suprathreshold pSTAT3 expression was found to be associated with a high content of c-Myc and p53 transcription factors in tumor cells (p = 0.015 and p = 0.010, respectively). In the group of patients with isolated overexpression of pSTAT3, the 5-year OS and PFS were lower, and the risk of death and disease progression was almost 1.5 times higher than in patients with low protein expression (p = 0.015 and p = 0.011, respectively). When studying the co-expression of pSTAT3 and pSyk, the lowest OS and PFS were recorded in the subjects with a simultaneous high expression of these proteins. With this combination of markers, the probability of an adverse event in patients when calculating OS increased by 2.9 times (p = 0.003; hazard ratio 2.9; 95 % confidence interval 1.43–5.85), and when analyzing PFS – by 2.3 times (p = 0.021; hazard ratio 2.3; 95 % confidence interval 1.14–4.87) compared with other variants of their simultaneous expression. Conclusion . Overexpression of pSTAT3 is associated with unfavorable biological tumor characteristics and poor patient survival. The combined suprathreshold expression of the pSTAT3 and pSyk proteins is associated with lower OS and PFS values compared to their isolated expression.

Cytokeratin 7 and cytokeratin 20 expression in cancer: A tissue microarray study on 15,424 cancers

Combined analysis of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) is often used for assessing the origin of metastatic cancer. To evaluate the diagnostic utility of CK7 and CK20, tissue microarrays containing 15,424 samples from 120 different tumor types and subtypes and 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. CK7 positivity was seen in 52% (8.7% weak, 5.9% moderate, 37% strong) and CK20 positivity in 23% (5.1% weak, 3.4% moderate, 15% strong) of interpretable tumors. Of 8390 positive tumors, 1181 (14%) showed positivity for CK7 and CK20, 5380 (64%) showed positivity for CK7 alone, and 1829 (22%) showed positivity for CK20 alone. CK20 predominated in gastrointestinal tract, urothelial and Merkel cell carcinomas. CK7 was usually negative in prostate cancer and colorectal cancer. Combined evaluation of CK7/CK20 revealed the best diagnostic utility in CK20 positive tumors, where CK7 negativity is often linked to colorectal origin while CK7 positivity argues for urothelial origin or mucinous ovarian cancer. Associations with unfavorable tumor features were found for cytokeratin 7 loss in breast cancer of no special type, urothelial and renal cell carcinomas, for CK7 overexpression in high-grade serous ovarian and gastric cancer, and for CK20 overexpression in urothelial carcinoma. CK20 loss was linked to MSI in gastric (p = 0.0291) and colorectal adenocarcinoma (p < 0.0001). These analyses provide comprehensive data on the frequency of CK7 and CK20 immunostaining - alone or in combination - in human cancers. These data facilitate interpretation of CK7/CK20 immunostaining in cancers.